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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Classic Ehlers-Danlos Syndrome" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2024/02/01" /><meta name="citation_author" content="Fransiska Malfait" /><meta name="citation_author" content="Sofie Symoens" /><meta name="citation_author" content="Delfien Syx" /><meta name="citation_pmid" content="20301422" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1244/" /><meta name="citation_keywords" content="Classical Ehlers-Danlos Syndrome" /><meta name="citation_keywords" content="Ehlers-Danlos Syndrome, Classical Type" /><meta name="citation_keywords" content="cEDS" /><meta name="citation_keywords" content="Classical Ehlers-Danlos Syndrome" /><meta name="citation_keywords" content="Ehlers-Danlos Syndrome, Classical Type" /><meta name="citation_keywords" content="cEDS" /><meta name="citation_keywords" content="Ehlers-Danlos Syndrome, Classic Type, COL5A1-Related" /><meta name="citation_keywords" content="Ehlers-Danlos Syndrome, Classic Type, COL5A2-Related" /><meta name="citation_keywords" content="Collagen alpha-1(I) chain" /><meta name="citation_keywords" content="Collagen alpha-1(V) chain" /><meta name="citation_keywords" content="Collagen alpha-2(V) chain" /><meta name="citation_keywords" content="COL1A1" /><meta name="citation_keywords" content="COL5A1" /><meta name="citation_keywords" content="COL5A2" /><meta name="citation_keywords" content="Classic Ehlers-Danlos Syndrome" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Classic Ehlers-Danlos Syndrome" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Fransiska Malfait" /><meta name="DC.Contributor" content="Sofie Symoens" /><meta name="DC.Contributor" content="Delfien Syx" /><meta name="DC.Date" content="2024/02/01" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1244/" /><meta name="description" content="Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (GJH). The skin is soft, velvety, or doughy to the touch. In addition, the skin is hyperextensible, meaning that it extends easily and snaps back after release. 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 poor, and stretching, thinning, and pigmentation of scars is characteristic, leading to the presence of atrophic and/or hemosiderotic scars. Easy bruising is also a hallmark of cEDS. GJH is present in most but not all affected individuals, evidenced by the presence of a Beighton score of five or greater, either on examination or historically. Joint instability complications may comprise sprains and dislocations/subluxations. Mild muscle hypotonia with delayed motor development, fatigue and muscle cramps, and some skeletal morphologic alterations (scoliosis, pectus deformities, genus/hallux valgus, pes planus) are regularly observed. While aortic root dilatation and mitral valve prolapse are seen in cEDS, they are rarely clinically significant. Arterial aneurysm and rupture have been reported in a few individuals with cEDS." /><meta name="og:title" content="Classic Ehlers-Danlos Syndrome" /><meta name="og:type" content="book" /><meta name="og:description" content="Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (GJH). The skin is soft, velvety, or doughy to the touch. In addition, the skin is hyperextensible, meaning that it extends easily and snaps back after release. 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 poor, and stretching, thinning, and pigmentation of scars is characteristic, leading to the presence of atrophic and/or hemosiderotic scars. Easy bruising is also a hallmark of cEDS. GJH is present in most but not all affected individuals, evidenced by the presence of a Beighton score of five or greater, either on examination or historically. Joint instability complications may comprise sprains and dislocations/subluxations. Mild muscle hypotonia with delayed motor development, fatigue and muscle cramps, and some skeletal morphologic alterations (scoliosis, pectus deformities, genus/hallux valgus, pes planus) are regularly observed. While aortic root dilatation and mitral valve prolapse are seen in cEDS, they are rarely clinically significant. Arterial aneurysm and rupture have been reported in a few individuals with cEDS." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK1244/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/gene/eds/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK1244/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script><meta name="book-collection" content="NONE" />
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK1244_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1244_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/ctlm/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/galactosemia/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK1244_"><span class="title" itemprop="name">Classic Ehlers-Danlos Syndrome</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Classical Ehlers-Danlos Syndrome; Ehlers-Danlos Syndrome, Classical Type; cEDS</div><p class="contrib-group"><span itemprop="author">Fransiska Malfait</span>, MD, PhD, <span itemprop="author">Sofie Symoens</span>, PhD, and <span itemprop="author">Delfien Syx</span>, PhD.</p><a data-jig="ncbitoggler" href="#__NBK1244_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1244_ai__"><div class="contrib half_rhythm"><span itemprop="author">Fransiska Malfait</span>, MD, PhD<div class="affiliation small">Center for Medical Genetics<br />Ghent University Hospital<br />Ghent, Belgium<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="eb.tnegu@tiaflam.aksisnarf" class="oemail">eb.tnegu@tiaflam.aksisnarf</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Sofie Symoens</span>, PhD<div class="affiliation small">Center for Medical Genetics<br />Ghent University Hospital<br />Ghent, Belgium<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="eb.tnegu@sneomys.eifos" class="oemail">eb.tnegu@sneomys.eifos</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Delfien Syx</span>, PhD<div class="affiliation small">Center for Medical Genetics<br />Ghent University Hospital<br />Ghent, Belgium<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="eb.tnegu@xys.neifled" class="oemail">eb.tnegu@xys.neifled</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">May 29, 2007</span>; Last Update: <span itemprop="dateModified">February 1, 2024</span>.</p><p><em>Estimated reading time: 28 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="eds.Summary" itemprop="description"><h2 id="_eds_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (GJH). The skin is soft, velvety, or doughy to the touch. In addition, the skin is hyperextensible, meaning that it extends easily and snaps back after release. 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 poor, and stretching, thinning, and pigmentation of scars is characteristic, leading to the presence of atrophic and/or hemosiderotic scars. Easy bruising is also a hallmark of cEDS. GJH is present in most but not all affected individuals, evidenced by the presence of a Beighton score of five or greater, either on examination or historically. Joint instability complications may comprise sprains and dislocations/subluxations. Mild muscle hypotonia with delayed motor development, fatigue and muscle cramps, and some skeletal morphologic alterations (scoliosis, pectus deformities, genus/hallux valgus, pes planus) are regularly observed. While aortic root dilatation and mitral valve prolapse are seen in cEDS, they are rarely clinically significant. Arterial aneurysm and rupture have been reported in a few individuals with cEDS.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of cEDS is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with characteristic clinical features and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>COL1A1</i>, <i>COL5A1</i>, or <i>COL5A2</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> 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. 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. Braces as needed to improve joint stability; referral to orthopedist, rheumatologist, or physical therapist and occupational therapist as needed. Mobility devices as needed. Adjust sleep surface as needed to improve sleep quality and decrease pain. Those with hypotonia, joint instability, and chronic pain may need to adapt lifestyles accordingly. Anti-inflammatory drugs may alleviate joint pain. Children with hypotonia and delayed motor development benefit from physiotherapy. Non-weight-bearing exercise promotes muscle strength and coordination. Ascorbic acid (vitamin C) may reduce bruising. DDAVP<sup>®</sup> (desmopressin) may be useful to normalize bleeding time. Cardiovascular manifestations are treated in a standard manner.</p><p><i>Surveillance:</i> Assess for skin fragility, joint instability, occupational and physical therapy needs, mobility issues, and pain at each visit or as needed. Evaluation for hypotonia and motor development at each visit in infants and children. Assess for easy bruising and/or prolonged bleeding at each visit. Evaluation of clotting factors if severe easy bruising is present. Yearly echocardiogram when aortic dilatation and/or mitral valve prolapse are present.</p><p><i>Agents/circumstances to avoid:</i> Sports with heavy joint strain.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Classic EDS is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner. Approximately 50% of individuals diagnosed with cEDS have an affected parent; approximately 50% of individuals diagnosed with cEDS have the disorder as the result of a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. Each child of an individual with cEDS has a 50% chance of inheriting the pathogenic variant. Once the cEDS-related pathogenic variant has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p></div></div><div id="eds.Diagnosis"><h2 id="_eds_Diagnosis_">Diagnosis</h2><p>There are no consensus clinical diagnostic criteria for classic Ehlers-Danlos syndrome (cEDS); diagnosis requires molecular testing.</p><div id="eds.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Classic EDS should be suspected in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with either of the following:</p><ul><li class="half_rhythm"><div><a href="#eds.Establishing_the_Diagnosis">Major criteria</a> skin hyperextensibility and atrophic scarring</div><div>OR</div></li><li class="half_rhythm"><div><a href="#eds.Establishing_the_Diagnosis">Major criterion</a> generalized joint hypermobility (GJH) and/or ≥3 <a href="#eds.Establishing_the_Diagnosis">minor criteria</a></div></li></ul><p>
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<b>Major criteria</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Skin hyperextensibility</b> (see <a class="figpopup" href="/books/NBK1244/figure/eds.F1/?report=objectonly" target="object" rid-figpopup="figedsF1" rid-ob="figobedsF1">Figure 1</a>) is measured by pinching and lifting the cutaneous and subcutaneous layers of the skin on the volar surface at the middle of the nondominant forearm as described by <a class="bk_pop" href="#eds.REF.remvig.2009.227">Remvig et al [2009]</a>. Skin is hyperextensible if it can be stretched over a standardized cutoff in three of the following areas: 1.5 cm for the distal part of the forearms and the dorsum of the hands; 3 cm for neck, elbows, and knees.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Atrophic scarring</b> (See <a class="figpopup" href="/books/NBK1244/figure/eds.F2/?report=objectonly" target="object" rid-figpopup="figedsF2" rid-ob="figobedsF2">Figure 2</a>.)</div></li><li class="half_rhythm"><div class="half_rhythm"><b>GJH</b> (see <a class="figpopup" href="/books/NBK1244/figure/eds.F3/?report=objectonly" target="object" rid-figpopup="figedsF3" rid-ob="figobedsF3">Figure 3</a>) depends on an individual's age, sex, and family and ethnic background. Joint hypermobility in cEDS is usually general, affecting both large and small joints, and is usually noted when a child starts to walk. It should be assessed using the Beighton scale, the most widely accepted grading system for the objective semiquantification of joint hypermobility (see <a href="/books/NBK1244/table/eds.T.beighton_criteria_for_joint_hyperm/?report=objectonly" target="object" rid-ob="figobedsTbeightoncriteriaforjointhyperm">Table 1</a>). A Beighton score of ≥5 is considered positive for the presence of GJH.<div id="eds.T.beighton_criteria_for_joint_hyperm" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Beighton Criteria for Joint Hypermobility</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1244/table/eds.T.beighton_criteria_for_joint_hyperm/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds.T.beighton_criteria_for_joint_hyperm_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Joint/Finding</th><th id="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Negative</th><th id="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Unilateral</th><th id="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Bilateral</th></tr></thead><tbody><tr><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Passive dorsiflexion of the 5th finger >90°</td><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td></tr><tr><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Passive flexion of thumbs to the forearm</td><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td></tr><tr><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hyperextension of the elbows beyond 10°</td><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td></tr><tr><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hyperextension of the knees beyond 10°</td><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td></tr><tr><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Forward flexion of the trunk with knees fully extended and palms resting on the floor</td><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0</td><td headers="hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_3 hd_h_eds.T.beighton_criteria_for_joint_hyperm_1_1_1_4" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">1</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">A total score of ≥5 is considered positive for the presence of generalized joint hypermobility.</p></div></dd></dl></div></div></div>
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</div><div class="half_rhythm">Since laxity decreases with age, individuals with a Beighton score of <5 may be considered positive based on historical observations. The five-point questionnaire is as follows (adapted from <a class="bk_pop" href="#eds.REF.hakim.2003.163">Hakim & Grahame [2003]</a>):</div><dl class="temp-labeled-list"><dt>1.</dt><dd><p class="no_top_margin">Can you now (or could you ever) place your hands flat on the floor without bending your knees?</p></dd><dt>2.</dt><dd><p class="no_top_margin">Can you now (or could you ever) bend your thumb to touch your forearm?</p></dd><dt>3.</dt><dd><p class="no_top_margin">As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits?</p></dd><dt>4.</dt><dd><p class="no_top_margin">As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion?</p></dd><dt>5.</dt><dd><p class="no_top_margin">Do you consider yourself "double-jointed"?</p></dd></dl><div class="half_rhythm">Note: A "yes" answer to ≥2 questions suggests joint hypermobility with 80%-85% <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> and 80%-90% specificity.</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col fig" id="figedsF1" co-legend-rid="figlgndedsF1"><a href="/books/NBK1244/figure/eds.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figedsF1" rid-ob="figobedsF1"><img class="small-thumb" src="/books/NBK1244/bin/eds-Image001.gif" src-large="/books/NBK1244/bin/eds-Image001.jpg" alt="Figure 1. " /></a><div class="icnblk_cntnt" id="figlgndedsF1"><h4 id="eds.F1"><a href="/books/NBK1244/figure/eds.F1/?report=objectonly" target="object" rid-ob="figobedsF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">Skin hyperextensibility </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figedsF2" co-legend-rid="figlgndedsF2"><a href="/books/NBK1244/figure/eds.F2/?report=objectonly" target="object" title="Figure 2. " class="img_link icnblk_img figpopup" rid-figpopup="figedsF2" rid-ob="figobedsF2"><img class="small-thumb" src="/books/NBK1244/bin/eds-Image002.gif" src-large="/books/NBK1244/bin/eds-Image002.jpg" alt="Figure 2. " /></a><div class="icnblk_cntnt" id="figlgndedsF2"><h4 id="eds.F2"><a href="/books/NBK1244/figure/eds.F2/?report=objectonly" target="object" rid-ob="figobedsF2">Figure 2. </a></h4><p class="float-caption no_bottom_margin">Widened atrophic scars </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figedsF3" co-legend-rid="figlgndedsF3"><a href="/books/NBK1244/figure/eds.F3/?report=objectonly" target="object" title="Figure 3. " class="img_link icnblk_img figpopup" rid-figpopup="figedsF3" rid-ob="figobedsF3"><img class="small-thumb" src="/books/NBK1244/bin/eds-Image003.gif" src-large="/books/NBK1244/bin/eds-Image003.jpg" alt="Figure 3. " /></a><div class="icnblk_cntnt" id="figlgndedsF3"><h4 id="eds.F3"><a href="/books/NBK1244/figure/eds.F3/?report=objectonly" target="object" rid-ob="figobedsF3">Figure 3. </a></h4><p class="float-caption no_bottom_margin">Flexion of the thumb to forearm, illustrating joint hypermobility </p></div></div><p>
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<b>Minor criteria</b>
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</p><ul><li class="half_rhythm"><div>Easy bruising</div></li><li class="half_rhythm"><div>Soft, doughy skin</div></li><li class="half_rhythm"><div>Skin fragility (or traumatic splitting)</div></li><li class="half_rhythm"><div>Molluscoid pseudotumors: fleshy, heaped-up lesions associated with scars over pressure points such as the elbows and knees</div></li><li class="half_rhythm"><div>Subcutaneous spheroids: small, spherical hard bodies, frequently mobile, palpable on the forearms and shins. Spheroids may be calcified and detectable radiologically.</div></li><li class="half_rhythm"><div>Hernia (or history thereof)</div></li><li class="half_rhythm"><div>Epicanthal folds</div></li><li class="half_rhythm"><div>Complications of joint hypermobility (e.g., sprains, dislocations/subluxations, pain, flexible flat foot)</div></li><li class="half_rhythm"><div>Family history of a <a class="def" href="/books/n/gene/glossary/def-item/first-degree-relative/">first-degree relative</a> with a diagnosis of cEDS</div></li></ul></div><div id="eds.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of cEDS <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with <a href="#eds.Suggestive_Findings">suggestive findings</a> and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variant in one of the genes listed in <a href="/books/NBK1244/table/eds.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobedsTmoleculargenetictestingusedin">Table 2</a> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "<a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bk_pop" href="#eds.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variant" in this <i>GeneReview</i> is understood to include any likely pathogenic variant. (2) Identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> variant of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> in one of the genes listed in <a href="/books/NBK1244/table/eds.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobedsTmoleculargenetictestingusedin">Table 2</a> does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b>multigene targeted testing</b> and <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>). Gene-targeted testing requires that the clinician determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved (see <a href="#eds.Option_1">Option 1</a>), whereas comprehensive genomic testing does not (see <a href="#eds.Option_2">Option 2</a>).</p><div id="eds.Option_1"><h4>Option 1</h4><p><b>Multigene targeted testing.</b> Sequence analysis of <i>COL5A1</i> and <i>COL5A2</i> (multigene targeted panels may also include <i>COL1A1</i> and other EDS-related genes; see <a href="#eds.Differential_Diagnosis">Differential Diagnosis</a>) is performed first to detect <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants and small intragenic deletions/insertions. If the <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a> only includes <i>COL5A1</i> and <i>COL5A2</i>, targeted testing of <i>COL1A1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <a href="/books/NBK1244/table/eds.T.pathogenic_variants_referenced_in/?report=objectonly" target="object" rid-ob="figobedsTpathogenicvariantsreferencedin">c.934C>T</a> should be done next if no <i>COL5A1</i> or <i>COL5A2</i> pathogenic variants are identified. Note: Depending on the sequencing method used, single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a>, multiexon, or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> of <i>COL5A1</i> and <i>COL5A2</i> to detect exon and whole-gene deletions or duplications.</p><p>Note: (1) Multigene targeted analysis implies that the coding regions for the genes, included in the <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>, are enriched. (2) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (3) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (4) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (5) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests.</p><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</p></div><div id="eds.Option_2"><h4>Option 2</h4><p>When the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> is indistinguishable from many other inherited disorders characterized by hypermobility, <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> is likely involved. <b>Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible in some diagnostic centers.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="eds.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Classic Ehlers-Danlos Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1244/table/eds.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene <sup>1, 2</sup></th><th id="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_2" style="text-align:left;vertical-align:middle;">Proportion of cEDS Attributed to Pathogenic Variants in Gene</th><th id="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>3</sup> Detectable by Method</th></tr><tr><th headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_3" id="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>4</sup></th><th headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_3" id="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>5</sup></th></tr></thead><tbody><tr><td headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL1A1</i>
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</td><td headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3% <sup>6</sup></td><td headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_eds.T.molecular_genetic_testing_used_in_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <sup>6</sup></td><td headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_eds.T.molecular_genetic_testing_used_in_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported <sup>6,7</sup></td></tr><tr><td headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL5A1</i>
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||
</td><td headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">81% <sup>8</sup></td><td headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_eds.T.molecular_genetic_testing_used_in_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">99% <sup>8</sup></td><td headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_eds.T.molecular_genetic_testing_used_in_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1% <sup>8</sup></td></tr><tr><td headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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||
<i>COL5A2</i>
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||
</td><td headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">16% <sup>8</sup></td><td headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_eds.T.molecular_genetic_testing_used_in_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">99% <sup>8</sup></td><td headers="hd_h_eds.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_eds.T.molecular_genetic_testing_used_in_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1% <sup>8, 9</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">cEDS = classic Ehlers-Danlos syndrome</p></div></dd><dt>1. </dt><dd><div id="eds.TF.2.1"><p class="no_margin">Genes are listed in alphabetic order.</p></div></dd><dt>2. </dt><dd><div id="eds.TF.2.2"><p class="no_margin">See <a href="/books/NBK1244/#eds.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>3. </dt><dd><div id="eds.TF.2.3"><p class="no_margin">See <a href="#eds.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>4. </dt><dd><div id="eds.TF.2.4"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants and small intragenic deletions/insertions; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>5. </dt><dd><div id="eds.TF.2.5"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications. In addition, in silico prediction software, such as ExomeDepth, is available for predicting deletions/duplications in large, comprehensive datasets (e.g., from <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>).</p></div></dd><dt>6. </dt><dd><div id="eds.TF.2.6"><p class="no_margin"><a class="bk_pop" href="#eds.REF.brady.2017.70">Brady et al [2017]</a>, <a class="bk_pop" href="#eds.REF.malfait.2017.8">Malfait et al [2017]</a>, <a class="bk_pop" href="#eds.REF.colman.2021.1294">Colman et al [2021]</a></p></div></dd><dt>7. </dt><dd><div id="eds.TF.2.7"><p class="no_margin">Large deletions in <i>COL1A1</i> have not been reported in individuals with cEDS.</p></div></dd><dt>8. </dt><dd><div id="eds.TF.2.8"><p class="no_margin"><a class="bk_pop" href="#eds.REF.symoens.2012.1485">Symoens et al [2012]</a>, <a class="bk_pop" href="#eds.REF.ritelli.2013.58">Ritelli et al [2013]</a></p></div></dd><dt>9. </dt><dd><div id="eds.TF.2.9"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bk_pop" href="#eds.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd></dl></div></div></div></div><div id="eds.Other_Testing"><h4>Other Testing</h4><p><b><i>COL5A1</i> <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> test.</b> If a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> cannot be identified on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>, a type V collagen abnormality can sometimes be demonstrated by the <i>COL5A1</i> null allele test if the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a polymorphic marker in <i>COL5A1</i> at the <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> DNA (<a class="def" href="/books/n/gene/glossary/def-item/gdna/">gDNA</a>) level. Copy DNA is analyzed from fibroblasts to identify the presence of one or both markers; if one marker is not expressed, that allele is assumed to be nonfunctional (i.e., "null"). This type of testing is not widely available.</p><p><b>Transmission electron microscopy (TEM).</b> If <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> is not available, TEM findings of collagen flowers on skin biopsy can support the clinical diagnosis, but do not confirm it, as collagen flowers are not pathognomonic for cEDS.</p></div></div></div><div id="eds.Clinical_Characteristics"><h2 id="_eds_Clinical_Characteristics_">Clinical Characteristics</h2><div id="eds.Clinical_Description"><h3>Clinical Description</h3><p>Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and generalized joint hypermobility.</p><p><b>Skin.</b> Skin is hyperextensible; it extends easily and snaps back after release (unlike lax, redundant skin, as in cutis laxa).</p><p>The skin is soft, velvety, or doughy to the touch.</p><p>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). Skin fragility may cause dehiscence of sutured incisions in skin or mucosa.</p><p>Wound healing is poor, and stretching, thinning, and pigmentation of scars is characteristic. Scars become wide, with a "cigarette-paper"-like (papyraceous) appearance, also referred to as atrophic and/or hemosiderotic scars.</p><p>Other dermatologic features in cEDS:</p><ul><li class="half_rhythm"><div>Molluscoid pseudotumors</div></li><li class="half_rhythm"><div>Subcutaneous spheroids</div></li><li class="half_rhythm"><div>Piezogenic papules: small, painful, reversible herniations of underlying adipose tissue globules through the fascia into the dermis, such as on medial and lateral aspects of the feet upon standing</div></li><li class="half_rhythm"><div>Elastosis perforans serpiginosa: characterized by skin-colored to erythematous keratotic papules, some enlarging outward in serpiginous or arcuate configurations, leaving slightly atrophic centers</div></li><li class="half_rhythm"><div>Acrocyanosis: painless constriction or narrowing of the small blood vessels in the skin (affecting mainly the hands) in which the affected areas turn blue and become cold and sweaty; localized swelling may also occur</div></li><li class="half_rhythm"><div>Chilblains: cold injuries, characterized by red, swollen skin that is tender and hot to the touch and may itch; can develop in less than two hours in skin exposed to cold</div></li></ul><p><b>Tissue fragility.</b> Manifestations of generalized tissue extensibility and fragility can be observed in multiple organs:</p><ul><li class="half_rhythm"><div>Cervical insufficiency during pregnancy</div></li><li class="half_rhythm"><div>Inguinal and umbilical hernia</div></li><li class="half_rhythm"><div>Hiatal and incisional hernia</div></li><li class="half_rhythm"><div>Recurrent rectal prolapse in early childhood</div></li></ul><p><b>Joints.</b> Complications of joint hypermobility including dislocations/subluxations of large and small joints (e.g., shoulder, patella, digits, hip, radius, and clavicle) may occur and usually resolve spontaneously or are easily managed by the affected individual. Many individuals with cEDS experience chronic joint and limb pain, despite normal skeletal radiographs.</p><p>Other problems related to joint hypermobility are joint instability, foot deformities such as <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> clubfoot or pes planus, and temporomandibular joint dysfunction [<a class="bk_pop" href="#eds.REF.bowen.2017.27">Bowen et al 2017</a>].</p><p><b>Neurologic features.</b> Primary muscular hypotonia may occur and may cause delayed motor development, problems with ambulation, and mild motor disturbance in children with cEDS. Fatigue and muscle cramps are relatively frequent.</p><p><b>Easy bruising.</b> Easy bruising is a common finding and manifests as spontaneous ecchymoses, frequently recurring in the same areas and causing a characteristic brownish discoloration of the skin, especially in exposed areas such as shins and knees. There is a tendency toward prolonged bleeding (e.g., following brushing of the teeth) in spite of a normal coagulation status.</p><p><b>Cardiovascular.</b> Structural cardiac malformations are uncommon in cEDS.</p><p>Mitral valve prolapse and (less frequently) tricuspid valve prolapse may occur. Stringent criteria should be used for the diagnosis of mitral valve prolapse. When it does occur, mitral valve prolapse tends to be of little clinical consequence [<a class="bk_pop" href="#eds.REF.atzinger.2011.826">Atzinger et al 2011</a>].</p><p>Aortic root dilatation has been reported in individuals with cEDS [<a class="bk_pop" href="#eds.REF.wenstrup.2002.112">Wenstrup et al 2002</a>, <a class="bk_pop" href="#eds.REF.mcdonnell.2006.129">McDonnell et al 2006</a>, <a class="bk_pop" href="#eds.REF.atzinger.2011.826">Atzinger et al 2011</a>]. It appears to be more common in young individuals and rarely progresses [<a class="bk_pop" href="#eds.REF.bowen.2017.27">Bowen et al 2017</a>].</p><p>Individuals with cEDS are at risk for spontaneous rupture of large arteries, although the prevalence of such complications is much lower than in those with vascular EDS.</p><p><b>Dental.</b> Classic EDS may be associated with abnormal dentinogenesis resulting in localized root anomalies, with shortened or bulbous roots, that lead to loosening of the teeth. Calcification of the pulp is another common finding in cEDS. This is usually of little clinical significance but may complicate root canal treatment [<a class="bk_pop" href="#eds.REF.lepperdinger.2021.520">Lepperdinger et al 2021</a>].</p><p><b>Pregnancy.</b> Pregnancy in a woman with cEDS places both the newborn and the mother at risk for complications (see <a href="#eds.Pregnancy_Management">Pregnancy Management</a>). As a whole, the complications are more frequent than in the normal population, although it is difficult to quantitate the incidence of each complication in affected individuals because no good studies exist [<a class="bk_pop" href="#eds.REF.kang.2020.118">Kang et al 2020</a>].</p><ul><li class="half_rhythm"><div>Premature rupture of the membranes and prematurity are reported to be twice as common in fetuses with cEDS born to healthy mothers, compared with fetuses without EDS born to a mother with cEDS.</div></li><li class="half_rhythm"><div>Because of hypotonia, breech presentation is more frequent if the baby is affected and may lead to dislocation of the hips or shoulder of the newborn.</div></li><li class="half_rhythm"><div>Intrauterine growth restriction may occur.</div></li><li class="half_rhythm"><div>Perineal tearing, postpartum hemorrhage, pelvic prolapse, and incontinence following delivery may occur.</div></li></ul></div><div id="eds.Phenotype_Correlations_by_Gene"><h3>Phenotype Correlations by Gene</h3><p><b><i>COL5A2.</i></b> Although numbers are still limited, pathogenic variants in <i>COL5A2</i> are thought to result in a <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> at the more severe end of the cEDS spectrum [<a class="bk_pop" href="#eds.REF.colman.2021.1294">Colman et al 2021</a>].</p></div><div id="eds.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a> have emerged to date.</p></div><div id="eds.Penetrance"><h3>Penetrance</h3><p>Penetrance is presumably 100% in both males and females, but in some individuals the condition is very mild, and may be undiagnosed.</p></div><div id="eds.Nomenclature"><h3>Nomenclature</h3><p>As a result of the 1997 Villefranche conference on EDS [<a class="bk_pop" href="#eds.REF.beighton.1998.31">Beighton et al 1998</a>], EDS type I and type II were collectively reclassified "EDS, classical type." In 2017, the International EDS Consortium proposed a revised EDS classification system in which the nomenclature for "EDS, classical type" was changed to "classical EDS" or cEDS [<a class="bk_pop" href="#eds.REF.malfait.2017.8">Malfait et al 2017</a>].</p></div><div id="eds.Prevalence"><h3>Prevalence</h3><p>The prevalence of cEDS has been estimated at 1:20,000 [<a class="bk_pop" href="#eds.REF.byers.2001">Byers 2001</a>]. However, it is likely that some individuals with milder manifestations (previously classified as EDS type II) do not come to medical attention and thus go undetected.</p></div></div><div id="eds.Genetically_Related_Allelic_Disorder"><h2 id="_eds_Genetically_Related_Allelic_Disorder_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> pathogenic variants in <i>COL5A2</i>.</p><p>Other phenotypes associated with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> pathogenic variants in <i>COL1A1</i> and <i>COL5A1</i> are summarized in <a href="/books/NBK1244/table/eds.T.allelic_disorders/?report=objectonly" target="object" rid-ob="figobedsTallelicdisorders">Table 3</a>.</p><div id="eds.T.allelic_disorders" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Allelic Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1244/table/eds.T.allelic_disorders/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds.T.allelic_disorders_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds.T.allelic_disorders_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_eds.T.allelic_disorders_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th></tr></thead><tbody><tr><td headers="hd_h_eds.T.allelic_disorders_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL1A1</i>
|
||
</td><td headers="hd_h_eds.T.allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The majority of pathogenic variants in <i>COL1A1</i> are assoc w/<a href="/books/n/gene/oi/">osteogenesis imperfecta</a>.</td></tr><tr><td headers="hd_h_eds.T.allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Arthrochalasia EDS (OMIM <a href="https://omim.org/entry/130060" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">130060</a>)</td></tr><tr><td headers="hd_h_eds.T.allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">EDS/OI overlap phenotypes (OMIM <a href="https://omim.org/entry/619115" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">619115</a>)</td></tr><tr><td headers="hd_h_eds.T.allelic_disorders_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/caffey/">Caffey disease</a> (infantile cortical hyperostosis)</td></tr><tr><td headers="hd_h_eds.T.allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>COL5A1</i>
|
||
</td><td headers="hd_h_eds.T.allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multifocal fibromuscular dysplasia (OMIM <a href="https://omim.org/entry/619329" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">619329</a>)</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">EDS = Ehlers-Danlos syndrome; OI = osteogenesis imperfecta</p></div></dd></dl></div></div></div></div><div id="eds.Differential_Diagnosis"><h2 id="_eds_Differential_Diagnosis_">Differential Diagnosis</h2><p>Other forms of Ehlers-Danlos syndrome (EDS) should be considered in individuals with easy bruising, joint hypermobility, and/or chronic joint dislocation. Clinical overlap with classic EDS (cEDS) is seen with all other forms of EDS, in particular with hypermobile EDS (hEDS) and the EDS types listed in <a href="/books/NBK1244/table/eds.T.ehlersdanlos_syndromerelated_genes/?report=objectonly" target="object" rid-ob="figobedsTehlersdanlossyndromerelatedgenes">Table 4</a>.</p><p>Hypermobile EDS is generally considered the least severe type of EDS, although significant complications, primarily musculoskeletal, can occur. Similar to cEDS, generalized joint hypermobility, mild atrophic scarring, mild skin hyperextensibility, and soft, velvety skin are seen in hEDS. Unlike cEDS, hEDS is not associated with truly papyraceous and/or hemosiderotic scars. The diagnosis of hEDS is based entirely on clinical evaluation and family history. The <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) in which pathogenic variants cause hEDS are unknown.</p><div id="eds.T.ehlersdanlos_syndromerelated_genes" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Ehlers-Danlos Syndrome-Related Genes of Interest in the Differential Diagnosis of Classic Ehlers-Danlos Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1244/table/eds.T.ehlersdanlos_syndromerelated_genes/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds.T.ehlersdanlos_syndromerelated_genes_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_2" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Clinical Features of Disorder</th></tr><tr><th headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4" id="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/cEDS</th><th headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4" id="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from cEDS</th></tr></thead><tbody><tr><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ADAMTS2</i>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dermatosparaxis EDS (OMIM <a href="https://omim.org/entry/225410" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">225410</a>)</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Atrophic scarring</div></li><li class="half_rhythm"><div>Easy bruising</div></li><li class="half_rhythm"><div>GJH</div></li><li class="half_rhythm"><div>Skin hyperextensibility</div></li><li class="half_rhythm"><div>Soft, doughy skin</div></li></ul>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Extreme skin fragility (usually > than in cEDS)</div></li><li class="half_rhythm"><div>Redundant, almost lax, skin</div></li><li class="half_rhythm"><div>Unusual craniofacial features</div></li><li class="half_rhythm"><div>Postnatal growth restriction</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>AEBP1</i>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Classic-like EDS type 2 (OMIM <a href="https://omim.org/entry/618000" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">618000</a>)</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Atrophic scarring</div></li><li class="half_rhythm"><div>Easy bruising</div></li><li class="half_rhythm"><div>GJH</div></li><li class="half_rhythm"><div>Skin hyperextensibility</div></li></ul>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Prematurely aged appearance</div></li><li class="half_rhythm"><div>Thinning of hair or (partial) alopecia</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>COL1A1</i>
|
||
<br />
|
||
<i>COL1A2</i>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Arthrochalasia EDS (OMIM <a href="https://omim.org/entry/130060" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">130060</a>, <a href="https://omim.org/entry/617821" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">617821</a>)</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Atrophic scarring</div></li><li class="half_rhythm"><div>Easy bruising</div></li><li class="half_rhythm"><div>GJH</div></li><li class="half_rhythm"><div>Skin hyperextensibility</div></li></ul>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bilateral <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> hip dislocation</td></tr><tr><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>COL1A2</i>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiac valvular EDS (OMIM <a href="https://omim.org/entry/225320" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">225320</a>)</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Atrophic scarring</div></li><li class="half_rhythm"><div>Easy bruising</div></li><li class="half_rhythm"><div>(Generalized) joint hypermobility</div></li><li class="half_rhythm"><div>Skin hyperextensibility</div></li></ul>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe progressive cardiac valvular problems</td></tr><tr><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>COL3A1</i> <sup>1</sup></td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/eds4/">Vascular EDS</a> <sup>1</sup></td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Atrophic scarring</div></li><li class="half_rhythm"><div>Easy bruising</div></li><li class="half_rhythm"><div>GJH</div></li><li class="half_rhythm"><div>Skin hyperextensibility</div></li><li class="half_rhythm"><div>Doughy skin</div></li></ul>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Gastrointestinal rupture</div></li><li class="half_rhythm"><div>Pneumothorax</div></li><li class="half_rhythm"><div>Severe hematoma formation, incl muscle hematoma</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>FKBP14</i>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/fkbp14-keds/"><i>FKBP14</i>-related kyphoscoliotic EDS</a>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Easy bruising</div></li><li class="half_rhythm"><div>GJH</div></li><li class="half_rhythm"><div>Skin hyperextensibility</div></li></ul>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Congenital muscle hypotonia</div></li><li class="half_rhythm"><div>Muscle atrophy</div></li><li class="half_rhythm"><div>Congenital hearing impairment</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PLOD1</i>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/eds6/"><i>PLOD1</i>-related kyphoscoliotic EDS</a>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Atrophic scarring</div></li><li class="half_rhythm"><div>Easy bruising</div></li><li class="half_rhythm"><div>GJH</div></li><li class="half_rhythm"><div>Skin hyperextensibility</div></li></ul>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Congenital muscle hypotonia</td></tr><tr><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TNXB</i>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/tnxb-eds/"><i>TNXB</i>-related classic-like EDS</a>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Easy bruising</div></li><li class="half_rhythm"><div>GJH</div></li><li class="half_rhythm"><div>Skin hyperextensibilityy</div></li><li class="half_rhythm"><div>Velvety skin</div></li></ul>
|
||
</td><td headers="hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_1_4 hd_h_eds.T.ehlersdanlos_syndromerelated_genes_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absence of atrophic scarring</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; cEDS = classic Ehlers-Danlos syndrome; EDS = Ehlers-Danlos syndrome; GJH = generalized joint hypermobility; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a></p></div></dd><dt>1. </dt><dd><div id="eds.TF.4.1"><p class="no_margin">Glutamic acid to lysine substitutions in <i>COL3A1</i> have been reported in individuals with features of both vascular EDS and cEDS [<a class="bk_pop" href="#eds.REF.ghali.2019.2081">Ghali et al 2019</a>].</p></div></dd></dl></div></div></div></div><div id="eds.Management"><h2 id="_eds_Management_">Management</h2><p>For a detailed review of complications and management of classic Ehlers-Danlos syndrome (cEDS), see <a class="bk_pop" href="#eds.REF.bowen.2017.27">Bowen et al [2017]</a>.</p><div id="eds.Evaluations_Following_Initial_Diagno"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease in an individual diagnosed with cEDS, the evaluations summarized in <a href="/books/NBK1244/table/eds.T.classic_ehlersdanlos_syndrome_reco/?report=objectonly" target="object" rid-ob="figobedsTclassicehlersdanlossyndromereco">Table 5</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="eds.T.classic_ehlersdanlos_syndrome_reco" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Classic Ehlers-Danlos Syndrome: Recommended Evaluations Following Initial Diagnosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1244/table/eds.T.classic_ehlersdanlos_syndrome_reco/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds.T.classic_ehlersdanlos_syndrome_reco_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Skin</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical exam of skin w/assessment of skin hyperextensibility, atrophic scars & bruises, & other manifestations of cEDS</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Joints</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval of joint mobility w/Beighton score</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval for hypotonia & motor development in infants & children</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hematologic</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assessment for easy bruising &/or prolonged bleeding</div></li><li class="half_rhythm"><div>Eval of clotting factors (platelet count, aPTT, PT, thrombin time) if severe easy bruising is present</div></li></ul>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiovascular</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram w/aortic diameter measurement</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic counseling</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & their families re nature, MOI, & implications of cEDS to facilitate medical & personal decision making</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">cEDS = classic Ehlers-Danlos syndrome; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; aPTT = activated partial thromboplastin time; PT = prothrombin time</p></div></dd><dt>1. </dt><dd><div id="eds.TF.5.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="eds.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see <a href="/books/NBK1244/table/eds.T.classic_ehlersdanlos_syndrome_trea/?report=objectonly" target="object" rid-ob="figobedsTclassicehlersdanlossyndrometrea">Table 6</a>).</p><div id="eds.T.classic_ehlersdanlos_syndrome_trea" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Classic Ehlers-Danlos Syndrome: Treatment of Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1244/table/eds.T.classic_ehlersdanlos_syndrome_trea/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds.T.classic_ehlersdanlos_syndrome_trea_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Skin</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Dermal wounds should be closed w/o tension, preferably in 2 layers.</div></li><li class="half_rhythm"><div>Deep stitches should be applied generously.</div></li><li class="half_rhythm"><div>Cutaneous stitches should be left in place twice as long as usual, & additional fixation of adjacent skin w/adhesive tape can help prevent stretching of the scar.</div></li></ul>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Very young children w/pronounced skin fragility can wear protective pads or bandages over the forehead, knees, & shins to avoid skin tears.</div></li><li class="half_rhythm"><div>Older children who are active can wear soccer pads or ski stockings w/shin padding during activities.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Joint instability</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Braces are useful to improve joint stability.</div></li><li class="half_rhythm"><div>Orthopedist, rheumatologist, or physical therapist referral for knee or ankle braces as needed</div></li><li class="half_rhythm"><div>Occupational therapist referral for ring splints (to stabilize interphalangeal joints) & wrist or wrist & thumb braces for small joint instability</div></li><li class="half_rhythm"><div>A soft neck collar, if tolerated, may help w/neck pain & headaches.</div></li><li class="half_rhythm"><div>Wheelchair or scooter as needed to decrease stress on lower-extremity joints</div></li><li class="half_rhythm"><div>Wheelchair customizations (e.g., lightweight, motorized, seat pads, specialized wheels, wheel grasps) as needed to accommodate pelvic & upper-extremity issues</div></li><li class="half_rhythm"><div>A waterbed, adjustable air mattress, or viscoelastic foam mattress (&/or pillow) may increase support for improved sleep quality & less pain.</div></li></ul>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Those w/hypotonia, joint instability, & chronic pain may need to adapt lifestyle accordingly.</div></li><li class="half_rhythm"><div>Note: Surgical stabilization of joints may lead to disappointing, or only temporary, improvement.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Joint pain – analgesics</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Acetaminophen: 4,000 mg daily in 3-4 divided doses</div></li><li class="half_rhythm"><div>NSAIDs, as tolerated by upper GI symptoms, for arthralgia, myalgia, & secondary inflammatory conditions (e.g., bursitis, tendinitis, costochondritis, postdislocation pain)</div></li><li class="half_rhythm"><div>COX-2 inhibitors have similar efficacy to NSAIDS but may be better tolerated.</div></li><li class="half_rhythm"><div>Topical lidocaine (cream or patch) may be useful for localized pain.</div></li><li class="half_rhythm"><div>Topical capsaicin is of questionable utility but is safe.</div></li><li class="half_rhythm"><div>Tramadol w/acetaminophen & NSAID or COX-2 inhibitor before resorting to other opioids (Nausea is the most common side effect.)</div></li><li class="half_rhythm"><div>Opioids for myofascial pain & neuropathic pain; should be reserved after failing the above medications. Administer w/other analgesics to minimize total opioid requirements. Typically used chronically (or at least several months), the primary formulation should be long acting (e.g., sustained-release oxycodone or morphine or topical fentanyl patch) w/short-acting forms of the same drug as needed for breakthrough pain. Routine use of ≥2 daily doses of a short-acting form should prompt an increase in the long-acting dose or another adjustment to the pain regimen.</div></li></ul>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Bruising is not a contraindication to NSAID therapy, but occasionally requires dose reduction or change to a COX-2 inhibitor.</div></li><li class="half_rhythm"><div>Those w/muscle hypotonia & joint instability w/chronic pain may have to adjust lifestyle & professional choices accordingly.</div></li><li class="half_rhythm"><div>Emotional support & behavioral & psychological therapy may help in developing acceptance & coping skills.</div></li><li class="half_rhythm"><div>Long-term chronic pain may result in the need for mental health services.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_1" rowspan="9" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Pain – other pharmaceutical treatment options</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><b>Serotonin/norepinephrine receptor inhibitors</b> (SNRIs) (e.g., venlafaxine, desvenlafaxine, duloxetine, milnacipran) offer combined benefit for depression & neuropathic pain.</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Venlafaxine may ↑ blood pressure a few points, which may be helpful for those w/neurally mediated hypotension.</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Some <b>anti-seizure medications</b> (e.g., gabapentin, pregabalin, topiramate, lamotrigine) have been used in cEDS, are effective for neuropathic pain, & can be used in addition to tricyclic antidepressants &/or SNRIs.</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>All require gradual titration before reaching therapeutic levels.</div></li><li class="half_rhythm"><div>Gabapentin should be titrated as tolerated to at least 1,200 mg 3x per day before declaring failure, but dose is often limited by sedation &/or GI side effects.</div></li><li class="half_rhythm"><div>Pregabalin, titrated to at least 300 mg divided 2-3x/day, tends to be better tolerated than gabapentin.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Short courses of <b>steroids</b> can be very effective for controlling acute flares of pain assoc w/secondary inflammation.</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Classic EDS is not an intrinsically inflammatory condition, & there is no role for chronic steroid use.</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Muscle relaxants</b> in combination w/analgesics to treat myofascial spasm & neuropathic pain</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Limited by sedation; metaxalone may be least sedating</div></li><li class="half_rhythm"><div>Muscle relaxants may ↑ joint instability by ↓ muscle tone.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Magnesium</b> (topical as Epsom salt baths or oral) may ↓ muscle spasm & pain.</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>No specific formulation or dosage is established as superior.</div></li><li class="half_rhythm"><div>Adverse effects (sedation, nausea, abdominal pain, & diarrhea) are more common w/oral rather than topical supplementation.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><b>Tricyclic antidepressants</b> are often effective for neuropathic pain, w/additional benefits of mild sedation (for those w/sleep disturbance) & a little mood elevation.</div></li><li class="half_rhythm"><div>Typical doses are nortriptyline (25-150 mg) or trazadone (50-300 mg) every evening.</div></li></ul>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Constipation, a common side effect, can be managed w/fluids, fiber, stool softeners, & laxatives.</div></li><li class="half_rhythm"><div>For those w/diarrhea-predominant irritable bowel syndrome, the constipating effect may be therapeutic.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Glucosamine & chondroitin</b> may help to prevent or treat osteoarthritis in the general population.</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">These have not been studied specifically in cEDS but are not contraindicated.</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Cannabinoids</b> such as dronabinol & marijuana (where legal) may be helpful for several different types of pain.</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Benefits should be weighed against the potential for dependency &/or psychoactive effects.</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Benzodiazepines</b> may offer some short-term reduction in muscle spasm.</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Routine use of benzodiazepines is not recommended, because of the high risk of tolerance, dependency, & addiction.</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Physiotherapeutic program for children w/hypotonia &/or delayed motor development</div></li><li class="half_rhythm"><div>Non-weight-bearing muscular exercise (e.g., swimming) to promote muscular development & coordination</div></li></ul>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hematologic</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ascorbic acid (vitamin C) may ↓ easy bruising; general dose is 2 g per day for adults, w/proportionally reduced doses for children.</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">DDAVP<sup>®</sup> (desmopressin) may be useful to normalize bleeding time.</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DDAVP<sup>®</sup> may be beneficial w/bruising or epistaxis, or before procedures such as dental extractions.</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiovascular</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment for cardiovascular manifestations</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_trea_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">cEDS = classic Ehlers-Danlos syndrome; GI = gastrointestinal; NSAIDs = nonsteroidal anti-inflammatory drugs</p></div></dd></dl></div></div></div></div><div id="eds.Surveillance"><h3>Surveillance</h3><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in <a href="/books/NBK1244/table/eds.T.classic_ehlersdanlos_syndrome_reco_1/?report=objectonly" target="object" rid-ob="figobedsTclassicehlersdanlossyndromereco1">Table 7</a> are recommended.</p><div id="eds.T.classic_ehlersdanlos_syndrome_reco_1" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Classic Ehlers-Danlos Syndrome: Recommended Surveillance</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1244/table/eds.T.classic_ehlersdanlos_syndrome_reco_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds.T.classic_ehlersdanlos_syndrome_reco_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Skin</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment for skin fragility</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">At each visit or as needed</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Joints/Pain</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment for joint instability, occupational & physical therapy needs, mobility issues, pain</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval for hypotonia & motor development</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit in infants & children</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hematologic</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment for easy bruising &/or prolonged bleeding</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Eval of clotting factors (platelet count, aPTT, PT, & thrombin time)</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If severe easy bruising is present</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiovascular</b>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><b>In those w/normal initial echocardiogram:</b>
|
||
<ul><li class="half_rhythm"><div>Children: frequency of follow up per pediatric cardiologist</div></li><li class="half_rhythm"><div>Adults: no follow-up echocardiogram necessary</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_reco_1_1_1_1_3" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;"><b>In those w/abnormal echocardiogram</b> (aortic dilatation, mitral valve prolapse): annually</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">aPTT = activated partial thromboplastin time; PT = prothrombin time</p></div></dd></dl></div></div></div></div><div id="eds.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Sports with heavy joint strain should be avoided (contact sports, fighting sports, football, running).</p></div><div id="eds.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> of the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.</p><p>See <a href="#eds.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="eds.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Because of the increased risk for skin lacerations, postpartum hemorrhages, and prolapse of the uterus and/or bladder, monitoring of women throughout pregnancy and in the postpartum period is recommended.</p><p>Ascorbic acid (vitamin C) may reduce easy bruising. In general, 2 g per day is recommended for adults; however, no strict guidelines exist regarding recommended dose during the third trimester of pregnancy.</p><p>Physiotherapist referral should be made to address pelvic instability and pain.</p><p>Monitoring for intrauterine growth restriction and cervical insufficiency through cervical length screening can be valuable.</p><p>Monitoring of pregnant women for preterm labor is warranted during the third trimester, when the risk for preterm premature rupture of the membranes is increased.</p><p>For vaginal delivery, prompt episiotomy should be considered to prevent excessive perineal damage.</p><p>Prophylactic desmopressin and tranexamic acid, along with postpartum oxytocin, should be considered in view of the increased risk for postpartum hemorrhage.</p></div><div id="eds.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="eds.Genetic_Counseling"><h2 id="_eds_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="eds.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Classic Ehlers-Danlos syndrome (cEDS) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p></div><div id="eds.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>Approximately 50% of individuals diagnosed with cEDS have an affected parent.</div></li><li class="half_rhythm"><div>A <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with cEDS may have the disorder as the result of a <i>COL1A1</i>, <i>COL5A1</i>, or <i>COL5A2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> that occurred as a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> event in the proband or as a <a class="def" href="/books/n/gene/glossary/def-item/postzygotic/">postzygotic</a> <i>de novo</i> event in a mosaic, apparently unaffected parent. Approximately 50% of individuals diagnosed with cEDS have the disorder as the result of a <i>de novo</i> pathogenic variant.</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> appears to be the only affected family member (i.e., a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case), recommendations for both parents of the proband include:</div><ul><li class="half_rhythm"><div>Evaluation for manifestations of cEDS (i.e., physical examination of the skin with special attention to delayed wound healing, easy bruising, joint hypermobility or recurrent dislocations, and chronic articular pain);</div></li><li class="half_rhythm"><div>Molecular genetic testing for the cEDS-related <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> to evaluate the genetic status of the parents and inform <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> assessment.</div></li></ul></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> inherited a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> from a parent with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> (or somatic and germline) <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a> [<a class="bk_pop" href="#eds.REF.chesneau.2021.771">Chesneau et al 2021</a>, <a class="bk_pop" href="#eds.REF.micale.2021.1928">Micale et al 2021</a>]. Note: Testing of parental leukocyte DNA may not detect all instances of <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a> and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.</div></li></ul></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with cEDS may appear to be negative because of failure to recognize the disorder in family members with very mild phenotypes. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (to establish that neither parent is <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>).</div></li></ul><p><b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is affected and/or known to have the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband, the risk to the sibs is 50%. Intrafamilial phenotypic variability is observed; the severity, specific manifestations, and progression of the disorder are variable and cannot be predicted in a sib who inherits a pathogenic variant.</div></li><li class="half_rhythm"><div>If the cEDS-related <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> cannot be detected in the leukocyte DNA of either parent, the <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>. Paternal mosaicism for a <i>COL5A1</i> pathogenic variant has been reported in two families [<a class="bk_pop" href="#eds.REF.chesneau.2021.771">Chesneau et al 2021</a>, <a class="bk_pop" href="#eds.REF.micale.2021.1928">Micale et al 2021</a>].</div></li><li class="half_rhythm"><div>If the parents appear to be unaffected but their genetic status is unknown, the risk to the sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> appears to be low but increased over that of the general population because of the possibility of a very mild <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> in an undiagnosed <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parent and of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>.</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Each child of an individual with cEDS has a 50% chance of inheriting the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents: if a parent has the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the parent's family members may be at risk.</p></div><div id="eds.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#eds.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p><b>At-risk individuals.</b> The severity, specific symptoms, and progression of the disorder are variable and cannot be predicted based on family history or results of <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.</div></li></ul></div><div id="eds.Prenatal_Testing_and_Preimplantation"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the cEDS-related <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible. However, the severity, specific manifestations, and progression of cEDS are variable and cannot be predicted based on family history or the presence of a pathogenic variant identified on <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="eds.Resources"><h2 id="_eds_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>Ehlers-Danlos Society - Europe</b>
|
||
</div><div>United Kingdom</div><div><b>Phone:</b> +44 203 887 6132</div></li><li class="half_rhythm"><div>
|
||
<b>Ehlers-Danlos Support UK</b>
|
||
</div><div>United Kingdom</div><div><b>Phone:</b> 0800 907 8518</div><div>
|
||
<a href="http://www.ehlers-danlos.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ehlers-danlos.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>The Ehlers-Danlos Society</b>
|
||
</div><div><b>Phone:</b> 248-716-8336</div><div>
|
||
<a href="https://www.ehlers-danlos.com/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ehlers-danlos.com</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>MedlinePlus</b>
|
||
</div><div>
|
||
<a href="http://www.nlm.nih.gov/medlineplus/ehlersdanlossyndrome.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Ehlers-Danlos Syndrome</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>DICE EDS and HSD Global Registry</b>
|
||
</div><div>
|
||
<a href="https://www.ehlers-danlos.com/eds-global-registry/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ehlers-danlos.com/eds-global-registry</a>
|
||
</div></li></ul>
|
||
</div><div id="eds.Molecular_Genetics"><h2 id="_eds_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="eds.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Classic Ehlers-Danlos Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1244/table/eds.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_eds.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_eds.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_eds.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_eds.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_eds.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_eds.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_eds.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/1277" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>COL1A1</i>
|
||
</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=1277" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">17q21<wbr style="display:inline-block"></wbr>.33</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P02452" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Collagen alpha-1(I) chain</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://databases.lovd.nl/shared/genes/COL1A1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL1A1 @ LOVD</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=COL1A1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL1A1</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=COL1A1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL1A1</a>
|
||
</td></tr><tr><td headers="hd_b_eds.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/1289" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>COL5A1</i>
|
||
</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=1289" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">9q34<wbr style="display:inline-block"></wbr>.3</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P20908" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Collagen alpha-1(V) chain</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://databases.lovd.nl/shared/genes/COL5A1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL5A1 @ LOVD</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=COL5A1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL5A1</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=COL5A1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL5A1</a>
|
||
</td></tr><tr><td headers="hd_b_eds.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/1290" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>COL5A2</i>
|
||
</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=1290" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">2q32<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P05997" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Collagen alpha-2(V) chain</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://databases.lovd.nl/shared/genes/COL5A2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL5A2 @ LOVD</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=COL5A2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL5A2</a>
|
||
</td><td headers="hd_b_eds.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=COL5A2[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL5A2</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="eds.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="eds.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Classic Ehlers-Danlos Syndrome (<a href="/omim/120150,120190,120215,130000" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1244/table/eds.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/120150" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">120150</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">COLLAGEN, TYPE I, ALPHA-1; COL1A1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/120190" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">120190</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">COLLAGEN, TYPE V, ALPHA-2; COL5A2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/120215" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">120215</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">COLLAGEN, TYPE V, ALPHA-1; COL5A1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/130000" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">130000</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EHLERS-DANLOS SYNDROME, CLASSIC TYPE, 1; EDSCL1</td></tr></tbody></table></div></div><div id="eds.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>COL1A1</i> encodes the pro-α1 chains of type I collagen, whose triple helix comprises two α1 chains and one α2 chain. Type I collagen is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis, and tendon.</p><p><i>COL5A1</i> and <i>COL5A2</i> encode the pro-α1 and the pro-α2 chain of type V collagen, respectively. Type V collagen is a minor fibril-forming collagen that is mainly present as [α1(V)]<sub>2</sub> α2(V) heterotrimers in skin, bone, and tendon. It forms heterotypic fibrils with type I collagen and regulates the diameter of those fibrils, presumably through its partially retained amino-terminal propeptide. The pathogenic mechanism underlying classic Ehlers-Danlos syndrome (cEDS) is hypothesized to be "functional" haploinsufficiency of type V collagen, caused either by loss of expression of one <i>COL5A1</i> <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>, inefficient trafficking of mutated protein through the endoplasmic reticulum, or impaired incorporation of mutated α chains into type V collagen heterotrimers. Given its important regulatory role during the formation of heterotypic type I/V collagen fibrils, reduced availability of type V collagen is expected to negatively impact interactions with other extracellular matrix (ECM) components and hence compromises the general organization of the ECM [<a class="bk_pop" href="#eds.REF.symoens.2012.1485">Symoens et al 2012</a>].</p><div id="eds.T.classic_ehlersdanlos_syndrome_gene" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Classic Ehlers-Danlos Syndrome: Gene-Specific Mechanism of Disease Causation</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1244/table/eds.T.classic_ehlersdanlos_syndrome_gene/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds.T.classic_ehlersdanlos_syndrome_gene_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds.T.classic_ehlersdanlos_syndrome_gene_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_eds.T.classic_ehlersdanlos_syndrome_gene_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mechanism of Disease Causation</th></tr></thead><tbody><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_gene_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>COL1A1</i> c.934C>T</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_gene_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown; possible <a class="def" href="/books/n/gene/glossary/def-item/dominant-negative/">dominant-negative</a> activity</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_gene_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>COL5A1</i>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_gene_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Haploinsufficiency: diminished type V collagen caused by <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a> or frameshift variants may alter normal collagen fibrillogenesis [<a class="bk_pop" href="#eds.REF.symoens.2012.1485">Symoens et al 2012</a>, <a class="bk_pop" href="#eds.REF.ritelli.2013.58">Ritelli et al 2013</a>].</div></li><li class="half_rhythm"><div>Dominant-negative activity: the abnormal type V collagen interferes w/protein derived from the normal <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_gene_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>COL5A2</i>
|
||
</td><td headers="hd_h_eds.T.classic_ehlersdanlos_syndrome_gene_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Likely <a class="def" href="/books/n/gene/glossary/def-item/dominant-negative/">dominant-negative</a> activity; the abnormal forms interfere with protein derived from the normal <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="eds.TF.8.1"><p class="no_margin">Genes from <a href="/books/NBK1244/table/eds.T.beighton_criteria_for_joint_hyperm/?report=objectonly" target="object" rid-ob="figobedsTbeightoncriteriaforjointhyperm">Table 1</a> in alphabetic order.</p></div></dd></dl></div></div></div><p><b><i>COL1A1</i>-specific laboratory technical considerations</b>. Although most pathogenic variants in <i>COL1A1</i> cause osteogenesis imperfecta, the specific <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variant c.934C>T causes cEDS.</p><div id="eds.T.pathogenic_variants_referenced_in" class="table"><h3><span class="label">Table 9. </span></h3><div class="caption"><p>Pathogenic Variants Referenced in This <i>GeneReview</i> by Gene</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1244/table/eds.T.pathogenic_variants_referenced_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds.T.pathogenic_variants_referenced_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>COL1A1</i>
|
||
</td><td headers="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000088.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000088<wbr style="display:inline-block"></wbr>.4</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000079.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000079<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.934C>T</td><td headers="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg312Cys</td><td headers="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pathogenic variant identified in 35 persons from 12 families [<a class="bk_pop" href="#eds.REF.colman.2022.46">Colman et al 2022</a>]</td></tr><tr><td headers="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>COL5A1</i>
|
||
</td><td headers="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000093.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000093<wbr style="display:inline-block"></wbr>.5</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000084.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000084<wbr style="display:inline-block"></wbr>.3</a>
|
||
</td><td headers="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1588G>A</td><td headers="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly530Ser</td><td headers="hd_h_eds.T.pathogenic_variants_referenced_in_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">May be disease modifying in the <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> state & disease causing in the <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> state [<a class="bk_pop" href="#eds.REF.giunta.2000.72">Giunta & Steinmann 2000</a>, <a class="bk_pop" href="#eds.REF.giunta.2002.284">Giunta et al 2002</a>]</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd><dt>1. </dt><dd><div id="eds.TF.9.1"><p class="no_margin">Genes from <a href="/books/NBK1244/table/eds.T.beighton_criteria_for_joint_hyperm/?report=objectonly" target="object" rid-ob="figobedsTbeightoncriteriaforjointhyperm">Table 1</a> are in alphabetic order.</p></div></dd></dl></div></div></div></div></div><div id="eds.Chapter_Notes"><h2 id="_eds_Chapter_Notes_">Chapter Notes</h2><div id="eds.Author_Notes"><h3>Author Notes</h3><p>The <a href="https://www.malfaitlab.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Malfait Lab</a> (Center for Medical Genetics Ghent [CMGG] at Ghent University Hospital and Department for Biomolecular Medicine at Ghent University, Belgium) performs integrative translational research on Ehlers-Danlos syndromes (EDS). CMGG at Ghent University Hospital, in which the Malfait Lab is embedded, has a strong reputation as an internationally recognized center of expertise for research, diagnostics, and clinical management related to a range of hereditary connective tissue disorders (CTD), including, among others, EDS.</p><p>At the Malfait Lab, PI Prof Fransiska Malfait, MD, PhD, and Postdoctoral Fellow Delfien Syx, PhD, lead studies in the following areas of interest:</p><ul><li class="half_rhythm"><div>Unraveling the molecular basis of hereditary CTD, with a special focus on EDS and other hypermobility-related disorders, and studying their natural history and <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a>;</div></li><li class="half_rhythm"><div>Elucidating molecular and physiologic mechanisms underlying hereditary CTD pathogenesis, using an integrated approach of in vitro and in vivo techniques, on tissue samples of humans and animal models (zebra fish, mice);</div></li><li class="half_rhythm"><div>Studying prevalence, nature, and pathophysiologic mechanisms of pain in individuals with EDS and in relevant animal models.</div></li></ul><p>Fransiska Malfait (<a href="mailto:dev@null" data-email="eb.tnegu@tiaflam.aksisnarf" class="oemail">eb.tnegu@tiaflam.aksisnarf</a>) is actively involved in clinical research regarding individuals with EDS. Prof Malfait would be happy to communicate with persons who have any questions regarding diagnosis of EDS or other considerations.</p><p>Prof Malfait is also interested in hearing from clinicians treating families affected by EDS in whom no causative variant has been identified through <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> of the genes known to be involved in this group of disorders.</p><p>Contact Dr Sofie Symoens (<a href="mailto:dev@null" data-email="eb.tnegu@sneomys.eifos" class="oemail">eb.tnegu@sneomys.eifos</a>) to inquire about cEDS-related variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>.</p></div><div id="eds.Acknowledgments"><h3>Acknowledgments</h3><p>This work is supported by the Research Foundation Flanders (12Q5920N to D.S.; 1842318N & 3G041519 to F.M.), Ghent University (GOA019-21 to F.M.), Association française des syndromes d'Ehlers-Danlos (AFSED), The Ehlers-Danlos Society, Zebrapad VZW. The authors wish to thank the International Consortium on the Ehlers-Danlos Syndromes for their contribution.</p></div><div id="eds.Author_History"><h3>Author History</h3><p>Anne De Paepe, MD, PhD; Ghent University Hospital (2003-2024)<br />Fransiska Malfait, MD, PhD (2003-present)<br />Sofie Symoens, PhD<br />Delfien Syx, PhD<br />Richard Wenstrup, MD; Cincinnati Children's Hospital Medical Center (2003-2024)</p></div><div id="eds.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>1 February 2024 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>26 July 2018 (ha) Comprehensive update posted live</div></li><li class="half_rhythm"><div>18 August 2011 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>24 July 2008 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>10 April 2006 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>29 October 2003 (ca) Review posted live</div></li><li class="half_rhythm"><div>20 June 2003 (rw, ad) Original submission</div></li></ul></div></div><div id="eds.References"><h2 id="_eds_References_">References</h2><div id="eds.Published_Guidelines__Consensus_Stat"><h3>Published Guidelines / Consensus Statements</h3><ul class="simple-list"><li class="half_rhythm"><div>Bowen JM, Sobey GJ, Burrows NP, Colombi M, Lavallee ME, Malfait F, Francomano CA. Ehlers-Danlos syndrome, classical type. Am J Med Genet C Semin Med Genet. 2017;175:27-39. [<a href="https://pubmed.ncbi.nlm.nih.gov/28192633/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</div></li><li class="half_rhythm"><div>Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175:8-26. 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</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=medgen&DbFrom=books&Cmd=Link&LinkName=books_medgen&IdsFromResult=1462320" ref="log$=recordlinks">MedGen</a><div class="brieflinkpop offscreen_noflow">Related information in MedGen</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=omim&DbFrom=books&Cmd=Link&LinkName=books_omim&IdsFromResult=1462320" ref="log$=recordlinks">OMIM</a><div class="brieflinkpop offscreen_noflow">Related OMIM records</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=1462320" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=1462320" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=gene&DbFrom=books&Cmd=Link&LinkName=books_gene&IdsFromResult=1462320" ref="log$=recordlinks">Gene</a><div class="brieflinkpop offscreen_noflow">Locus Links</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/36108117" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> TNXB-Related Classical-Like Ehlers-Danlos Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> TNXB-Related Classical-Like Ehlers-Danlos Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">van Dijk FS, Ghali N, Demirdas S, Baker D. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301510" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Dietz H. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301635" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Rohrbach M, Giunta C. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301456" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hypermobile Ehlers-Danlos Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hypermobile Ehlers-Danlos Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Hakim A. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301312" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Loeys-Dietz Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Loeys-Dietz Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Loeys BL, Dietz HC. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=20301422" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=20301422" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" 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