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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 175C:27–39 (2017)

R E S E A R C H R E V I E W

Ehlers–Danlos Syndrome, Classical TypeJESSICA M. BOWEN, GLENDA J. SOBEY, NIGEL P. BURROWS, MARINA COLOMBI,MARK E. LAVALLEE, FRANSISKA MALFAIT, AND CLAIR A. FRANCOMANO*

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Glenda J SobSheffield. Her uclinic for patieninternationally

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Mark Lavalleserved as a boalaboratory studseveral publicaconnective tiss

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Classical EDS is a heritable disorder of connective tissue. Patients are affected with joint hypermobility, skinhyperextensibilty, and skin fragility leading to atrophic scarring and significant bruising. These clinical featuressuggest consideration of the diagnosis which then needs to be confirmed, preferably by genetic testing. Themost recent criteria for the diagnosis of EDS were devised in Villefranche in 1997 [Beighton et al. (1998); Am JMed Genet 77:31-37].The aims set out in the Villefranche Criteria were: to enable diagnostic uniformity forclinical and research purposes, to understand the natural history of each subtype of EDS, to informmanagementand genetic counselling, and to identify potential areas of research. The authors recognized that the criteriawould need updating, but viewed the Villefranche nosology as a good starting point. Since 1997, there havebeen major advances in the molecular understanding of classical EDS. Previous question marks over geneticheterogeneity have been largely surpassed by evidence that abnormalities in type V collagen are the cause.Advances inmolecular testing havemade it possible to identify the causativemutation in themajority of patients.This has aided the further clarification of this diagnosis. The aim of this literature review is to summarize thecurrent knowledge and highlight areas for future research. © 2017 Wiley Periodicals, Inc.

KEYWORDS: Ehlers–Danlos syndrome; classical type; cEDS; joint hypermobility; skin fragility; skin hyperextensibility

How to cite this article: Bowen JM, Sobey GJ, Burrows NP, Colombi M, Lavallee ME, Malfait F,Francomano CA. 2017. Ehlers–Danlos syndrome, classical type. Am JMed Genet Part C Semin Med Genet

175C:27–39.

INTRODUCTION

TheCommittee met by phone through-out 2015 to discuss the Villefranche

is a registered genetic counsellor speal Diagnostic Service since its foundDS. Jess has a particular interest iney is co-founder of the Ehlers–Danlonit is responsible for the diagnosis ots at risk of blood vessel rupture. Dr. She is particularly interested in prorrows is a Consultant Dermatologistt groups (EDS Support UK andAnnapublications on EDS, he has writtenmbi is a full professor ofMedical Geue disorders including Ehlers–Dann, clinical spectrum, and pathogene is a board certified Family Medicirdmember and founding chairmanies of the COL3A1 gene at Penn Stattions and research projects in relatiue diseases.alfait is a rheumatologist and clinicale she directs the research, clinical sedisorders of connective tissue. Shecomano is a clinical geneticist withered on Ehlers–Danlos Syndrome. SHarvey Institute for Human Geneti

ve Board and the Medical and Sciennterests: None of the authors has adence to: Clair A. Francomano, Grea, MD 21204. E-mail: cfrancomano@2/ajmg.c.31548published online 13 February 2017

ey Periodicals, Inc.

diagnostic criteria for classical Ehlers–Danlos Syndrome (classical EDS) andhow they might be modified to improve

cializing in Ehlers–Danlos syndrome,withwide experation. Together with colleagues in the service, Jess hthe psychosocial outcomes and consequences of es SyndromeNational Diagnostic Service in the UK anf rare and atypical EDS, and together with cardiology. Sobey has published widely and plays an active rolemoting early diagnosis in rare disease to allow optat Addenbrooke's Hospital, Cambridge, UK. He is o

belles Challenge). He is actively involved in themanagseveral book chapters and also lectures on nation

netics at the School ofMedicine, University of Brescialos syndromes, for which she has provided newesis.ne and Sports Medicine Physician. He joined the Ehof their Professional Advisory Council. His career hase University, and the founding of Ehlers–Danlos Clinion to EDS, specifically regarding the use of exercise

geneticist. She is an Associate Professor at the Centrvice and laboratory facility for diagnosis and genetcurrently is the Chair of the Medical and Scientific

a long interest in the hereditary disorders of connecthe is Director of Adult Genetics and of the Ehlerscs, and Associate Professor of Medicine at Johns Hoptific Board of the Ehlers–Danlos Society.conflict of interest to report.ter BaltimoreMedical Center� Harvey Institute forgbmc.org

in Wiley Online Library (wileyonlinelibrary.com).

specificity and sensitivity. A comprehen-sive review of the literature was con-ducted, led by two of the authors

ience of all types of EDS. She hasworked in theas developed an emergency card for patientsarly and accurate diagnosis of rare disease.d Honorary Senior Lecturer at the University ofcolleagues she runs a specialist EDS cardiologyin teaching and lecturing both nationally andimal outcome for patients and families.n the medical advisory board for two UK EDSement of patients with EDS and, in addition toal courses on EDS., Italy. Her major interests are diverse heritableinsights in the molecular basis, phenotypic

lers–Danlos National Foundation in 1987, andfocused on Ehlers–Danlos syndrome, includingcs in Indiana and Pennsylvania. Dr. Lavallee hasto improve the quality of life in patients with

re for Medical Genetics at the Ghent Universityic testing for the Ehlers–Danlos Syndrome andBoard of the Ehlers–Danlos Society.ive tissue. Her professional work in the last 10–Danlos Society Center for Clinical Care andkins University School of Medicine. She serves

Human Genetics, 6701N. Charles Street, Suite

28 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

(Bowen and Sobey). The diagnosticcriteria presented here represent theconsensus of the group after review ofthe literature and considering the pro-fessional experience of each of theauthors.

The committee agrees to retain thename “classical EDS.”

METHODS

Each member of the committee carriedout a literature search for classical EDS.The results were collated. All articleswere reviewed for relevance and addi-tional articles were identified from theliterature. The articles were summarizedand divided into themes. Themes thatwere suggested by the Steering Com-mittee of the International Consortiumon the Ehlers–Danlos syndromes werealso included to assess where there weregaps in the literature. Each theme waswritten up to include the relevantliterature in that area, focusing oninformation since the Villefranche no-sology. The original list of articles wasthen reviewed to ensure all areas of thecurrent literature had been covered.

Organ System Review

Musculoskeletal: Joint hypermobility ispresent. This will be evidenced by thepresence of a Beighton score of 5 orgreater, either on examination or his-torically. Joint instability complicationsmay comprise sprains, dislocation/sub-luxation, temporomandibular joint dys-function, pain and pes planus, dyspraxia,and early osteoarthritis. Mild musclehypotonia, and some skeletal morpho-logical alterations (scoliosis, pectus de-formities, elbow/genus/hallux valgus)are regularly observed. Pre-menopausalosteopenia or an increased bone fragilityin the presence of a bonemineral densitywithin the range may occur [Mazziottiet al., 2016].

Skin: The skin involvement is keyto establishing the diagnosis of classicalEDS. Skin is hyperextensible and soft,with severe atrophic scarring and hae-mosiderin deposition over the shins andextensor surfaces. Easy bruising is also ahallmark of classical EDS.

Cardiovascular: While aortic rootdilation and mitral valve prolapse areseen in classical EDS, they are rarelyclinically significant. Arterial aneurysmand rupture have been reported in a fewindividuals and families with COL5A1mutations.

Gastrointestinal: Gastrointestinalcomplaints are more commonly de-scribed in the hypermobile type of EDS,although they can be present in patientswith classical EDS and may include:dysphagia, dyspepsia, reflux disease withor without hiatal hernia, irritable-boweldisease-like symptoms, unspecified ab-dominal pain, defecatory dysfunctions(constipation, diarrhea), and rectocele[Ritelli et al., 2013; Nelson et al., 2015].

Neurologic: Pain is a commonfeature of EDS. One report suggeststhat pain intensity in classical EDSpatients is mild and less frequentcompared to hypermobile EDS.

Literature Review

The literature was divided into 8themes: The history of classical EDS,the mechanism of disease, clinicaldescription, testing strategy, manage-ment, differential diagnoses, geneticcounselling, and gaps/future research.

THE HISTORY OFCLASSICAL EDS

Classical EDS (OMIM #130000) is aheritable disorder of connective tissuecharacterized by skin hyperextensibility,poor wound healing, and joint hyper-mobility. Classical EDSwas first noted tobe a distinct type of EDS in the 1960swhen Beighton reviewed 100 patientsand described a patient with distinctfeatures which he termed EDS gravis[Beighton, 1968]. Patients were noted tohave characteristic findings on electronmicroscopy, which helped to differenti-ate between EDS diagnoses [Vogel et al.,1979]. In 1988, gravis type was termedEDS type I and themilder, mitis typewaslabelled EDS type II [Beighton et al.,1988]. Type V collagen was implicatedafter mouse models with mutations inCOL5A2 showed features of the condi-tion [Andrikopoulos et al., 1995]. This

was shortly followedby the first reports ofCOL5A1 mutations in patients withclassical EDS [Nicholls et al., 1996;Wenstrup et al., 1996; De Paepe et al.,1997]. Linkage to COL5A1 also sug-gested the EDS types I and II werephenotypic variation of the same condi-tion [Burrows et al., 1996]. In 1996, abalanced translocation interrupting theCOL5A1 gene was identified and hap-loinsufficiency was suggested as the causeof the patient’s EDS phenotype [Torielloet al., 1996]. The name classical EDSwasgiven when the Villefranche nosologywas written in 1997 [Beighton et al.,1998]. Initially other genes were thoughtto be involved, as COL5A1 andCOL5A2 mutations were only foundto account for around half of classicalEDS patients [Schwarze et al., 2000;Malfait et al., 2005]. Advances inmolecular testing have allowed moretype V collagen abnormalities to beidentified, and recent reports indicatethat the majority of patients with classicalEDS do have a mutation in eitherCOL5A1 or COL5A2 [Symoens et al.,2012; Ritelli et al., 2013].

Classical EDS (OMIM#130000) is a heritable

disorder of connective tissuecharacterized by skin

hyperextensibility, poorwound healing and joint

hypermobility. Classical EDSwas first noted to be a distincttype of EDS in the 1960s

when Beighton reviewed 100patients and described a

patient with distinct featureswhich he termed EDS gravis.

THE MECHANISM OFDISEASE

Reduction in the amount of type Vcollagen is central to the pathogenesis of

RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 29

classical EDS [Symoens et al., 2008; DePaepe and Malfait, 2012]. Type Vcollagen has a regulatory function infibrillogenesis. The phenotype is causedby disturbance in the regulatory func-tion of type V collagen [Symoens et al.,2012].

Type V collagen is a fibrillarcollagen present in small amounts in awide variety of tissues [Malfait and DePaepe, 2005]. It is mainly found invertebrate tissues as the heterotrimer a1(V)2a2(V) [Viglio et al., 2008]. Type Vcollagen and type I collagen cometogether to form collagen fibrils.COL5A1 haploinsufficiency is, there-fore, a limiting factor for an adequateproduction of heterotrimers, hencecompromising the regulatory role infibrils assembly. Most of the a1(V)2a2(V) heterotrimer is embedded withinthe fibril, apart from the amino-terminalpropeptide domain which remains ex-posed on the surface and has a role infibril assembly and regulating fibrildiameter [Birk, 2001].

TheCOL5A1 gene encodes the a1chain and is located at 9q34.2-q34.3.The COL5A2 gene encodes the a2chain and is located at 2q31. Both genesare large, comprising 66 and 52 exons,respectively. The majority of patientshave mutations inCOL5A1. A report of93 gene positive patients found 73 hadCOL5A1 mutations, 13 had COL5A2mutations, and in 7 cases the mutationcould not be identified; however,COL5null allele testing confirmed the abnor-mality was in type V collagen [Symoenset al., 2012]. In this series two thirds ofthe mutations were found to be de novo.A series of 40 patients achieved amutation detection rate of 93% [Ritelliet al., 2013]. Both studies confirmedthat COL5A1 and COL5A2 are themajor, if not the only genes involved.

The most common molecular de-fects result in nonsense mediated decayof the mutated COL5A1 mRNA[Schwarze et al., 2000]. Whilst hap-loinsufficiency is seen most often,dominant-negative mutations are alsoreported [Wenstrup et al., 2000]. Ingeneral genotype–phenotype correla-tions are not found, but there are acouple of possible exceptions.

Mutations in the highly conservedamino-terminal propeptide domain ofa1(V) that cause atypical splicing out-comes have been associated with a moresevere classical EDS phenotype withkyphoscoliosis and retinal detachment[Symoens et al., 2011]. There is onereport that questions whether mutationsinvolving glycine substitutions near theC-terminal end cause an increasedarterial risk [Monroe et al., 2015].Although numbers are still limited,COL5A2 gene mutations are thoughtto result in a phenotype at the moresevere end of classical EDS spectrum[Symoens et al., 2012].

CLINICAL DESCRIPTION

The Villefranche criteria list three majorcriteria for classical EDS [Beightonet al., 1998]:

(1)
Skin hyperextensibility (2) Widened atrophic scars (manifestation
of tissue fragility)
(3) Joint hypermobility
In addition, there are a number ofminor criteria which show less diagnos-tic specificity:

(1)
Smooth velvety skin (2) Molluscoid pseudotumours (3) Subcutaneous spheroids/spherules (4) Complications of joint hypermobility
(e.g., sprains, dislocations/subluxa-tions, pes planus)

(5)
Muscle hypotonia, delayed gross mo-tor development
(6)
Easy bruising (7) Manifestations of tissue extensibility
and fragility (e.g., hiatus hernia, analprolapse in childhood, cervicalinsufficiency)

(8)
Surgical complications (postoperativehernias)
(9)
Positive family history
The Villefranche criteria are stillconsidered relevant for classical EDS.A study of 126 suspected classical EDSpatients found that 93 out of the 102 thatdemonstrated all three major Ville-franche criteria for classical EDS werefound to have a type V collagen

abnormality [Symoens et al., 2012].They suggested making the diagnosticcriteria more stringent as fulfilling allthree major criteria was seen to be areliable indicator of a type V collagenmutation. Another review of 40 patientsalso found that these three major criteriaare considered to still be useful forclinical diagnoses in the majority ofpatients [Ritelli et al., 2013].

A study of 126 suspectedclassical EDS patients foundthat 93 out of the 102 thatdemonstrated all three major

Villefranche criteria forclassical EDS were found to

have a type V collagenabnormality.

There have been a number oftypical case histories of classical EDSdescribed. These suggest that investiga-tions into childhood bruising are oftenthe first presentation to medical pro-fessionals, and if skin hyperextensibilityand joint hypermobility are noted at thistime, the diagnosis is generally made [DePaepe and Malfait, 2012; Byers, 2013;Morais et al., 2013; Sobey, 2014].Bruising is generally a feature seenwhen children start to crawl and walk,with the characteristic scarring becom-ing apparent after knocks and bumpsaround the same time. Hypermobilitymay delay motor development, butintellectual development is unaffected.

Skin Features

Skin hyperextensibility has been shownto be a reliable and reproducible featureof classical EDS [Remvig et al., 2010].This group confirmed that patients withclassical EDS show extensibility beyondthe normal range (Fig. 1). However,they found skin consistency to be anunreliable test and concluded that skinconsistency should not be included inthe diagnostic criteria for classical EDS.

Figure 1. Hyperextensible skin in Classical Ehlers-Danlos Syndrome.


Figure 2. Typical scarring in classical EDS.


Other reports have also found skinhyperextensibility to be a good indicatorfor classical EDS, as it quite specific tothis diagnosis [Heidbreder et al., 2008;Catala-P�etavy et al., 2009] Skin fragilitywith atrophic scarring and poor woundhealing is a hallmark of the classical typeof EDS [Beighton et al., 1998] (Fig. 2).

Cardiovascular Involvement

Nine patients (three in one family) havebeen reported to have molecularlyconfirmed classical EDS and vascularevents [Monroe et al., 2015]. To deter-mine whether there is any reporting biasit is helpful to compare these cases to thelarger patient series that have beenreported. Twenty-five patients withproven type V collagen abnormalitiesshowed no vascular events at the time ofwriting [Malfait et al., 2005]. A series of102 patients, 93 with collagen type Vabnormalities, had two patients withvascular complications which includedaneurysm and dissection of mediumsized artery [Symoens et al., 2012]. Theyreported that severe or progressivecardiac-valvular disease was absent intheir cohort. A report of 40 patientsshowed no patients with type V collagenabnormalities that had severe cardiovas-cular involvement [Ritelli et al., 2013].

The family of three are two brothersand their mother who were given aclinical diagnosis of vascular EDS[Monroe et al., 2015]. One brotherdied age 43 due to a subarachnoid bleed,after previously having a ruptured leftsubclavian artery age 15 years and acoeliac artery aneurysmwas resected age18 years with significant bleeding. Hismother had died at age 28 while underanaesthesia for dental extraction; thepost mortem revealed a renal artery tear.The other brother died age 34 followinga right iliac artery rupture; his tissueswere compared to rice paper in theoperating theatre. They were all shownto have a COL5A1 p.(Gly1537Val)mutation. This family represents theonly report of familial vascular eventswith a COL5A1mutation. The authorswondered about modifying genes in thefamily or whether there could be agenotype–phenotype correlation. They

speculated there could be increasedarterial risk in cases involving glycinesubstitutions near the C-terminal end.

Another report of a patient with aglycine substitution at theC-terminal endof the triple helix domain had a symp-tomatic superior mesenteric artery aneu-rysm age at 9 years [de Leeuwet al., 2012].This patient was said to fit clinically with aclassical EDS diagnosis and was found tohave a COL5A1 p.(Gly1564Asp) muta-tion. Two further vascular events havebeen reported at young ages.One report isof a 13-year-old girl with classical EDSwho had a superior mesenteric arteryrupture andwas found to have aCOL5A1missense mutation c.1532G>Tp.(Gly511Val) [Yasuda et al., 2013].Another patient with a COL5A1 p.(Gly922Asp) mutation was diagnosedwith classical EDS at 4 years of age andpresented at age 11 with a superiormesenteric artery aneurysm with throm-bosis [Karaa and Stoler, 2013]. Thispatient was treated with anticoagulation,and a week later he ruptured his inferiormesenteric artery.

Two patients with classical EDS andhypertension have been reported follow-ing vascular events. A patient with aCOL5A1 mutation c.3184C>T p.(Arg1062�) who already had a clinicaldiagnosis of classical EDSwent on tohavea left common iliac artery rupture at age42 years [Borck et al., 2010]. This patienthad been diagnosed with hypertension at40 and treated with clonidine, metopro-lol and valsartan/hypochlorothiazide.The authors felt they could not excludea chance association between the classicalEDS diagnosis and the rupture, but felt acausal relationship was more likely. Theyconsidered whether the concurrent hy-pertension might have played a part,causing a second hit. However, theirview was that a systematic counselling ofthe risk of arterial rupture in classicalEDS should await confirmation of thisassociation in larger series. Anotherpatient with chronic hypertension(although well controlled) with aCOL5A1 nonsense mutationc2185C>T p.(Gln729�) had an iliacartery dissectionwhilst resistance training[Mehta et al., 2012]. This time theauthors considered a triple hit effect;

chronic hypertension, elevated vascularstress from resistance training, and hisunderlying weakened collagen matrixdue to classical EDS. They suggestedavoiding intense resistance training and/or tighter control of blood pressure.

Aortic root dilation has been re-ported in classical EDS [Wenstrup et al.,2002; McDonnell et al., 2006; Atzingeret al., 2011]. It appears to be morecommon in young patients and rarelyprogresses [Atzinger et al., 2011]. Mitralvalve prolapse can occur in up to 6% ofcases but tends to be of little clinicalsignificance [Atzinger et al., 2011].

Newly recognized featuresFeatures not mentioned in the Ville-franche criteria that arise in the literatureinclude premature rupture of fetalmembranes, characteristic facial fea-tures, absence of striae, scoliosis, cardiacand blood vessel fragility. Prematurerupture of fetal membranes can result inprematurity and this was reported toaffect half of classical EDS patients, but isnow thought not to be so common[Wenstrup et al., 2000]. The character-istic facial features described are; epi-canthic folds, excess skin on eyelids, aprematurely aged appearance, and scarson the forehead and chin [Malfait andDe Paepe, 2005]. Absence of striae hasbeen noted in classical EDS patients[Sobey, 2014], although some patientswith confirmed classical EDS have beenseen to have striae. Three patients out of40 were reported to have striae in onestudy [Ritelli et al., 2013]. Dual-energyX-ray absorptiometry (DXA) and quan-titative vertebral morphometry wereperformed in 12 unrelated adult patientswith classical EDS which showed bonemineral density below the expectedrange for age (osteopenia) in about33.3% of patients and pre-menopausalosteoporosis in one patient. Giantbladder diverticula have been describedin four cases, all male [Burrows et al.,1998]. In two reports the subtype ofEDS was not given but the descriptionswere compatible with classical EDS.

Gastrointestinal findingsGastrointestinal (GI) manifestationswere analyzed among a cohort of 73


unrelated adult patients with classicalEDS. The most common upper GIsymptoms were nausea (46.5%), vomit-ing (30.2%), and gastroesophageal reflux(30.2%); the most common lower GIsymptom was chronic constipation(37.2%) [Nelson et al., 2015]. Gastro-esophageal reflux and defecatory dys-functions (i.e., chronic constipation)were also described in the cohort of39 classical EDS patients reported inRitelli et al. [2013].

Oral findingsOverall periodontal status in EDS ispoor. One case of abnormal pulp shapeand seven with pulp calcification wereseen out of nine classical EDS patientsexamined [De Coster et al., 2005a]. Ithas been suggested that the absence ofthe inferior labial and lingual frenulae isa helpful marker for hypermobile andclassical EDS, but the total numbers ofclassical EDS patients reported to dateare too small to conclude that this isuseful sign in this subtype [De Feliceet al., 2001]. Pierro et al. [2006] reportedon ligneous periodontitis in Ehlers-Danlos syndrome. Temporomandibularjoint dysfunction is a common featureand a frequent cause of secondaryheadache in classical EDS patients withgeneralized joint laxity [De Coster et al.,2005b].

Ocular findingsMacro- and microstructural changes ofthe cornea were found in classical EDSpatients [Villani et al., 2013]. ClassicalEDS patients have been shown to havethin, steep and transparent corneas aswell as floppy eyelids [Segev et al.,2006; Villani et al., 2013]. Both studiesfound that these changes did not causean increase in refractory errors (includ-ing astigmatism) nor an increase inkeratoconus. This supports the lack ofcorrelation between corneal thicknessand refractive error. Villani et al.[2013] also found that the patientsreported no complaints of ocularsurface symptoms, despite having ab-normal ocular surface symptoms andreduced tear secretion when comparedto controls. One caveat concerning thereport by Villani et al. [2013] is that the

diagnosis of classical EDS was notsupported by molecular testing in thereported population.

Pain and Neurological FeaturesPain is considered a common feature inEDS patients, but it has been shown tobe more prevalent and more severe inpatients with hypermobile EDS than inthose with classical or vascular EDS[Voermans et al., 2010]. The authorscorrelate pain intensity with the degreeof joint hypermobility, dislocations, andprevious surgery. A decrease in quality oflife has been reported but found not tobe significantly different between classi-cal and hypermobile patients, providedthey have been diagnosed and are undermultidisciplinary management [Castoriet al., 2010]. When compared topatients with vascular EDS and patientswith homozygous and heterozygousTNXB mutations, the patients withclassical EDS reported the most neuro-muscular complaints [Voermans et al.,2009]. This study found mild, moderateor severe muscle weakness on examina-tion of all of 10 classical EDS patients.They suggest that the neuromuscularinvolvement is due to the abnormalextracellular matrix within muscle andperipheral nerve. This is an alternativeexplanation to the view that it is exerciseavoidance, for fear of dislocations andsprains, which leads to muscle weaknessand fatigue. Rowe et al. [1999] reportedan association between orthostatic in-tolerance, chronic fatigue, and Ehlers-Danlos syndrome. Autonomic burdenhas been reported to be lower in classicalEDS than in hypermobile EDS, andclassical EDS patients had levels morecomparable to those reported by vascu-lar EDS patients [De Wandele et al.,2014].

TESTING STRATEGY

The diagnosis of classical EDS can beconfirmed by identifying the pathogeniccausative mutation in COL5A1 orCOL5A2. As the number of identifiablemutations has increased, molecular test-ing has been the main route for classicalEDS testing. Testing strategies generallystart with COL5A1 sequencing. If

COL5A1 is negative, sequenceCOL5A2 and proceed to MultiplexLigation-dependent Probe Amplifica-tion (MLPA) for COL5A1 [De PaepeandMalfait, 2012; Ritelli et al., 2013]. Ifthe causative mutation is not identified,COL1A1 sequencing should be consid-ered, at least in a subset of patients withvascular and/or valvular involvement,or history thereof [Ritelli et al., 2013;Colombi et al., 2016] (see also “Ehlers–Danlos Syndromes, Rare Subtypes” byBrady et al., this issue).

The diagnosis of classicalEDS can be confirmed byidentifying the pathogeniccausative mutation in

COL5A1 or COL5A2. Asthe number of identifiablemutations has increased,

molecular testing has been themain route for classical EDStesting. Testing strategies

generally start with COL5A1sequencing.

Molecular investigations identifymutations in the majority, but currentlynot all, patients with the diagnosis[Symoens et al., 2012]. Pathogenicitymust be determined and there is aregistry of reported collagen genevariants [Dalgleish, 1998].

The pathogenicity of one reportedvariant remains unclear. Thep.(Gly530Ser) variant in COL5A1 isreported to be potentially disease modi-fying in the heterozygous state anddisease causing in the homozygous state[Giunta and Steinmann, 2000; Giuntaet al., 2002]. However, there is still someuncertainty about whether this variant isdisease causing, due to its frequency inthe general population and the fact thatnot all molecular causes of classical EDScan currently be identified. Anotherstudy found the frequency of the


p.(Gly530Ser) variant to be similar inpatients with classical EDS, vascularEDS, osteogenesis imperfecta (OI),and the three control groups they usedas comparison [Mitchell et al., 2009].They state that if homozygosity of thisvariant did cause classical EDS, 1 in 400people would be affected. This is muchhigher than the current suspectedfrequency of classical EDS. Hence,they consider homozygosity of thisvariant is unlikely to cause classical EDS.

When a pathogenic mutation can-not be found, type V collagen abnormal-ity can be sometimes be demonstrated bythe COL5A1 null allele test [Greenspanand Pasquinelli, 1994; Schwarze et al.,2000;Mitchell et al., 2009;DePaepe andMalfait, 2012; Symoens et al., 2012]. Thepatient must be heterozygous for apolymorphic marker in COL5A1gDNA. cDNA from a skin biopsy isthen tested to look for the presence ofone or both markers. If a marker is notexpressed that allele is assumed not to befunctional, that is, “null” [Malfait andDePaepe, 2005].

Typical frequent collagen flowers onelectron microscopy (EM) of skin can bea helpful diagnostic tool for classical EDS,however collagen flowers are not uniqueto this condition. Electronmicroscopyofa skin biopsy can be used to direct testing[Sobey, 2015], and electron microscopycan aid diagnosis [Vogel et al., 1979;Hausser and Anton-Lamprecht, 1994].The absence of typical collagen flowerswould go against the diagnosis, as thereare no reports of patients with type Vcollagen abnormalities without collagenflowers on EM [de Moraes et al., 2000;Proske et al., 2006; Symoens et al., 2012].However, collagen flowers are notspecific to classical EDS and have beenreported in other connective tissuedisorders including OI and Ullrichcongenital muscular dystrophy(UCMD) [Kirschner et al., 2005;Hermanns-Le and Pi�erard, 2007;Balasubramanian et al., 2015].Collagen flowers on EM should be anindicator to look for COL1A1 muta-tions, when clinical features of classicalEDS are present in the absence of aCOL5 abnormality.

Collagen protein analysis of culturedfibroblasts is not an effective diagnostictool for classical EDS as typeV collagen isonly synthesized at low levels [Malfaitet al., 2010]. This analysis may be used toexclude alternative diagnoses in theabsence of genetic confirmation andmay be helpful for the confirmation ofthemutation effect, that is, recognitionofsplice site mutations.

MANAGEMENT

The key management advice is fairlyconsistent and focuses on the skin andjoints [Steinmann et al., 2002;Proske et al.,2006; Malfait et al., 2010; Sobey, 2014].

The advice on managing the skin isto:

Avoid undue trauma. Children areparticularly prone to injury and benefitfrom protective pads and bandages.Custom made shin pads can beobtained from local appliance depart-ments. Contact sports should beavoided.

Wounds should be expertly closedvia sutures without tension. Patientsshould be known to their local plasticsurgeons to enable access in emergencies.Stitches should be applied generously, inlayers and left in place twice as long asusual. Tape can also help prevent stretch-ing of the scar, but needs careful removal.

Wounds should be expertlyclosed via sutures withouttension. Patients should beknown to their local plasticsurgeons to enable access inemergencies. Stitches shouldbe applied generously, in

layers and left in place twiceas long as usual. Tape can

also help prevent stretching ofthe scar, but needs careful

removal.

Ascorbic acid (2 g/day for adults)may reduce bruising, but does not affectthe basic clinical picture.

Surgery may be difficult due totissue fragility and original problem mayreoccur, for example, hernia.

Deamino-Delta-D-Arginine Vaso-pressin (DDAVP) may be useful tonormalize bleeding time. Althoughbleeding is related to tissue and capillaryfragility rather than clotting time, it maybe beneficial in case of bruising, epistaxisor before procedures such as dentalextractions.

Avoid excessive sun exposure toreduce the risk of premature skin aging.

Plastic surgery to remove mollus-coid pseudotumors may be consideredin presence of psychological/aestheticissues.

The musculoskeletal managementadvice is:

Physiotherapy is beneficial for chil-dren with hypotonia and delayed motordevelopment.

Light, non-weightbearing, musclestrengthening exercise such as isometrictraining and swimming are beneficial forhypermobile joints and painmanagement.

Competitive activities, such asgymnastics, repetitive heavy lifting,and sports that cause heavy joint stress,are not advisable. Mild strength traininghas shown benefit in joint stabilizationand hypotonia.

Avoid “showing off” hypermobil-ity and excessive stretching of thehypermobile joints.

Joint hypermobility is best managedby Rheumatology, Physiatry and SportsMedicine, together with physiotherapy,proprioception exercises, and occupa-tional therapy (OT).

Ring splints, carefully consideredbracing, and orthotics may be beneficial.

Skin fragility,muscle hypotonia, jointinstability, and pain are key aspects of thecondition and should be recognized anddiscussed with the patient. Lifestyle andprofessional choices may need to beadapted.

There are several articles givingcontradictory advice on resistanceexercise. One report found heavy


resistance training was both feasible andsafe, although their numbers were smallthey saw an improvement in muscu-lotendinous function and a reductionin fatigue [Møller et al., 2014].Another report describes a case of iliacartery dissection following vigorousphysical exercise [Mehta et al., 2012].Schroeder and Lavallee [2006] offerguidance for athletes with EDS of alltypes.

The advice on pain managementincludes:

Anti-inflammatory drugs and painmedications using narcotics only as avery last resort.

Neurological assessment in patientswith symptoms suggestive of neuro-pathic pain/compression neuropathy.

Regular, light, non-weightbearingexercise.

Relaxation techniques includingmindfulness-based stress reduction andbiofeedback.

Counselling support including cog-nitive behavioral therapy. See also “PainManagement in Ehlers-Danlos Syn-drome” by Chopra et al., this issue.

Cardiac Management

Cardiac assessment including echo-cardiography to look for aortic rootdilation and mitral valve prolapse.Mitral valve prolapse may need man-agement. Aortic root size and mitralvalve prolapse are increased in pa-tients with classical EDS, but theytend to be of little clinical signifi-cance. Echocardiography may bewarranted, but in symptom-freeadults frequency can be reduced[Atzinger et al., 2011]. If this isnormal in adulthood no follow up isrequired [Malfait et al., 2010].

Consider vascular imaging/use ofblood pressure medication if the patienthas a glycine substitution identified nearthe C-terminal end of the triple helix, oron the basis of their family history[Monroe et al., 2015].

Gastrointestinal Management

Endoscopy and colonoscopy should beperformed with care due to a possibly

increased risk of mucosal bleeding andtissue fragility.

Pregnancy Management

Follow up throughout pregnancy iswarranted.

Preterm delivery is more likely whenthe fetus is affected and is mainly due topremature rupture of the membranes.

Breech presentation is more com-mon if the baby is affected.

After delivery, extension of episiot-omy incisions and pelvic prolapseleading to urinary/faecal incontinencemay occur due to tissue fragility andextensibility. Treatment of symptomaticpelvic prolapse remains problematic inclassical EDS.

DIFFERENTIAL DIAGNOSIS

There are a large number of con-ditions reported to be amongst thedifferentials when a diagnosis ofclassical EDS is being considered.One paper specifically on classicalEDS gives a detailed description of18 differential diagnoses [Malfait et al.,2010]. Another highlights the need todistinguish hyperelastic skin from theredundant skin seen in cutis laxasyndromes and Menkes disease[Malfait and De Paepe, 2005].

A paper describing the differentialdiagnoses for connective tissue diseasesin general, mentions features similar tothose of classical EDS in four otherconditions [Murphy-Ryan et al., 2010]:

(1)
Cardiac-valvular EDS—In this condi-tion, patients sometimes present withthe skin and joints of classical EDS buthave an increased risk of cardiacvalvular complications and autosomalrecessive inheritance (see also“Ehlers–Danlos Syndromes,Rare Sub-types” by Brady et al., this issue).
(2)
Classical-like EDS due to completetenascin X deficiency—can presentwith a phenotype similar to classicalEDS but without the typical scarring,and with autosomal recessive inheri-tance (see also “Ehlers–Danlos Syn-dromes, Rare Subtypes” by Bradyet al., this issue).
(3)
Spondylodysplastic EDS due toSLC39A13 mutations—a rare reces-sive condition caused by mutations inSLC39A13, which presents withatrophic scarring similar to that seenin classical EDS, in addition to fragileskin which appears prematurely agedon hands and feet. Muscleatrophy, pes plans, postnatal growthdeficiency, and small jointcontractures are also characteristic[Giunta et al., 2008] (see also“Ehlers–Danlos Syndromes, RareSubtypes” by Brady et al., this issue).
(4)
Loeys–Dietz syndrome—which canpresent with a whole spectrum offeatures including the translucent andvelvety skin and joint laxity seen inclassical EDS, but also craniofacialfeatures and vascular tortuosity nottypical of cEDS. A review on the differential diag-
noses of joint hypermobility syndrome(JHS)/EDS hypermobile type (hEDS)includes classical EDS [Colombi et al.,2015]. In a small number of cases,patients with classical EDS and thosewith JHS/hEDS can present similarly. Inone study, two adult patients withconfirmed classical EDS were reportedto have no atrophic scars [Ritelli et al.,2013]. Another study reported hEDSpatients with hyperextensible skin[Castori et al., 2015].

Also to be included in the differen-tial diagnosis of classical EDS is thedermatosporatic type of EDS, which isan autosomal recessive disorder charac-terized by extreme skin fragility withcongenital or post-natal skin tears.Typically the skin is redundant, withexcessive palmar wrinkling and severebruisability with a risk of subcutaneoushematomas and haemorrhage Postnatalgrowth retardation with short limbs,hand and feet, which are not typicallyfeatures of cEDS, are seen in thedermatosporatic type (see also“Ehlers–Danlos Syndromes, Rare Sub-types” by Brady et al., this issue).

A review of case reports and patientseries reveals a number of incidenceswhere a clinical diagnosis of classical EDSwas altered after genetic testing identifiedan alternative diagnosis. In all cases, theyall involved mutations in type I collagen.


There are currently three reportedforms of type I collagen abnormalitythat can present with EDS features:

(1)
Cardiac valvular EDS—an autosomalrecessive condition caused by totalabsence of a2(1) collagen chain [DePaepe and Malfait, 2012]. The condi-tion was named because three patientswere reported to have aortic or mitralvalve requiring replacement surgery inadulthood [Schwarze et al., 2004]. Areview of all reported cases concludesthat loss of function mutations result ina phenotype similar to hEDS orclassical EDS but with cardiac valvedisease in adulthood while gain offunction mutations lead to a severe OIphenotype [Malfait et al., 2006] (seealso “Ehlers–Danlos Syndromes, RareSubtypes” by Brady et al., this issue).
(2)
“Classic EDS-like with a propensityfor arterial rupture”/“vascular-likeclassical EDS” are two names thathave been used for the conditioncaused by COL1A1 mutations involv-ing substitutions of arginine for cyste-ine. This condition can present asclassical EDS with an increased risk forarterial dissection [Malfait et al., 2007;Ritelli et al., 2013; Gaines et al., 2015].Three patients were described whohad arginine to cysteine substitutionsin the pro-alpha (l) collagen chain andone had presented as classical EDS[Malfait et al., 2007]. They suggestthat this shows the need to differentiateCOL1 patients (given the phenotypicsimilarity) as there is vessel fragility inpatients with COL1A1 arginine tocysteine mutations. The molecularcharacterization of 40 patients withclassical EDS showed that one patienthad a COL1A1 p.(Arg312Cys) muta-tion [Ritelli et al., 2013]. This patientwas reported to be similar to the otherclassical EDS patients except that hehad vascular involvement (see also“Ehlers–Danlos Syndromes, RareSubtypes” by Brady et al., this issue).
(3)
OI/EDS overlap syndrome.
Patients with mutations at theN-terminal end of both COL1A1 andCOL1A2, which are seen to affect theprocessing of the N-propeptide, can

present phenotypically as EDS ratherthan OI [Malfait et al., 2013]. This is incontrast to patients with mutations in thesame regionwhodonot showdelayed typeI procollagen N-propeptide processing onSDS–PAGE analysis, who present with anOI phenotype. The potential risk forvascular rupture associated with thesemutationsmeans theyneed tobediagnosedcorrectly, particularly given the clinicaloverlap. This again highlights the need toconsider type I collagen in patientspresentingwith EDS features. The authorsrecognized that the further work wasneeded to fully characterize this pheno-type, but suggest being aware of thepotential for vascular aneurysm or ruptureat ayoungage and recommendcautionandconsideration of the riskof vascular fragilityin event of surgical or other invasiveprocedures.

GENETIC COUNSELING

Classical EDS is inherited in anautosomal dominant pattern. Affectedindividuals have a 50% chance ofpassing on the condition in eachpregnancy. For siblings of an affectedperson it will depend on whether oneof the patents is also affected. If a parentis affected the other children will have a50% chance of being affected. Intra-familial variability has been reported[Burrows et al., 1996]. About 50% ofcases are thought to be de novo[Malfait et al., 2010]. If the parentsare unaffected there is a theoretical riskto the other children due to gonadalmosaicism, however, this has not yetbeen reported [Malfait et al., 2010].

Once the molecular cause is knownfor a patient, cascade testing is possible toconfirm or exclude the diagnosis inrelativeswhomayhave amilder phenotype[Ritelli et al., 2013]. Prenatal testing andpreimplantation genetic diagnosis are pos-sible once the mutation is known; how-ever, requests for these are not common forconditions that do not affect intellect or lifespan [Malfait et al., 2010].

Diagnostic Criteria

After review of the literature, andconsidering the clinical experience of

the authors, we recommend the follow-ing diagnostic criteria:

Major criteria

(1)
Significant skin hyperextensibility andatrophic scarring.
(2)
Generalized joint hypermobility.
Minor criteria

(1)
Easy bruising. (2) Soft, doughy skin. (3) Skin fragility (or traumatic splitting). (4) Molluscoid pseudotumours. (5) Subcutaneous spheroids. (6) Hernia (or history thereof). (7) Epicanthal folds. (8) Complications of joint hypermobility
(e.g., sprains, dislocation/subluxation,pain, pes planus).

(9)
Family history of a first degree relativewho meets clinical criteria.
Minimal criteria suggestive for a diagnosisof classical EDSMajor criteria (1)—Skin hyperextensi-bility and atrophic scarring

PlusEither: Major criteria (2)—generalizedjoint hypermobility

Or: three of the nine minor criteria

CommentsSkin is hyperextensible if it can bestretched over a standardized cut off inthe following areas: 1.5 cm for the distalpart of the forearms and the dorsum ofthe hands; 3 cm for neck, elbow andknees; 1 cm on the volar surface of thehand (palm).

Abnormal scarring can range inseverity. Most patients have extensiveatrophic scars at a number of sites. Aminority of patients are more mildlyaffected. The relevance of surgical scarsshould be considered with caution inclassical EDS, they can appear normal inpatients with classical EDS if well man-aged. Atrophic surgical scars can be foundin the general population due to mechan-ical factors and site of the incision.

Joint hypermobility (JHM) is eval-uated according to the Beighton score; a


Beighton score of >5 is consideredpositive for the presence of generalizedjoint hypermobility. Since joint hyper-mobility decreases with age, patientswith a Beighton score <5/9 may beconsidered positive based on theirhistorical observations.

Easy bruising can occur anywhereon the body, including unusual sites.The pretibial area often remains stainedwith hemosiderin from previous bruises.

Subjective abnormality of the skintexture is appreciable by touching the skin.

Molluscoid pseudotumors are fleshylesions associated with scars, found overpressure points (e.g., elbow, fingers).

Subcutaneous spheroids are smallspherical hard bodies, frequently mobileand palpable, on the forearms and shins.Spheroids may be calcified and detect-able radiologically.

Epicanthal folds are often seen inchildhood but may also be seen in adults.

Verification of clinical diagnosisConfirmatory analysis is recommendedfor any patient meeting the aboveclinical criteria.

Molecular analysis of COL5A1 andCOL5A2 genes identifies a causal muta-tion in more than 90% of the patients[Symoens et al., 2012;Ritelli et al., 2013].Molecular screening by means of targetedresequencing of a gene panel that includesat least the COL5A1, COL5A2, andCOL1A1 gene, or by WES or WGS isindicated. When no mutation is identi-fied, this approach should be comple-mented with a copy number variant(CNV) detection strategy to identify largedeletions or duplications.

If genetic testing is not available,electron microscopy findings of collagenflowers on skin biopsy can support theclinical diagnosis.

Absence of these confirmatoryfindings does not exclude the diagnosis;however, alternative diagnoses shouldbe considered in the absence of a type Vcollagen gene mutation or electronmicroscopy findings.

GAPS/FUTURE RESEARCH

A study of the management of vascularcomplications in EDS described 15

patients with clinical diagnoses of classi-cal EDS with two having thoracic aorticaneurysm repair and two having ab-dominal aortic aneurysm repair [Brookeet al., 2010]. The authors recognizedthat they were limited by reliance onclinical criteria for diagnosis whenbiochemical and genetic testing ismore accurate. The evidence thatCOL1 mutations have an increasedvascular risk raises this particular ques-tion for these patients. This highlightsthe benefit of molecular confirmation ofpatients for research purposes.

A large proportion of the currentliterature on patients that have hadmolecular testing focuses on con-firming the diagnosis, while theliterature on clinical features andmanagement is often not based onmolecularly characterized popula-tions. Further studies of associatedfeatures in confirmed classical EDSpatients is warranted. There are somerecent large patient reviews that havehelped to develop the understandingof classical EDS. There is hugepotential for research using theselarge patient groups with molecularlyconfirmed diagnoses.

Mutations in COL5A2 account fora relatively small number of cases. Asmore mutation analysis is carried out,genotype-phenotype correlations maybecome more apparent.

Large scale studies on vascular riskand cardiac features would aid manage-ment. A few cases studies may beskewing the data and further clarifica-tion of this would be helpful for patientswith type V collagen mutations. How-ever, it is clear that in the absence ofmolecular testing, the potential for atype I collagen mutation with anincreased risk of arterial rupture cannotbe ruled out.

Another question that would ben-efit from further research is whether alack of striae can be used as a goodindicator for classical EDS and help todirect molecular testing.

Literature is lacking on the fre-quency of dysautonomia, chronic fatiguesyndrome, gastrointestinal involvement,Chiari and cranio-cervical instability inthis patient population.

Pregnancy and delivery in classicalEDS is another area that would benefitfrom clear management guidelines.

More data are needed in regard tomild, persistent strength training inrelation to the treatment of the hypoto-nia seen in some cases of classical EDS.The role of fitness, exercise, andrehabilitation in the functional abilityand quality of life measure in those withclassical EDS is an area for furtherinvestigation.

Finally, there is a lack of goodprevalence and natural history data forclassical EDS.

SUMMARY

A diagnosis of classical EDS is indicatedby the well-described triad of hyper-extensible skin, atrophic scarring, andhypermobile joints. Although a set ofclinical criteria has predominated diag-nosis, other conditions do presentsimilarly. Confirmation of diagnosisinforms management and is vital forresearch purposes. Much of the earlyliterature on classical EDS is limited bythe lack of laboratory confirmation ofdiagnoses.

The diagnosis of classical EDS canbe confirmed by identifying the path-ogenic causative mutation in COL5A1or COL5A2. Molecular investigationsidentify mutations in the majority, butcurrently not all patients with a clinicalpicture compatible with the diagnosis.Where genetic confirmation has notbeen possible, a type V collagenabnormality can sometimes be demon-strated by the COL5A1 null allele test.Typical frequent collagen flowers onelectron microscopy (EM) of skin canbe a helpful diagnostic tool for classicalEDS, however, collagen flowers are notunique to this condition. Collagenflowers on EM should be an indicatorto test COL1A1 and COL1A2 whenclinical features of classical EDS arepresent in the absence of a COL5abnormality. Patients with a type 1collagen abnormality can present witha similar initial clinical appearance toclassical EDS, but they have a higherrisk of vascular events and needappropriate management.


The management advice for classi-cal EDS has remained consistent over anumber of years. There are now a largenumber of patients with molecularlyconfirmed classical EDS and theseprovide a basis for further research onmanagement. Further evidence on car-diac risks, skin care management, exer-cise potential, and associated featureswould aid the understanding and man-agement of the condition.

ACKNOWLEDGMENT

The authors wish to acknowledgeChristina Schwarting, representative ofDeutsche Ehlers Danlos Initiative e.V.for her input and support during thewriting of this manuscript.

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