differential diagnosis and diagnostic flow chart of joint

American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 169C:6–22 (2015)

A R T I C L E

Differential Diagnosis and Diagnostic Flow Chartof Joint Hypermobility Syndrome/Ehlers–DanlosSyndrome Hypermobility Type Compared toOther Heritable Connective Tissue DisordersMARINA COLOMBI, CHIARA DORDONI, NICOLA CHIARELLI, AND MARCO RITELLI

Marina ColoGenetics, Depathe Universityinclude heritabvarious book c

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Joint hypermobility syndrome/Ehlers–Danlos syndrome hypermobility type (JHS/EDS-HT) is an evolving andprotean disorder mostly recognized by generalized joint hypermobility and without a defined molecular basis.JHS/EDS-HT also presents with other connective tissue features affecting a variety of structures and organs, suchas skin, eye, bone, and internal organs. However, most of these signs are present in variable combinations andseverity inmany other heritable connective tissue disorders. Accordingly, JHS/EDS-HT is an “exclusion” diagnosiswhich needs the absence of any consistent feature indicative of other partially overlapping connective tissuedisorders. While both Villefranche and Brighton criteria include such an exclusion as a mandatory item, asystematic approach for reaching a stringent clinical diagnosis of JHS/EDS-HT is still lacking. The absence of aconsensus on the diagnostic approach to JHS/EDS-HT concerning its clinical boundaries with similar conditionscontribute to limit our actual understanding of the pathologic andmolecular bases of this disorder. In this review,we revise the differential diagnosis of JHS/EDS-HT with those heritable connective tissue disorders which show asignificant overlap with the former and mostly include EDS classic, vascular and kyphoscoliotic types,osteogenesis imperfecta, Marfan syndrome, Loeys–Dietz syndrome, arterial tortuosity syndrome, and lateralmeningocele syndrome. A diagnostic flow chart is also offered with the attempt to support the less experiencedclinician in stringently recognizing JHS/EDS-HT and stimulate the debate in the scientific community for bothmanagement and research purposes. © 2015 Wiley Periodicals, Inc.

KEY WORDS: joint hypermobility syndrome; Ehlers–Danlos syndrome hypermobility type; differential diagnosis; heritable connective tissuedisorders; diagnostic flow chart

How to cite this article: Colombi M, Dordoni C, Chiarelli N, Ritelli M. 2015. Differential diagnosis anddiagnostic flow chart of joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type

compared to other heritable connective tissue disorders. Am J Med Genet Part C 169C:6–22.

mbi is full professor of Medical Genetics at the School of Medicine, University of Brescia and Director of the Division of Biology andrtment ofMolecular and TranslationalMedicine, and of the Postgraduate School ofMedical Genetics. She has various responsibilities atof Brescia with focus on clinical genetics of rare diseases and genetic laboratory testing. Her major diagnostic and research interestsle connective tissue disorders, genodermatoses, and their pathomechanisms. She is author of 90 papers in international journals andhapters.oni is a M.D. resident in Medical Genetics at the School of Medicine, University of Brescia. She has a full-time involvement in the clinicalctivity of the Division of Biology and Genetics, Department of Molecular and Translational Medicine. Her interests mostly includeective tissue disorders.elli is a biologist, Ph.D., and resident in Medical Genetics at the School of Medicine, University of Brescia. He has a full-time involvementand diagnostic activity of the Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of

erests mostly include the molecular characterization of patients affected with heritable connective tissue disorders and the study of thesms of these rare diseases.i is a biologist with residency in Medical Genetics at the School of Medicine, University of Brescia. He has a full-time involvement inresearch activity of the Division of Biology and Genetics, Department of Molecular and Translational Medicine. His interests mostlylecular characterization of patients affected with heritable connective tissue disorders and the study of the pathomechanisms of thesee is author of 30 papers in international journals, most of them on Ehlers–Danlos syndrome and related disorders.funding was active on this project.

nterest: The authors have no conflicts of interest to declare.dence to: Marina Colombi, Ph.D., Division of Biology and Genetics, Department of Molecular and Translational Medicine, School ofersity of Brescia, Viale Europa 11, I-25123 Brescia, Italy. E-mail: [email protected]/ajmg.c.31429published online in Wiley Online Library (wileyonlinelibrary.com).

ey Periodicals, Inc.

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 7

INTRODUCTION

Joint Hypermobility Syndromeand Ehlers-Danlos SyndromeHypermobility Type(JHS/EDS-HT)

Joint hypermobility syndrome (JHS)and Ehlers–Danlos syndrome hyper-mobility type (EDS-HT) (OMIM#130020) are two markedly overlap-ping heritable connective tissue disor-ders (HCTDs), which are recentlyconsidered as the same nosologic entity[Beighton et al., 1998; Grahame et al.,2000; Tinkle et al., 2009; Castori et al.,2014]. EDS-HT (estimated prevalence1:5,000–15,000) reported in the lastEDS classification, i.e., the Villefranchenosology (Table I), shows an autosomaldominant inheritance, and it is definedby the association of two major criteria,i.e., generalized joint hypermobility(JHM), and smooth, velvety, poorlyhyperextensible skin. Recurring jointdislocations, chronic joint/limb pain,and positive family history are minordiagnostic criteria (Table I) [Beightonet al., 1998]. EDS-HT is the mostcommon disorder belonging to theexpanding group of EDS, and togetherwith Marfan syndrome (MFS) is themost frequent HCTD known so far.Nevertheless, in contrast to the otherEDS variants, its molecular basis re-mains unknown [Castori et al., 2014;Malfait and De Paepe, 2014]. JHS,originally considered a condition dis-tinct from EDS-HT, is assessed byBrighton criteria [Grahame et al.,2000], which consider JHM and itscomplications (pain, dislocations) andother skin, ocular, soft tissue signs ofconnective tissue involvement(Table II). The further set of diagnosticcriteria proposed by Levy [2004]includes additional features not previ-ously considered, i.e., functional boweldisorders, neurally mediated hypoten-sion or postural orthostatic tachycardia,high narrow palate and dental crowd-ing. In the last years JHS/EDS-HT hasemerged as a multisystemic diseaseassociated with a wide inter- andintrafamilial variability with mucocu-taneous [Castori, 2012 Castori et al.,

2015], skeletal [Castori, 2012], cardi-ovascular [Camerota et al., 2014],gastrointestinal [Zarate et al., 2010;Danese et al., 2011], gynecological[Castori et al., 2012a], neurological[Voermans et al., 2009; Garcia Cam-payo et al., 2011; De Wandele et al.,2014], and psychiatric manifestations[Pasquini et al., 2014] (Table III).

Joint Hypermobility (JHM)

JHM is still the most clinically relevantfeature of JHS/EDS-HT. It refers to theability to actively and/or passively movethe joints beyond normal limits[Beighton et al., 1973]. JHM may affecta few joints (i.e., monoarticular orlocalized JHM) or several joints inmultiple body sites (i.e., generalizedJHM). JHM can be directly assessedusing the Beighton score (BS), a nine-point evaluation (Beighton et al., 1973;Fig. 1). In patients without JHMaccording to the BS, a 5-point ques-tionnaire is available to investigatehistorical JHM [Grahame et al., 2000;Hakim and Grahame, 2003; Tinkleet al., 2009] (Table II). JHM is a sign,not a disease, and its occurrence varies byage, sex, and ethnicity. In fact, themajority of hypermobile individualsare asymptomatic, and loose joints aremore common among females andchildren than males and older people[Beighton et al., 1973]; lastly, even someoccupational and sport activities maynaturally improve JHM [Castori, 2012].In JHS/EDS-HT generalized JHMcontributes to generate various ortho-pedic complications, which includeincreased tendency to recurrent gener-alized dislocations, widespread chronicpain, soft-tissue lesions (i.e., bursitis,tenosynovitis) and pes planus [Castoriet al., 2010a; Castori, 2012].

JHS/EDS-HT Natural History

The natural history of JHS/EDS-HT ischaracterized by a progressiveworseningof the phenotype, usually mild in theinfancy and more severe in the adult-hood [Castori et al., 2010a, 2013]. Theexistence of two distinct sets of diag-nostic criteria for JHS/EDS-HT prob-

ably reflects the natural history within asingle condition, which may have differ-ent clinical presentations at various ages[Tinkle et al., 2009; Castori et al., 2014].Indeed, the diagnostic criteria for JHS/EDS-HT reported by the Villefranchenosology [Beighton et al., 1998] areadequate for children and young adultsevaluation, whereas the Brighton cri-teria, considering the natural progressiveloss of joint mobility by age, are moresuitable to assess adults [Grahame et al.,2000; Tinkle et al., 2009; Castori,2013a].

Diagnosis and DifferentialDiagnosis of JHS/EDS-HT

To date, the diagnosis of JHS/EDS-HTis clinical and based on the agreement oflargely accepted diagnostic criteria to-gether with the exclusion of otherpartially overlapping HCTDs. No in-strumental, histopathologic/ultrastruc-tural, and molecular finding isconsidered pathognomonic of this dis-order. Assessment of JHS/EDS-HT layson accurate clinical history taking andextensive physical examination, includ-ing dermatologic, oral cavity, orthope-dic, and neurologic evaluations [Castori,2013a].

The wide clinical variability ofJHS/EDS-HT identifies a great numberof partially overlapping acquired andgenetic disorders showing the variableassociation of mucocutaneous fragility,JHM, chronic musculoskeletal pain, andfatigue. Among them, there are otherHCTDswith JHM, the “battered child”syndrome, bleeding disorders, develop-mental coordination disorder, and var-ious rheumatologic conditions withchronic musculoskeletal pain, such asankylosing spondylitis, rheumatoid ar-thritis, and fibromyalgia. Some neuro-logic disorders, including multiplesclerosis, amyotrophic lateral sclerosis,hereditary and acquired sensory-motorand/or autonomic polyneuropathies,and chronic fatigue syndrome, as wellas myopathies featuring JHM have to beconsidered [Castori, 2012, 2013a].Among the various HCTDs sharingsome musculoskeletal features withJHS/EDS-HT, there is the growing

TABLEI.

TheVillefran

cheCriteriafortheHistoricalEDSTyp

es[B

eigh

tonet

al.,1998]an

dtheUnderlyingMolecu

larDefect

EDStype

Major

criteria

Minor

criteria

Gene(s)

Classic

AD

OMIM

#130000,

#130010

Skinhyp

erex

tensibilitya

Widen

edatrophic

scars

JHM

Smoo

th,velvetyskin

Mollu

scoid

pseudotumors

Subcutaneous

spheroids

Com

plications

ofJH

M(e.g.,sprains,dislo

catio

ns/sub

luxatio

ns,pesplanus)

Musclehypo

tonia,delayedgrossmotor

developm

ent

Easybruisin

gManifestations

oftissuefragility

(e.g.,hiatalhernia,analprolapse

inchildho

od,

cervicalinsufficiency)

Surgicalcomplications

(postoperativehernias)

Positivefamily

history

COL5A

1COL5A

2

Hyp

ermobility

AD

OMIM

#130020

Skin

involvem

ent(hyperextensibility

and/or

smoo

th,velvetyskin)

Generalized

JHM

Recurring

jointdislo

catio

nsChronic

joint/limbpain

Positivefamily

history

?

Vascu

lar

AD

OMIM

#130050

Thin,

translu

cent

skin

Arterial/intestinal/u

terinefrag

ilityorrupture

Exten

sive

bruising

Characteristic

facialappearance

Acroge

ria

Hypermob

ility

ofsm

alljoints

Tend

onandmusclerupture

Talipesequinovarus(clubfoo

t)Early-onset

varicose

veins

Arterioveno

us,carotid

-caverno

ussin

usfistula

Pneu

mothorax/

pneu

mohem

othorax

Gingivalrecession

Positivefamily

history,sudden

death

in(a)close

relative(s)

COL3A

1

Kyp

hoscoliotic

AR

OMIM

#225400

Generalized

JHM

Severe

musclehypo

toniaat

birth

Sco

liosisat

birth,progressive

Scleral

frag

ilityan

drupture

oftheocu

larglobe

Tissue

fragility,includ

ingatroph

icscars

Easybruisin

gArterialrupture

Marfanoid

habitus

Microco

rnea

Radiologically

considerable

osteop

enia

Family

history,i.e.,affected

sibs

PLOD1

Arthroch

alasia

AD

OMIM

#130060

Severe

generalized

JHM,with

recurrentsublux

ations

Conge

nital

bilateral

hip

dislocation

Skin

hyperextensib

ility

Tissue

fragility,includ

ingatroph

icscars

Easybruisin

gMusclehypo

tonia

Kypho

scoliosis

Radiologically

mild

osteop

enia

COL1A

1COL1A

2

8 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

TABLEI.

(Continued)

EDStype

Major

criteria

Minor

criteria

Gene(s)

Dermatosparax

isAR

OMIM

#225410

Severeskin

frag

ility

Sag

ging,

redundan

tskin

Soft,

doughy

skin

texture

Easybruisin

gPremature

rupture

offetalmem

branes

Large

hernias(umbilical,ingu

inal)

ADAMTS2

a Itemsin

bold

aredistinguish

ingfeatures

oftheparticular

EDStype.


group of the other EDSs, MFS, Loeys–Dietz syndrome (LDS), arterial tortuos-ity syndrome (ATS), milder forms ofosteogenesis imperfecta (OI), and lateralmeningocele syndrome (LMS) [Calle-waert et al., 2008a,b; Castori et al.,2013b; Malfait and De Paepe, 2014; VanDijk and Sillence, 2014; Van Laer et al.,2014]. The clinical overlap of JHS/EDS-HTwith these HCTDs, its evolv-ing and variable phenotype, and theabsence of the causal gene(s) make thediagnostic process difficult. This diffi-culty is hampered in pediatric patientswithout a complete manifestation of thespecific disorder by which they areaffected [Tofts et al., 2009]. JHS/EDS-HT often becomes the “default” diag-nosis either of a hypermobile child or anadult who does not meet the criteria fordiagnosis of one of the other HCTDs.Therefore, the JHS/EDS-HT is prob-ably a heterogeneous group and partic-ularly in pediatric patients the evaluationof parents and relatives should beconsidered, as well as the opportunityof genetic testing for other HCTDswithknown molecular basis, which mightaddress, by exclusion or confirmation, acorrect diagnosis. In this review, we willfocus on the differential diagnosis ofJHS/EDS-HTwith the other EDS typesand with HCTDs with JHM, cutane-ous, skeletal, vascular, and internalorgans overlapping manifestations andwill delineate a flow chart for a clinicaldiagnostic approach to JHS/EDS-HTpatients.

DIFFERENTIAL DIAGNOSISWITH OTHER EDS TYPESINCLUDED IN THEVILLEFRANCHENOSOLOGY

EDS needs to be considered when, inthe absence of another explanation, oneor more of the following manifestationsoccurs: (i) late walking with jointhypermobility, (ii) abnormal bruisingand bleeding, (iii) tissue fragility, atro-phic scarring or skin hyperextensibility,(iv) symptomatic joint hypermobilitywith or without dislocations, (v) un-explained vessel rupture or dissection,(vi) internal organ rupture [Sobey,

2014]. Although EDS variants show anextensive clinical overlap, the Ville-franche nosology identifies distinctivefeatures for the six historical forms,considered as major or minor clinicalcriteria for inclusion (Table I). Themajor specific criteria can be all presentor not and their combination withminor features suggests the diagnosis ina large majority of the cases. For therecently characterized EDS forms(Table IV) established diagnostic criteriaare not available, also due to the rarity ofthe patients. For all of the EDS variantsthe connective tissue signs are increasingas far as new patients are investigated andreported, and nowadays the clinicalpicture of EDSs is more puzzling thandepicted by the Villefranche nosology.JHS/EDS-HT is a clear example of thisexpanding knowledge (Table III). Be-sides JHS/EDS-HT, the other morefrequently observed EDS types are, indecreasing order, the classic, vascular,and kyphoscoliotic types. The arthro-calasia and the dermatosparaxis types areinfrequently observed entities. Derma-tosparaxis is clearly distinguishable fromJHS/EDS-HT (Table I) and is notconsidered in the differential diagnosis.

EDS Classic Type

JHS/EDS-HThas a great clinical overlapwith EDS classic type (cEDS) since theyboth share cutaneous and articular signsand their complications (Table I). How-ever, the high skin hyperextensibilitytogether with widened atrophic/papyra-ceous scars, and, more rarely, molluscoidpseudotumors, are more remarkable anddistinctive of cEDS [Ritelli et al., 2013](Table I). In fact, in JHS/EDS-HT skin isusually poorly hyperextensible and pap-yraceous scars and molluscoid pseudo-tumors are absent. Small atrophic scarsare observed in 1/4 of JHS/EDS-HTcases and orthopedic post-surgical atro-phic scars are also present in 1/4 of thesubjects, generally adults [Castori et al.,2015]. In a few cases, cEDS and JHS/EDS-HT may share similar cutaneouspresentations and cEDS patients withoutatrophic scars (5% of the cases), or withsmall atrophic scars [Ritelli et al., 2013],as well as JHS/EDS-HT patients with

TABLE II. Brighton Criteria for Assessing JHS and 5-Point Questionnaire for Historical JHM

Brighton criteria for JHS 5-point questionnaire for JHM

Major criteriaBeighton score �4/9Arthralgia for >3 months in >4 jointsMinor criteriaBeighton score 1–3Arthralgia in 1–3 jointsHistory of joint dislocationsSoft tissue lesions >3Marfan-like habitusSkin striae, hyperextensibility, or scarringDownslanting palpebral fissures, lid laxity, myopiaHistory of varicose veins, hernia, visceral prolapse

1. Could you ever place your hands flat on the floorwithout bending your knees?2. Could you ever bend your thumb to touch yourforearm?3. As a child did you amuse your friends bycontorting your body into strange shapes ORcould you do the splits?4. As a child or teenager did your shoulder orkneecap dislocate on more than one occasion?5. As a child or teenager did you consider yourselfdouble-jointed?

Agreement: both major, or 1 major and 2 minor, or4 minor criteria. Criteria major 1 and minor 1 aremutually exclusive as/are major 2 and minor 2.

Agreement: affirmative answer for two or morequestions.

Source: Grahame et al., [2000] and subsequentmodifications (see, for example, Tinkle et al.,[2009]).

Source: modified from Hakim and Grahame [2003].


marked hyperextensible skin are re-ported. In these patients, the carefulinvestigation of affected familymembers,possibly showing cEDS-like scars, andthe molecular analysis of the cEDS causalgenes, i.e., COL5A1 and COL5A2,allows for the distinction of cEDS fromJHS/EDS-HT patients [Ritelli et al.,2013]. JHS/EDS-HT remains an exclu-sion diagnosis for the absence of knowncausal gene(s). Concerning articularinvolvement, cEDS patients suffer fromchronic and/or generalized joint pain;however, in the majority of the cases itdoes not need chronic pharmacologicaltreatment [Ritelli et al., 2013]. In cEDSand in the other EDS forms chronic painmight be underestimated. In a very fewpatients with hyperextensible skin, atro-phic scarring, easy bruising, and JHM,propensity for arterial rupture at adult ageis present [Malfait et al., 2007; Ritelliet al., 2013] (Table IV). These patients,defined as vascular-like cEDS individu-als, typically carry arginine to cysteinesubstitution in the pro-a1(1) collagenchain.

EDS Vascular Type

JHS/EDS-HT is clearly distinguishablefrom the EDS vascular type (vEDS)

(Table I) for the vascular, skin, andinternal organs fragility, and for thecharacteristic facial appearance, i.e.,triangular face with sunken and largeeyes, thin lips and philtrum, small chin,and thin nose present in some patients.Generalized vascular fragility largelydominates the clinical picture of thislife-threatening condition, indeed themajority of vEDS patients (�80%within 40 years) experienced a majorvascular events (i.e., spontaneous aorticdissection or dissection of a previouslyaneurysmatic aorta), potentially result-ing in sudden death. Hence, in adult-hood vEDS patients commonly receivea diagnosis after referral to emergencysurgeons for vascular dissection/rupture[Pepin et al., 2000;Oderich et al., 2005].In JHS/EDS-HT aortic dissections areextremely rare, and aortic root ectasia isobserved with an overall incidence ofapproximatively 12% without an in-creased risk of dissection [Atzinger et al.,2011]. In vEDS visceral rupture (i.e.,bowel, lungs, liver, spleen, uterus duringpregnancy, heart) may also occur forinternal organs fragility [Drera et al.,2011; Murray et al., 2014]; in JHS/EDS-HT internal organs rupture is notreported, whereas visceroptosis due toligaments hypoplasia and deterioration

may be present (Table II) [Dordoni et al.,2013]. The fragility of the capillaries andof the perivascular connective tissues canlead to easy bruising with ecchymosis forminimal traumas both in vEDS andJHS/EDS-HT patients, though thesefeatures are more prominent in vEDS[De Paepe and Malfait, 2004]. In fact, inchildhood vEDS patients are usuallyreferred to pediatricians for the presenceof frequent ecchymosis and “batteredchild” syndrome can be considered asdifferential. Concerning cutaneoussigns, in vEDS skin is not hyperexten-sible but rather thin, transparent/trans-lucent, sometimes showing a visiblevenous pattern over the chest, abdomenand extremities, and fragile with mildatrophic scarring. Acrogeria can beobserved in patients harboring specificmutations in COL3A1 [Drera et al.,2011]. JHM in vEDS generally involvessmall joints, but can be generalized insome patients. The few vEDS patientswith generalized JHM and withoutmajor vascular events or internal organrupture may partially overlap with theJHS/EDS-HT phenotype; in thesecases, the presence of thin skin, visiblevenous network, acrogeria, vascularimaging diagnostic for arterial aneur-ysm, and positive family history for

TABLE III. Clinical spectrum of JHS/EDS-HT

System/apparatus Clinical finding Reference

Mucocutaneous Mildly hyperextensible skinVelvety/silky/soft skin textureStriae rubrae and/or distensae in young ageSmall or post-surgical atrophic scars (non-papyraceous)Keratosis pilarisInguinal/umbilical/incisional herniaLight blue scleraeGingival inflammation/recessionsHypoplastic lingual frenulumEasy bruisingResistance to local anaesthetic drugs

Beighton et al., [1998]Castori, [2012]Castori, [2013]Castori et al., [2015]Wiesmann et al., [2014]

Osteoarticular Generalized joint hypermobilityRecurrent dislocations (mostly at hips, shoulders,temporomandibular joint, fingers, and vertebrae)Recurrent soft-tissue lesions (bursitis, tendonitis,synovitis, tenosynovitis, and fasciitis)Temporomandibular joint dysfunctionChronic /recurrent not inflammatory joint painChronic generalized painMuscular/myofascialneuropathic/osteoarthriticEarly osteoarthritis

Beighton et al., [1998]Levy, [2004]Castori et al., [2010a]

Orthopedic High arched/narrow palateFlat footNot surgical pectus excavatumMild scoliosis, dorsal hyperkyphosis, lumbar hyperlordosisGenua, halluces, and cubita valgaMinor asymmetry at lower limbs and other body areasNon-postmenopausal reduced bone massMarfanoid habitus (i.e., arm span/height ratio >1.03, arachnodactyly)

Beighton et al., [1998]Grahame et al., [2000]Gulbahar et al., [2006]Castori, [2012]

Muscular Hypotonia of mild degreeRecurrent myalgias and crampsFibromyalgiaMyofascial painInvoluntary muscle contractionsReduced muscle power (rare)

Castori, [2012]Voemans et al., [2009]

Gastrointestinal Dysphagia and dysphoniaGastroesophageal refluxHiatal herniaChronic/recurrent gastritisDelayed gastric emptyDefecatory dysfunctionDelayed small bowel and colonic transitUnexplained abdominal painVarious food intolerancesVisceroptosis

Castori et al., [2010]Danese et al., [2011]Dordoni et al., [2013]Zarate et al., [2010]

Cardiovascular Valvular regurgitation with mild hemodynamic involvementMitral valve prolapse/insufficiencyVaricose veinsLow progressive aortic root dilatationRaynaud’s phenomenon/acrocyanosis/livedo reticularis

Atzinger et al., [2011]Camerota et al., [2014]De Wandele et al., [2014]

Uro-gynecological Meno/metrorrhagiasDisabling dysmenorrhea

Castori et al., [2012a]

(Continued)


TABLE III. (Continued)

System/apparatus Clinical finding Reference

Pelvic prolapseDyspareuniaUrinary stress incontinence

Neuropsychiatric Chronic fatigue (syndrome)Sleep disturbancesImpaired memory and concentrationHeadache and migraineRecurrent paresthesiasCardiovascular dysautonomia (e.g., postural orthostatictachycardia syndrome, neuromediated hypontension)Somatosensory/central sensitizationClumsinessAnxiety, panic, and fearsDepressionObsessive-compulsive disorder

Rombaut et al., [2010]Castori, [2012]Granata et al., [2013]De Wandele et al., [2014]Neilson et al., [2014]Pasquini et al., [2014]

Ocular Myopia and/or strabismusPalpebral ptosis

Castori, [2012]


arterial dissection in young age cansupport the diagnosis. Molecular anal-ysis ofCOL3A1 can confirm or excludethis diagnosis.

EDS Kyphoscoliotic Type

JHS/EDS-HT is distinguishable fromthe kyphoscoliotic type of EDS (kEDS)(Table I) for the recessive inheritance,the presence of early onset progressivekyphoscoliosis, neonatal thoracic sco-liosis, and severe muscular hypotoniawith delayed gross motor development,osteopenia, microcornea, and in somepatients scleral fragility with risk forrupture of the globe, and occurrence oflife-threatening rupture of medium-sized arteries [Rohrbach et al., 2011].Features common to kEDS and JHS/EDS-HT are mainly cutaneous, i.e.,fragile, hyperextensible, and bruisableskin with atrophic scarring, articular,i.e., generalized JHM, and skeletal. Thediagnosis of kEDS relies on the dem-onstration of an increased ratio ofdeoxypyridinoline to pyridinolinecrosslinks in urine, caused by deficientactivity of lysyl hydroxylase 1, theenzyme encoded by PLOD1. Alterna-tively, an assay of lysyl hydroxylaseenzyme activity in skin fibroblasts isdiagnostic. Mutations in PLOD1 arecausative [Rohrbach et al., 2011].

EDS Arthrochalasia Type

The arthrochalasia type of EDS (aEDS)is characterized by severe generalizedJHM and bilateral congenital hip dis-location (CHD) (Table I). GeneralizedJHM is shared as a major feature withJHS/EDS-HT; CHD can be also ob-served in JHS/EDS-HT patients, but itis not a major sign and in most cases isunilateral (our unpublished data). Othersigns distinguishing aEDS from JHS/EDS-HTare marked hypotonia at birth,short stature, and wormian bones[Klaassens et al., 2012]. Hence, bilateralCHD in patients with extreme JHM andsignificant hypotonia at birth suggestsaEDS andmolecular testing for a specificset of COL1A1 and COL1A2 muta-tions, involving their exons 6 splicejunctions, can confirm the diagnosis. Inpatients without a causal mutationclinical diagnosis of JHS/EDS-HT hasto be considered searching for cardio-vascular, gastrointestinal, gynecological,and neurological signs (Table III), whichat the moment are not reported in aEDSpatients.

DIFFERENTIAL DIAGNOSISWITH RARE EDS TYPES

Concerning the rare EDS forms notincluded in the Villefranche nosology,

detailed phenotypes are reported for thefew patients so far characterized(Table IV). The major cause of thehistorical EDSs appears to be impairedbiosynthesis and enzymatic modificationof the three main fibrillar collagens, butEDSs are also associated with proteogly-can abnormalities (the progeroid and themusculocontractural types of EDS), aswell as with alteration of an endoplasmicreticulum folding protein (EDS withprogressive kyphoscoliosis, myopathyand hearing loss), of transcription factors(Brittle cornea type 1 and 2), and of a zinctransporter (spondylocheirodysplasticEDS). This heterogeneity of causesinvolving several systems leads to thevariety of distinguishable phenotypesreported in Table IV. On the otherhand, since the genes involved in thisgrowing number of EDS types encodefor components or regulators of theconnective tissue extracellular matrix,common features are present in thedifferent variants which have to beconsidered in differential diagnosis withJHS/EDS-HT, especially for their artic-ular and cutaneous signs (Table IV)[Malfait and De Paepe, 2014; Miyakeet al., 2014; Sobey, 2014]. In particular,JHS/EDS-HT shows a marked overlapwith a small subset of patients withhomozygous /compound heterozygousTNXB mutations (TNX-deficient

Figure 1. Assessment of joint hypermobility with the Beighton score: (a) passive dorsiflexion of the fifth metacarpophalangeal joint to�90°, (b) opposition of the thumb to the volar aspect of the ipsilateral forearm, (c) hyperextension of the elbow to �10°, andhyperextension of the knee to�10°, d) placement of hands flat on the floor without bending the knees (Figure drawn by L. Manenti). TheBeighton score is incorporated into the diagnostic criteria for EDSs, MFS, LDS, ATS, and OI.


patients), but also with the heterozygouscarriers of mutations leading to TNXBhaploinsufficiency, including a recurrent30 kb deletion involving TNXB andCYP21A2 [Schalkwijk et al., 2001;Zweers et al., 2003], therefore suggestingthat the EDS phenotype associated withTNX-deficiency is a dose-dependentphenomenon. The patients with the30 kb deletion in homozygosity [Burchet al., 1997], or in compound hetero-zygosity with a second CYP21A2muta-tion [Mercke et al., 2013], also presentwith congenital adrenal hyperplasia(CAH). In patients with CAH andTNXBhaploinsufficiency (CAH-Xsyn-drome), mainly due to the recurrent30 kb deletion, JHM is the predominantclinical feature, in addition to variablefindings including joint dislocations,chronic joint pain, and soft tissue lesions[Mercke et al., 2013]. Therefore, inpatients with JHM and CAH thepresence of the 30 kb TNXB deletionshould be investigated. Patients withcomplete TNX-deficiency show amarked cEDS overlapping phenotypewithout atrophic scarring [Schalkwijket al., 2001], whereas TNXB haploin-sufficiency, without concomitant CAH,

results in JHS/EDS-HT phenotype[Zweers et al., 2003; Mercke et al.,2013]. Recently, it is emerging thatTNX-deficient patients also suffer frommyopathy, generalized muscle weakness,and possible distal contractures in adultage [Pénisson-Besnier et al., 2013; Voer-mans et al., 2014]. Myopathic pattern atelectromyography is observed also insome JHS/EDS-HT patients who com-plain of neuromuscular symptoms, i.e.,muscle cramps and myalgia, and in otherEDS variants, i.e., musculocontracturaltype 1 and type 2 EDS, progressivekyphoscoliosis, myopathy and hearingloss EDS, and progeroid type 1 and type 2EDS (Tables I, III, and IV) [Voermanset al., 2009; Baumann et al., 2012]. SinceJHM secondary to muscle hypotonia incombination with cutaneous features isalso observed in Ullrich congenitalmuscular dystrophy, and in the allelicBethlem myopathy [Voermans et al.,2008], also these myopathies have to beconsidered in the differential with JHS/EDS-HT, especially in pediatric patients.

The periodontitis EDS type isdistinguished for the severe periodontaldisease characterized by irreversible de-struction of the periodontal tissues

(periodontal ligament, alveolar bone,and connective tissue) leading to pre-mature loss of teeth, associatedwith JHMand atrophic scars [Reinstein et al.,2013]. For this heterogeneous disorderthe molecular basis is still unknown.Periodontal disease is common also inJHS/EDS-HT patients, but true paro-dontopathy with early tooth loss is rarelyobserved, whereas gingival fragility andinflammation causing bleeding, retrac-tion, and impaired oral cleansiness arecommon [Castori, 2012]. Otherwise,gingival mucosal fragility is not a specificsign of JHS/EDS-HT, as it is found inabout 74% of the EDS populationwithout any significant difference be-tween the most prevalent subtypes, i.e.,cEDS, JHS/EDS-HT, and vEDS [DeCoster et al., 2005]. Instead, dentindefects, i.e., abnormal pulp shape andpulp stones, appear to bemore specific ofcEDS or vEDS, and it was neverdescribed in JHS/EDS-HT [De Costeret al., 2005; Ferrè et al., 2012]. Gingivalregression was considered a minorVillefranche criterion for vEDS; how-ever, recent evidences suggested that it isinappropriate for its low frequencyamong vEDSpatients [Ferrè et al., 2012].

TABLE IV. EDS Forms Not Included in the Villefranche Nosology with the Clinical Features and the Involved Genes

EDS variant Feature Gene(s) Reference

Classic vascular-likeAD

Hyperextensible skinAtrophic scarringEasy bruisingJHMPropensity for arterial rupture at adult agea

COL1A1 Malfait etal., [2007]Ritelli etal., [2013]

Cardiac valvularAROMIM #225320

Severe mitral valve regurgitation/insufficiencyArrhythmia, atrial fibrillation and septal defect, leftventriculum enlargementJHMSkin hyperextensibility

COL1A2 Schwarzeet al.,[2004]

Tenascin-X deficiencyAROMIM #606408

Marked skin hyperextensibilityNormal scarringGeneralized JHMSevere easy bruising

TNXB Schalkwijket al.,[2001]Pénisson-Besnier etal., [2014]Voermanset al.,[2014]

EDS/OI overlapAD

Short statureBlue scleraeMild signs of bone fragilityOsteopeniaInfrequent fracturesGeneralized JHMSkin hyperextensibilityAtrophic/hypertrophic scarsEasy bruisingSigns of vascular fragilityValvular regurgitation

COL1A1COL1A2

Malfaitand DePaepe,[2014]

PeriodontitisADOMIM #130080

Gingival recessionsPeriodontitisPremature loss of permanent teethAlveolar bone resorption by the IIIrd decadeAtrophic scarsJHMUmbilical herniaArachnodactyly

LocusheterogeneityUnknowngenes

Reinsteinet al.,[2013b]

Musculocontracturaltype 1/D4ST1 deficiencyAROMIM #601776

Congenital contractures of thumbs and fingersCraniofacial dysmorphismsBlue scleraeMicrocorneaClubfootArachnodactylySevere kyphoscoliosisMuscle hypotoniaJHMHyperextensible skinAtrophic scarsEasy bruisingWrinkled palms

CHST14 Malfait etal., [2010]

Musculocontractural Joint dislocations and deformity DSE Müller et


TABLE IV. (Continued)


type 2AROMIM #615539

Hyperextensible fragile skinAtrophic scarringEasy bruisingMuscle hypoplasiaGross motor development delayFacial dysmorphismsArachnodactylyAdducted thumbsClubfootInguinal herniaGeneralized mild cerebral atrophy

al., [2013]

With progressivekyphoscoliosis,myopathy and hearinglossAROMIM #614557

Severe hypotonia and weakness at birthHyperextensible skinJHMSevere progressive scoliosisSensorineural hearing impairmentMyopathyVascular dissection

FKBP14 Baumannet al.,[2012]

Brittle cornea syndrometype 1AROMIM #229200

Blue scleraeCorneal ruptureKeratoconus/keratoglobusSkin hyperextensibilityJHM

ZNF469 BurkittWright etal., [2013]

Brittle cornea syndrometype 2AROMIM #614170

Corneal ruptureMicrocorneaCornea planaKeratoconus/keratoglobusMyopiaHyperextensible skinEasy bruisingJHM (localized)Pectus excavatumScoliosisMitral valve prolapseHearing loss (conductive and sensorineuraldeafness)

PRDM5 BurkittWright etal., [2011,2013]

SpondylocheirodysplasiaEDS-likeAROMIM #612350

Short statureProtuberant eyesBlue scleraeHyperextensible skinEasy bruisingJHMHands with wrinkled palmsTenar muscles atrophyTapering fingersSpondyloepiphyseal dysplasia

SLC39A13 Giunta etal., [2008]

Progeroid type 1AROMIM#130070

Aged appearanceShort statureForearm bones and elbow anomalies, radioulnarsynostosesBowing of the extremitiesFacial dysmorphismsHyperextensible skin

B4GALT7 Guo etal., [2013]


TABLE IV. (Continued)


Atrophic/papyraceous scarsJHMPes planusDevelopmental delayMuscle hypotonia

Progeroid type 2/Spondyloepimetaphysealdysplasia with jointlaxity type 1AROMIM #615349OMIM #271640

Aged appearanceDevelopmental delayDisproportionate short statureCraniofacial disproportionGeneralized severe osteopeniaDefective wound healingHyperextensible skinJHMMuscle hypotoniaSpondyloepimetaphyseal dysplasia

B3GALT6 Nakajimaet al.,[2013] Malfaitetal., [2013]Ritelli etal., [2015]

AD, autosomal dominant; AR, autosomal recessive.aItems in bold are distinguishing features of the particular EDS type.


In the rare spondylocheirodysplasia-likeand progeroid type 1 and 2 EDSvariants, JHM and hyperextensibleskin are associated with skeletal dyspla-sia, including moderate to severe dis-proportionate short stature,pathognomonic bone deformities,and/or severe kyphoscoliosis with pla-tyspondyly. Since short stature andevident bone deformities are absent inJHS-EDS-HT, differential diagnosis be-tween these conditions is straightfor-ward; skeletal and spine radiography canclassify bone and vertebral alterations,reinforcing clinical diagnosis of theseEDS types with skeletal dysplasia. InJHS/EDS-HT skeletal alterations in-clude moderate scoliosis and platyspon-dyly, leg length discrepancy, genua valga,hallux valgus, as well as early onsetosteopenia [Castori, 2012; our unpub-lished data]. These skeletal signs, ob-served also in other EDS, f.e., cEDS[Ritelli et al., 2013], are not specific ofJHS/EDS-HT and are not useful indifferential diagnosis.

JHM with recurrent dislocationsand soft/fragile/hyperextensible skin arealso found in a disorder with combinedconnective tissue and neurological fea-tures, i.e., the periventricular hetero-

topia EDS variant (OMIM #300537),in addition to bilateral nodular hetero-topia on brain MRI, aortic dilatationand dissection in early adulthood, ex-cessive bleeding and bruisability, andskeletal abnormalities. This X-linkeddisorder, due to dominant mutations infilamin A gene (FLNA), is lethal inmalesand presents with epilepsy in hetero-zygous females. Since some patients canprimarily present with JHM, screeningfor cardiovascular manifestations shouldbe offered when there are associatedseizures or an X-linked pattern ofinheritance [Reinstein et al., 2013].

DIFFERENTIAL DIAGNOSISWITH OTHER HCTDs

Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) comprises aheterogeneous group of diseases char-acterized by susceptibility to bonefractures with variable severity. Thelast available classification identifies OIwith mild to moderate severity, i.e.,non-deformingOIwith blue sclerae (typeI), common variable OI with normalsclerae (type IV), and OI with calcifica-tion and interosseous membranes (type

V); severe progressively deforming OI(type III), and perinatally lethal OI (typeII) [Van Dijk and Sillence, 2014].

JHM is reported in non-deformingOI with blue sclerae (OI type I, OMIM#166200); these patients are distin-guishable for the presence of blue scleraeand wormian bones; dentinogenesis im-perfecta (i.e., opalescent dentine) andsensorineural deafness may be present ina subset of the patients [Steiner et al.,2005]. Reduction in the synthesis oftype I procollagen and the presence ofmutations in COL1A1 confirm thediagnosis of OI type I with normalteeth, whereas COL1A2 mutations arepresent in OI type I patients withopalescent dentine. The other OI sub-types are not considered in the differ-ential with JHS/EDS-HT for: (i) theperinatal lethality (type II), (ii) thepresence of respiratory and swallowingproblems in newborns, and multiplelong-bone fractures at birth with pro-gressive deformity (type III), (iii) shortstature, basilar impression, and longbones bowing (type IV), (iv) calcifica-tion of the interosseous membranesand/or hypertrophic callus (type V)[Van Dijk and Sillence, 2014]. Occa-sionally, patients are encountered who


display a phenotype that combinesclinical manifestations of both OI andEDS. These OI/EDS patients presentrelevant bone fragility with repeatedfractures and overt blue sclerae togetherwith marked joint hypermobility andinstability, skin hyperextensibility and/or translucency, and signs of peripheralvascular fragility (Table IV). The ma-jority of OI/EDS patients harbor adominant mutation in the most N-terminal part of the type I collagenhelical region in either the a1- or a2-chain, which affects to some extentprocessing of the N-propeptide [Malfaitand De Paepe, 2014].

Marfan Syndrome

Marfan syndrome (MFS) (OMIM#154700) is a relatively common auto-somal dominant multisystem HCTDthat exhibits marked inter- and intra-familial variability with predominantmanifestations in the cardiovascular,skeletal, and ocular systems; additionally,the skin, fascia, lung, skeletal muscle,and adipose tissue may be involved[Pyeritz, 2000]. The clinical diagnosisis based on the revised Ghent nosology,which can include the presence of amutation in FBN1 encoding fibrillin 1[Loeys et al., 2010]. When moderateJHM is associated with a marfanoidhabitus (tall and slender build, arachno-dactyly and/or true dolichostenomelia,i.e., arm span/height ratio �1.05)coupled with a history of ectopia lentisand/or aortic dilatation or aneurysm,MFS should be strongly suspected. Inabout one-third of JHS/EDS-HT pa-tients a marfanoid habitus is recognizableand includes arachnodactyly, dolichos-tenomelia with an arm span:height ratio�1.03 (which is significantly differentfrom the cut-off of the revised Ghentcriteria which is 1.05), long hands andfeet, increased skin stretches in youngage, JHM and characteristic changes inthe pectus physiology [Hakim and Gra-hame, 2003; Grahame and Hakim,2013]. Aortic root ectasia, anotherdistinctive feature of MFS, is reportedin a subset (about 12%) of JHS/EDS-HT patients [Atzinger et al., 2011].However, aortic root ectasia in JHS-

EDS-HTyoung patients, unlike inMFS,does not show any progression inadulthood [Castori, 2012; Atzingeret al., 2011]. JHS-EDS-HT patientspresenting with marfanoid habitus andaortic root ectasia are comparable butdistinguishable from MFS patients forectopia lentis, which is not reported inJHS/EDS-HT. In most cases of MFS,JHM spares the elbows and pectusdeformities are common and generallymore impressive than in JHS/EDS-HT.

MASS syndrome (Mitral valve,Aorta, Skeleton, and Skin syndrome;OMIM #604308) is a MFS-relatedphenotype sharing skeletal features,i.e., scoliosis, marfanoid habitus, andJHM, and cutaneous signs, i.e., striaerubrae/distensae, and is distinguishable formitral valve prolapse (MVP), aortic rootectasia without progression to aneurysmor dissection, and absence of ectopia lentis[Glesby and Pyeritz, 1989; Dietz et al.,1993]. JHS/EDS-HT patients with amarfanoid habitus may show a greatoverlap with MASS phenotype whenMVP is present. The rate of MVP inJHS/EDS-HT is not well delineated.Contrasting data exist as in some reportsits incidence does not seem significantlyhigher than in controls [Atzinger et al.,2011], while others found a clearlyincrease in rate [Camerota et al.,2014]. Hence, in the small subset ofJHS/EDS-HT patients with marfanoidhabitus and MVP FBN1 molecularanalysis should be considered.

Loeys–Dietz Syndrome

Loeys–Dietz syndrome (LDS1–4,OMIM #609192, #610168, #613795,#614816) is an autosomal dominantaortic aneurysm syndrome with multi-system involvement and inter- andintrafamilial variability. LDS is charac-terized by a clinical triad includinghypertelorism, bifid uvula or cleft palate,and aortic aneurysm with arterial tor-tuosity. Natural history is significant forlife-threatening aortic dissection thatoccur at smaller aortic diameter andyounger age compared to MFS. Aorticaneurysms can be detected throughoutthe whole arterial tree. Furthermore, awidespread involvement of different

organ systems was also recognized andinclude craniofacial (e.g., craniosynos-tosis), musculoskeletal (JHM, marfanoidhabitus with arachnodactyly, dolichoste-nomelia, pectus deformities and jointcontractures), integumental (e.g. skinhyperextensibility, dural ectasia), andocular findings (e.g., strabismus) [Loeyset al., 2005; Loeys and Dietz, 2008]. Agroup of LDS patients, previouslydefined as LDSII, presents with severevascular involvement together withthin, translucent skin, atrophic scars,and marked easy bruising, and withoutcraniosynostosis and/or marfanoid hab-itus, thus resembling vEDS [Loeys andDietz, 2008; Drera et al., 2008, 2009;Fattori et al., 2012]. LDS3 can showosteoarthritis in young age [Van de Laaret al., 2011; Regalado et al., 2011;Wischmeijer et al., 2013]. LDS4presents a lower rate of life-threateningaortic dissection compared to the otherLDS types, a high rate of MVP, JHM,and skeletal signs common to MFS[Lindsay et al., 2012; Boileau et al.,2012; Ritelli et al., 2014a]. LDSclinically overlaps with MFS also foraortic root aneurysm and for skeletaldeformities and can be distinguished forthe absence of ectopia lentis and for thepresence of craniosynostosis, hyperte-lorism, bifid uvula, severe vascularinvolvement, and early osteoarthritis.JHS/EDS-HT with marfanoid habitusmay partially overlap with LDS withmild vascular involvement and withoutcraniosynostosis as LDS4; in these casesfamilial investigation and arterial evalu-ation are mandatory [Ritelli et al.,2014a]. Molecular analysis of the genesinvolved in LDS, i.e., TGFBR1,TGFBR2, SMAD3, and TGFB2, en-coding for components of the trans-forming growth factor beta (TGFb)signaling pathway, conclude the diag-nosis of LDS.

Recently also TGFB3 mutationswere reported to be associated withabnormal development of several mes-enchymal-derived tissues, includingmuscle and craniopalatofacial structures,accompanied by low muscle mass,growth retardation, distal arthrogrypo-sis, and other secondary changes(Rienhoff syndrome). The syndrome


shares some clinical features with theMFS and LDS, including arachnodac-tyly, pectus excavatum, pes planus, andhyperextensible large joints, as well ashypertelorism and bifid uvula withoutevidence of vascular disease [Rienhoffet al., 2013; Matyas et al., 2014;Rienhoff, 2014] and is distinguishablefrom JHS/EDS-HT for the absence ofmucocutaneous features, and the pres-ence of growth retardation, hypertelor-ism, distal arthrogryposis, and positiveTGFB3 genetic testing.

Arterial Tortuosity Syndrome

Arterial tortuosity syndrome (ATS,OMIM #208050) is a rare, autosomalrecessive HCTD chiefly characterizedby tortuosity and elongation of thelarge- and medium-sized arteries and apropensity towards aneurysm formationand vascular dissection. Additional car-diovascular features include aberrantorigin of aortic branches, arterial andpulmonary valve stenosis, and vaso-motor instability. ATS also shares withother HCTDs soft/velvety/hyperexten-sible skin, cutis laxa, mildly dysmorphicfacial features (i.e., elongated face,hypertelorism, cleft palate and/or bifiduvula, and micro/retrognathia), kerato-conus, abdominal hernias, joint hyper-mobility and instability, and otherskeletal anomalies. Systemic symptomsand sudden death due to acute respira-tory insufficiency and/or cardiac failurecan occur in the pediatric age [Call-ewaert et al., 2008b; Ritelli et al.,2014b]. ATS is caused by mutations inSLC2A10 [Coucke et al., 2006; Ritelliet al., 2014b], encoding for the facili-tative glucose transporter 10, GLUT10.For patients without cardiovascularcomplications, EDS can be suspectedand particularly JHS/EDS-HT for thecutaneous, articular and skeletal signs; inthese cases, cardiovascular evaluationand SLC2A10 molecular analysis allowthe distinction between these disorders[Castori et al., 2012b].

Lateral Meningocele Syndrome

Lateral meningocele syndrome (LMS), arare HCTD described in 14 patients

belonging to nine families, is charac-terized by widespread spinal lateralmeningoceles (meningeal diverticula)protruding through the intervertebralspaces, in association with facial dys-morphisms and variable signs of con-nective tissue involvement, includingJHM, present in about 74% of reportedpatients, and chronic musculoskeletalpain, found in about 64,3% of the cases[Castori et al., 2013b]. Cutaneous signs,i.e., hyperextensible and soft skin, arerarely disclosed (21% of the patients).Multiple meningeal diverticula havenever been reported in JHS/EDS-HTpatients or in cEDS, kEDS, MFS, andLDS, hence the presence of this clinicalsign can distinguish LMS.

DIAGNOSTIC FLOW CHARTOF JHS/EDS-HT

When a patient presents with JHM andvariable cutaneous signs, including soft,velvety, thin, hyperextensible skin, striaerubrae or distensae, and abnormal scar-ring, a clinical evaluation is mandatoryin order to identify other possible signsof connective tissue fragility, and his/herfamily history must be investigated. Inparticular, clinical signs indicative of thedifferent forms of EDS and of the partlyoverlapped HCTDs (MFS, LDS, ATS,OI, and LMS) should be sought. Asynthetic flow chart with the mainclinical signs present in JHS/EDS-HTand in the most frequently observedEDSs and HCTDs that have to beconsidered in the differential with JHS/EDS-HT is reported in Figure 2. Thisflow chart will address the diagnosticsuspicion of physicians or specialists inone of the different clinical fields ofinterest for JHS/EDS-HT. In a speci-alized center, the careful clinical evalua-tion and the assessment of the reportedfindings is sufficient to confirm the JHS/EDS-HT diagnosis in the majority ofthe cases (about 90% - Colombi,unpublished data). Only in pediatricpatients and in patients without acomplete or with a borderline pheno-type the diagnosis is doubtful andrequires a second evaluation in olderage or targeted molecular testing for theexclusion of overlapping disorders.

When specific signs of the differentEDSs or HCTDs are found, the initialdiagnosis is addressed accordingly.

When the presence of other EDSs,OI, MFS, LDS, ATS, or LMS issuspected, additional investigations forthe assessment of vascular, skeletal,ophthalmologic, and bone health shouldbe performed. In particular, when thesuspicion of a vascular disorder (i.e.,vEDS, LDS, ATS) persists, extensivevascular imaging (i.e., whole bodyangio-MRI, or brain angio-MRI plusthoracic and abdominal angio-CT, orheart, abdominal aorta, epiaortic andlimb vessels Doppler ultrasound) ismandatory. When MFS is suspectedheart ultrasound for MVP and aorticroot ectasia, ocular evaluation for ectopialentis and/or myopia, and spine MRI fordural ectasia must be performed. Inpatients with an OI type I resemblingphenotype, bone densitometry for earlyosteoporosis/osteopenia, skull radiogra-phy for wormian bones, orthodonticevaluation for dentinogenesis imperfecta arerequired. In LMS patients spine MRI isneeded.

In EDSs ultrastructural examina-tion of the skin usually reveals abnor-malities of collagen fibrils which includeirregular, disrupted fibrils (“collagenflowers”), and variability within theirdiameter. However, these abnormalitiesare common to several EDS variants andusually not specific enough to discrim-inate between individual EDS types,with the exception of the pathogno-monic hieroglyphic fibers observed inthe dermatosparaxis type of EDS [Mal-fait and De Paepe, 2014]. At themoment, ultrastructural abnormalitiesare only occasionally identified in JHS/EDS-HT and no finding is specific ofthis condition. Therefore, skin biopsyultrastructure is not included in thestandard diagnostic schedule of JHS/EDS-HT [Castori, 2013]. This is alsothe case of biochemical analyses, none isavailable for JHS/EDS-HT, whereassome have been developed for otherEDSs. In particular, the biochemicalevaluation of urinary pyridinoline con-firms the kEDS diagnosis and distin-guishes this form from EDS withprogressive kyphoscoliosis, myopathy

Figure 2. Diagnostic flow chart for a patient presenting with JHM and cutaneous features which considers JHS/EDS-HT, the mostfrequently observed EDSs, MFS, LDS, ATS, OI, and LMS.


and hearing loss and from JHS/EDS-HToverlapping phenotypes.

Genetic testing is available for all ofthe genes involved in the so far definedEDS types, except JHS/EDS-HT andthe periodontitis type, and for the otherHCTDs, except LMS, and mutationdetection can be performed on genomicDNA obtained from peripheral bloodsample either by Sanger sequencing orby targeting panel-based NGS. Themolecular evaluation of COL5A1 andCOL5A2 allows for the distinction ofcEDS patients without scarring andgeneralized JHM from JHS/EDS-HT;and if no mutations in these genes aredetected TNXB analysis could be per-formed. COL1A1 and COL1A2 anal-ysis permits the distinction of OI type IandOI/EDS from the overlapping JHS/EDS-HT phenotypes. Molecular test-ing for theCOL3A1, FBN1, TGFBR1,TGFBR2, SMAD3, TGFB2, andSLC2A10 genes confirms/excludes

the diagnosis of the HCTDs withprominent vascular involvement. Rapiddetection of such rarer HCTDs is crucialfor prognosis establishment due to theirhigh risk of vascular accidents, a com-plication never reported in JHS/EDS-HT. Exclusion of other overlappingHCTDs is a crucial step in borderlinepatients to confirm the clinical diagnosisof JHS/EDS-HT, allowing the multi-disciplinary management of these pa-tients, which covers pharmacologic,physical therapy, surgical, and nutra-ceutical aspects, as well as general life-style recommendations.

CONCLUSIONS

Diagnosis of JHS/EDS-HT can bedifficult due to the intrafamilial andinterfamilial variability, the evolvingpresentation, the multisystem involve-ment, the unknownmolecular basis, andthe overlap with a wide spectrum of

other disorders either inherited oracquired. Careful clinical evaluation ofJHS/EDS-HT patients and their fami-lies for all the known manifestations ofthis disorder, and the application of thediagnostic flow chart with the over-lapping HCTDs, should facilitate acorrect diagnosis to the different special-ists following these patients, includingclinical geneticists, rheumatologists,dermatologists, orthopedists, ophthal-mologists, cardiologists, gynecologists/obstetricians, neurologists, and clinicalpsychologists. All these patients shouldrefer to centers specialized in thediagnosis of these disorders also offeringgenetic testing to be diagnosed in a shorttime and to receive an appropriatemanagement. For JHS/EDS-HT thefuture challenge will be the definitionof its molecular basis; the knowledge ofthe causal gene(s) will give a powerfuldiagnostic tool and likely open noveltherapeutic perspectives.


ACKNOWLEDGMENTS

The authors want to thank all patientsand their families who taught themabout their disorders and chose to sharetheir sufferings hoping to help futuregenerations of affected people. Theauthors also thank Dr. M. Castori forhelpful suggestions during the manu-script preparation.

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differential diagnosis and diagnostic flow chart of joint

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