European Journal of Endocrinology 10.1530/EJE-17-0430 the EuropeanSocietyforPediatric Endocrinology, theEuropean SocietyofHumanReproductionandEmbryology the The guidelinehasbeenformally endorsedbytheEuropeanSocietyforEndocrinology, thePediatricEndocrineSociety, Embryology, TheAmericanHeartAssociation,Societyfor Endocrinology, andtheEuropean SocietyofCardiology. The EuropeanSocietyforPediatric Endocrinology, TheEndocrine Society, EuropeanSocietyof HumanReproductionand project wasinitiatedbytheEuropean SocietyforEndocrinologyandthePediatricEndocrine Society, incollaborationwith and mostoptimaltreatmentofshortstature,infertility, hypertension,andhormonalreplacement therapy. Theguidelines Evaluation) evaluationwithaseparatesystematicreview of theliterature.Thesefourquestionsrelatedtoefficacy pertinent questionsweresubmittedforformalGRADE(Grading ofRecommendations,Assessment,Developmentand comorbidities andneurocognitiveissues.Thesegroupsproduced proposalsforthepresentguidelines.Additionally, four childhood andadolescence,3)congenitalacquiredcardiovascular disease,4)transitionandadultcare,5)other groups eachaddressedimportantareasinTScare:1)diagnostic andgeneticissues,2)growthdevelopmentduring USA, andculminatedwithaConsensusMeetingheldinCincinnati, Ohio,USAinJuly2016.Priortothismeeting,five TS. Thispaperisbasedonaninternationaleffort that startedwithexploratorymeetingsin2014bothEuropeandthe advances havebeennotedrecently. Theseadvancescoverallspecialtyfieldsinvolvedinthe careofgirlsandwomenwith necessitating multidisciplinaryapproachtocare.Previous guidelineshavehighlightedthis,butnumerousimportant Turner syndromeaffects 25–50per100,000femalesandcaninvolvemultipleorgansthroughallstagesoflife, Abstract *(Details oftheInternationalTurner SyndromeConsensusGroupispresentedintheSummarysection) Medicine, Cincinnati,Ohio,USA Germany, and Netherlands, Pediatric Endocrinology, RadboudUniversityMedicalCenter, AmaliaChildren’s Hospital,Nijmegen,The Rare Diseases,DepartmentofPediatrics,AarhusUniversityHospital,Aarhus,Denmark, Children’s Hospital,Portland,Oregon,USA, 14 USA, USA, Island, NewSouthWales, Australia, 9 Pediatrics, MedicalGeneticsUnit,MassGeneralHospitalforChildren,Boston,Massachusetts,USA, USA, Netherlands, London, UK, University Hospital,Aarhus,Denmark, Departments of TurnerOn behalfoftheInternational Syndrome ConsensusGroup* Janielle A van Alfen-van derVelden Michael Silberbach Charmian A Quigley Mitchell E Geffner Claus H Gravholt TurnerInternational Syndrome Meeting proceedings from the2016Cincinnati girls andwomenwithTurner syndrome: Clinical practiceguidelinesforthecare of Division ofEndocrinology, NemoursChildren’s HealthSystem,Jacksonville,Florida,USA, Department ofPediatrics,Dordrecht,TheNetherlands, DOI: 10.1530/EJE-17-0430 www.eje-www.eje-online.org Guideline Clinical Practice 13 12 7 Rady Children’s Hospital,UniversityofCalifornia,SanDiego,USA, Department ofPediatricEndocrinology, SophiaChildren’s Hospital,Rotterdam,TheNetherlands, Division ofPsychology, DepartmentofPediatrics,UniversityMichigan,AnnArbor, Michigan, online.org 5 19 6 Department ofClinicalEpidemiology, LeidenUniversityMedicalCentre,Leiden,The The SabanResearchInstitute,Children’s HospitalLosAngeles,California, 20 Department ofPediatricEndocrinology, Children’s Hospital,UniversityofBonn, Cincinnati Children’s HospitalMedicalCenter, UniversityofCincinnatiCollege 1 Endocrinology andInternalMedicine,

1 , 2 6 , Niels H Andersen 15 , Karen O Klein 10 , Viveca Söderström-Anttila , Karen Rubin 11 © 2017EuropeanSociety ofEndocrinology © 2017EuropeanSociety ofEndocrinology Connecticut Children’s MedicalCenter, Hartford,Connecticut, 4 Department ofWomen’s Health,UniversityCollegeLondon, C HGravholtandothers 16 Väestöliitto FertilityClinics,Helsinki,Finland, 7 , Angela E Lin 11 18 , David E Sandberg , Joachim Woelfle 3 , Gerard S Conway Printed inGreatBritain 2 Molecular Medicineand 15 Department ofPediatrics,Doernbecher 16 8 , Nelly Mauras , Kirstine Stochholm 19 12 , Philippe F Backeljauw 4 , Olaf M Dekkers , Theo C J Sas practice guideline Turner syndromeclinical Published byBioscientifica Ltd. 3 Cardiology, Aarhus 8 Department of 18 9 Department of , 10 St Hubert’s 17 Center for 1 13, , 17 14 , 5 , , 20

[email protected] Email to CHGravholt should beaddressed Correspondence 177 177 : 3 :3 G1 –G70 European Journal of Endocrinology www.eje-online.org likelihood of short stature (e.g., short parents and short poor growth),thechildisalready shortorhasastrong in the absence of other treatable cause of over 6 months below 50th percentile height velocity (HV) observed the childalreadyhasevidenceofgrowthfailure(e.g., years)inthefollowing circumstances: before 12–13 ofage,andpreferably treatment early(around4–6 years R 2.1. 2. Growth andpuberty ( standard karyotyping individuals withYchromosomematerialidentified on R 1.5. ( syndrome (TS)inafemalewithtypicalsigns( R 1.4. ( karyotype management guidelineappliestoTSpatientswithany R 1.3. ( over theageof50 years withlessthan5%45,Xmosaicism distal toXq24ontheotherXchromosome,andinwomen of TS in females with one X chromosome and a deletion R 1.2. typical clinicalmanifestationsofTS( second sexchromosome,associatedwithoneormore X chromosomeandcompleteorpartialabsenceofthe containing one in phenotypic females with a karyotype R 1.1. 1.1. Diagnosisandgenetics methods usedforguidelinedevelopment’. and strong( low ( evidence behindtherecommendationsisclassifiedasvery recommendations fortherapeuticchoices.Thequalityof We formallygradedonlytheevidenceunderlying recommendation) and The recommendations(R)arewordedas 1. Summaryofrecommendations pre-meeting discussionsandintheconsensusmeeting. Endocrine Society. Advocacygroupsappointedrepresentativeswhoparticipatedin ⨁⨁⨁⨁ ⨁⨁◯◯ Clinical PracticeGuideline ⨁◯◯◯

We recommend initiating growth hormone (GH) We recommendagainstconsideringadiagnosis We recommendtoconsidertestingforTurner We recommend considering adiagnosis of TS We suggestthatthenewgeneralsurveillance We recommendgonadectomyinallfemale ). ). ⨁⨁◯◯ ⨁⨁⨁⨁ ), low( ). ). See further section ‘Summary of ). Seefurthersection‘Summary ⨁⨁◯◯ ⨁⨁◯◯ suggest (weakrecommendation). ). C HGravholtandothers ), moderate( ⨁⨁⨁⨁ recommend ). ⨁⨁⨁◯ al 2 Table (strong ) ) diagnosis) ( predicted adultheightoralreadypubertalatthetimeof annually ( promoting therapybymeasurementofIGF-Iatleast R 2.4. 6 monthsthereafter( every 4–6 months during the first yearof treatmentand atleast treatment bymeasurementofheightatleastevery R 2.3. potential issubstantiallycompromised( increasing to68 1.3–1.5 mg/m or R 2.2. their probabilitytoconceive spontaneouslydecrease R 3.1. technologies andpregnancy 3. Fertility, assistedreproductive treatment ( breakthrough bleedingoccurs,orafter2 years ofestrogen R 2.10. route andthatthetransdermalispreferred( preferred estrogenandthatitbeadministeredbyasystemic R 2.9. adult dosingover2–3 years( ofageincreasingto should startbetween11and12 years R 2.8. further promotegrowth( estrogen supplementation in the prepubertal years to R 2.7. with thestandardGHdosealone( and/or adultheightoutcomeislikelytobeunsatisfactory of TS(andthereforeGHtreatmentinitiation)isdelayed, day andmaintainedbelow0.05 oxandrolone fromtheageof10 years orolderat0.03 R 2.6. should guidefurtherGHdoseselection( IGF-I valuebetween+2SDSand+3SDS,clinicaljudgment above +3SDS,aGHdosedecreaseiswarranted.Foran SDS abovethemeanforage.IfanIGF-Ivalueismeasured nogreaterthan2 ideallybe the measuredIGF-Ishould R 2.5. practice guideline Turner syndromeclinical

We recommend using a GH dose of 45–50 We suggestthatlow-doseestradiol(E2)is the We recommendmonitoringthesafetyofgrowth- We suggestconcomitanttreatmentwith We recommendmonitoringgrowth-promoting We recommend that estrogen replacement We TSpatientstreatedwithGH suggestthat for We recommendcounseling femaleswithTSthat We suggest to notroutinelyadd very-low-dose We recommendaddingprogesteroneonce ⨁⨁◯◯ ⨁⨁⨁⨁ ⨁⨁⨁◯ 2 µg/kg/day (2.0 /day (4.0–4.5 IU/m /day

). ). ). ⨁⨁◯◯ ⨁⨁⨁◯ ⨁⨁⨁◯ mg/m mg/kg/day, ifthediagnosis (2017) Endocrinology European Journal of 2 ⨁⨁⨁⨁ /day) in most instances, /day) inmostinstances, ). 2 ). 177 /day) if adult height /day) ifadultheight 177 ). ⨁⨁⨁⨁ :3 ⨁◯◯◯ , G1–G70 ).

⨁◯◯◯ µg/kg/day µg/kg/day ). mg/kg/ ). G2 ). European Journal of Endocrinology ascending ASI R 3.12. approximately 20 weeksofgestation( at atleastonceduringpregnancy,previous aorticsurgery) (hypertension, bicuspid aortic valve, coarctation, TS withoutaorticdilatationorotherriskfactors R 3.11. ( at aspecialistcenteranddeliverbycesareansection closely pregnant thesewomenshouldbefollowedvery AoD shouldbeadvisedagainstpregnancy. Ifalready R 3.10. ( transverse aorta,coarctation oftheaortaandhypertension which include bicuspid aortic valve, elongation of the m index (ASI)of should beavoidedincaseofanascendingaorticsize R 3.9. therapy (ART)inallwomenwithTS( 2 years beforeplannedpregnancyorassistedreproductive and CT/cardiac magnetic resonance scan (CMR) within and heartwithatransthoracicechocardiography(TTE) R 3.8. pregnancy ( counseled abouttheincreasedcardiovascularriskof R 3.7. mentioned duringpreconceptioncounseling( such asadoptionorusingagestationalcarriershouldbe R 3.6. women withTS( specialists andcardiologistswithexpertiseinmanaging teamincludingmaternal–fetalmedicine multidisciplinary pregnant womenwithTSshouldbeundertakenbya R 3.5. counseling ( fertility, onlyafterthoroughscreeningandappropriate R 3.4. of 12 years( ofyoungTSgirlsbeforetheage for fertilitypreservation R 3.3. ( option hyperstimulation isapossiblefertilitypreservation aftercontrolledovarian that oocytecryopreservation with persistentovarianfunctionshouldbecounseled R 3.2. age ( should begiventoofferingfertilitytreatmentatayoung rapidly with age, if at all present, and consideration ⨁◯◯◯ ⨁◯◯◯ ⨁◯◯◯ Clinical PracticeGuideline 2 withassociatedriskfactorsforaorticdissection(AoD), ⨁⨁⨁⨁

We recommend that management of We suggestthatyoungmosaicTSwomen We recommendconsideringoocytedonationfor We suggest that ART or spontaneous conception We recommendagainstroutineoocyteretrieval We suggest that other options for motherhood We suggestthatallwomenwithTSshouldbe We recommendimagingofthethoracicaorta We suggestthat women withTSan We suggest performing TTE in women with We of suggestthatwomenwithahistory ). ). ). ⨁◯◯◯ ⨁◯◯◯ ⨁⨁⨁⨁ > > ). 2.5 cm/m 2.0 cm/m ⨁⨁⨁◯ ). ). ). 2 2 oranascendingASI2.0–2.5 oranyriskfactor(hypertension, ). C HGravholtandothers ⨁◯◯◯ ⨁◯◯◯ ⨁◯◯◯ ). ). cm/ ).

first, followedbyaorticsurgery, whichshouldbeperformed the fetusisviable,itreasonabletoperformcesareansection understandingthatfetalviabilitymaybeatrisk.If surgery AoD beforethefetusisviable,toperformemergencyaortic R 3.16. increase indiameter( isreasonableincaseofadilatedaortawithrapid surgery R 3.15. ( is strict(135/85 R 3.14. aorta, aorticarch ordescendingaorta( when thereissuspicionofdiseasethedistalascending gadolinium) shouldbeperformedduringpregnancy R 3.13. the first6 monthspostpartum( duringpregnancyand at 4-to8-weekintervals shouldbemonitoredfrequently,surgery) includingTTE bicuspid aorticvalve,coarctation, previousAoDor examined with transthoracic echocardiography (TTE) at R 4.1. Turner syndrome 4. Cardiovascular health issuesin ( ofAoD,acesareansectionshould beperformed history R 3.21. considered ( epidural anesthesiaandexpeditedsecondstagemaybe with cesarean sectionisreasonableoravaginaldelivery women withTSanascendingASI is preferredoracesareansectionmaybeconsidered.In with epiduralanesthesiaandexpeditedsecondstage ascending ASIof2.0–2.5 R 3.20. 2.0 cm/m in women with TS with an ascending ASI below R 3.19. ( ahighriskofAoD advised thatpregnancywouldcarry coarctation oftheaorta and/orhypertensionshouldbe bicuspid aorticvalve,elongationofthetransverseaorta, R 3.18. especially inwomenwithcoarctation ( can beusefultorevealexercise inducedhypertension, R 3.17. flow andavoidanceofvasoconstrictors( under near-normothermia,pulsatile perfusion, highpump practice guideline Turner syndromeclinical ⨁◯◯◯ ⨁◯◯◯ ⨁◯◯◯

We recommend that aninfantorchildis 2 We suggestthatexercise testingbeforepregnancy We suggestthatincaseofanacuteascending We suggestthatduringpregnancy, prophylactic We recommend that blood pressure control We suggestthatCMRimaging(without We recommend that inwomenwithTSa ( We suggestthatwomenwithaorticdilatation, We is reasonable suggest that vaginal delivery We suggestthatinwomenwithTSan ). ). ). ⨁◯◯◯ ⨁◯◯◯ mmHg) inallpregnant women withTS ⨁◯◯◯ ). ). cm/m ⨁◯◯◯ ). 2 , a vaginal delivery , avaginaldelivery 177 ⨁◯◯◯ ⨁◯◯◯ ⨁◯◯◯ www.eje-online.org :3 ). >

2.5 cm/m ). ). ). G3 2 , a

European Journal of Endocrinology www.eje-online.org should beperformed( or hasbeenconfirmedprenatally, afetalechocardiogram R 4.10. based onpublishedguidelines ( to anticipatedpregnancy(see 5 yearsevery 10 years inchildren,every inadults,orprior studies should be performed TTE or CMR surveillance valve orothersignificantdiseaseattheinitialscreening, R 4.9. is areasonableoption( an adultorchildcannottolerateaCMRstudy, aCTscan soon asitisfeasiblewithoutneedinggeneralanesthesia. If R 4.8. diagnosis isthepreferredapproach( cardiovascular screening withTTEandCMRatthetimeof R 4.7. ( aorta, coarctation ofthe aortaand/orhypertension) (i.e., bicuspidaorticvalve,elongationofthetransverse is and forwhomtheirascendingaortaTS-specificZ-score considered forwomenwithTS,whoare of theaorticrootand/orascendingaortamaybe R 4.6. factors forAoD( with anascendingASI considered forwomenwithTSwhoare of theaorticrootand/orascendingaortamaybe R 4.5. ( or hypertensionaccording to standard definitions of thetransverseaorta,coarctation oftheaortaand/ for AoD, including bicuspid aortic valve, elongation ascending ASI for women with TS who are of theaorticrootand/orascendingaortaarereasonable R 4.4. surgical consultation( period, needanoptimizationofmedicaltreatmentand aortic diameteroranincreaseof demonstrating anincreaseinTS-specificZ-scoreof1 R 4.3. sudden inonsetandsevere( shoulder, backorflankdiscomfort,particularlyifitis symptoms consistentwithAoD,suchaschest,neck, seek promptevaluationiftheyareexperiencingacute dilatation and/orbicuspidaorticvalvebecounseledto R 4.2. or postnatal cardiac examination was normal ( the timeofdiagnosis,eveniffetalechocardiogram ⨁◯◯◯ ⨁◯◯◯ Clinical PracticeGuideline ≥ 4.0, withorwithoutassociatedriskfactorsforAoD

We recommend,intheabsenceofabicuspidaortic We recommendthatin adolescents and adults TS We suggest that elective operations for aneurysm We suggest that elective operations for aneurysm We suggest that elective operations for aneurysm We recommendthatwomenwithTS We recommendthataCMRscanisperformed as We recommendthatgirlsorwomenwithaortic We recommendthat, ifTSishighlysuspected ). ). ≥ ⨁◯◯◯ 2.5 cm/m ⨁⨁◯◯ ⨁⨁◯◯ ≥ ⨁⨁◯◯ 2.5 cm/m ). 2 andassociatedriskfactors ⨁⨁◯◯ R 3.8 ≥ ⨁⨁◯◯ ). ). 6 years of age with an 16 C HGravholtandothers ). > 2 , andnoassociatedrisk 0.5 ) toevaluatetheaorta ⨁⨁◯◯ cm overaone-year ). < ≥ ). 16 years ofage, 16 years ofage 16 years ⨁⨁◯◯ ). ). > women withTSQTc prolongation(QTc interval exercise testingbeconsidered forriskestimationin R 4.14. QTc ( Hodge’s maybepreferredoverBazett’s formulatoestimate individual with TS at the time of diagnosis and that (ECG) withQTc measurementshouldbedoneinevery R 4.13. management plan( andpostnatalmultidisciplinary and modeofdelivery and physiologyofthespecificdefect,recommendedsite fetus withTStoprovide counseling regarding the anatomy when congenitalheartdiseaseisdetectedprenatallyina R 4.12. ( fetus orchildshouldpromptageneticevaluationforTS aortic valveoraleft-sidedobstructivelesioninfemale R 4.11. pressure shouldbeperformed andmedicaltreatment structural heart disease, annual assessment of blood R 4.21. competitive sports( > (TS-specific Z-scoreof moderately toseverelydilatedaorta,age R 4.20. competitive sportsmaybeadvised( participation inlowandmoderatestaticdynamic Z-score of2.5–3),orage to moderatelydilatedaorta(age R 4.19. to participateinallsports( < normal aorticsize(age R 4.18. be advised( ≥ ≥ R 4.17. athlete withTSandaorticdilation( determining participationrecommendationsforthe disease and/or hypertension should be considered in valve andthepresenceofany other congenital heart R 4.16. ( weeks after initiation of QT-prolonging drugs 1–2 they aredeemednecessary, ECGshouldbeperformed QTc, drugsthatprolongtheQTc shouldbeavoided.If R 4.15. practice guideline Turner syndromeclinical ⨁⨁◯◯ ⨁◯◯◯ s ( 460 ms) 2.5 orage 2.0 cm/m with amoderately dilated aorta(ascending ASI 16 years 2.3 cm/m ⨁⨁◯◯

We recommendreferraltoapediatriccardiologist We suggestthat,forgirlsandwomenwithamild We suggestthat,inindividualswithprolonged We recommend that the function of the aortic We suggestthat,forgirlsandwomenwithTS We suggestthatgirlsandwomenwitha We suggest that 24-h Holter monitoring and ⨁◯◯◯ We recommendthatdiagnosisofabicuspid We suggest that, for girls and women with We recommendthat inindividualswithout We suggestthatarestingelectrocardiogram 2 ). 2 ). ≥ ), avoidanceofintenseweight-trainingshould ) shouldbeadvisednotto participate inany ⨁◯◯◯ 16 years andASI ). ⨁⨁◯◯ ⨁◯◯◯ ). ). < ≥ 6 years;TS-specificZ-scoreof 16 > 16 years (ASI2.0–2.3 16 years ⨁◯◯◯ 3) orage < ). ). 2.0 cm/m < 16 years old(TS-specific ⨁◯◯◯ ⨁◯◯◯ 177 ). 2 :3 ≥ ), itisreasonable 6 years(ASI 16 ). ). < 6 years 16 cm/m G4 2 )), European Journal of Endocrinology throughout thelifespan( TSH measurementsbeginning inearlychildhoodand at diagnosisandthenannually with(free)T4and R 6.3. placement ofmyringotomytubesasindicated( ear diseaseandotitismedia(OM)withantibiotics R 6.2. ( and adequatetechnicalotherrehabilitativemeasures mid-frequency sensorineuralhearingloss,toassureearly and/or presenceofa hearing thresholdlevels,karyotype 5 yearsevery regardlessoftheinitialageatdiagnosis, R 6.1. throughout thelifespan 6. Healthsurveillanceforcomorbidities sharing ofexperiences( reduce stressanddistresspromotethereciprocal organizations toenhanceknowledgeandconfidence, to-parent) contactwithTSsupportandadvocacy their careteamsencouragepeer-to-peer(andparent- R 5.4. process ( establish a workflow to support acoordinated transition system,thepediatricandadulthealthcareteams delivery R 5.3. document thecoreelementsoftransition( team uses or adapts available transition tools to track and R 5.2. for theirpatientswithTS( planned andstagedtransitionprocessinearlyadolescence (or any other TS care provider/coordinator) implements a R 5.1. 5. Transition from pediatrictoadultcare TS-specific Z-scoreis ofageforwhomtheirascendingaorta who are≤16 years or ascendingaortamaybeconsideredforgirlswithTS to reducedilatation of anenlarged aortic rootand/ a beta-blocker, anangiotensinreceptorblockerorboth, R 4.22. for whomtheirascendingASIis risk forAoDinwomenwithTSwhoare an angiotensinreceptorblockerorbothtoreducethe We suggestmedicaltreatmenttoincludeabeta-blocker, thereof shouldbeconsideredifhypertensionispresent. ⨁⨁◯◯ Clinical PracticeGuideline

We suggestthatpediatricendocrinologistsand We suggestthat,irrespectiveofthehealthcare We suggestthatthepediatricendocrinology We recommendthatthepediatricendocrinologist ⨁⨁◯◯ We recommendaformalaudiometricevaluation We recommendaggressivetreatmentofmiddle- We recommend screening for hypothyroidism We suggestthatmedicaltreatment,including ). ). ≥ 3.0 ( ⨁⨁◯◯ ⨁⨁◯◯ ⨁⨁◯◯ ⨁◯◯◯ ≥ C HGravholtandothers ). 2.3 cm/m ). ). ). ≥ 16 years ofage 16 years ⨁⨁◯◯ 2 ( ⨁⨁◯◯ ⨁⨁◯◯ ). ). ).

menopause) ( discontinuation ofestrogen therapy(simulating bone mineraldensityinall womenwhenconsidering R 6.16. R 6.9. individual clinical findings and patient needs ( be basedonthestandardofdental/orthodonticcare, established. Futuremanagementandfollow-upshould at diagnosisifnopreviousdental/orthodontic care was R 6.8. edema therapist( skin atanyagebeassessedandtreatedbyaprofessional serious compromiseoffingernails,toenailsorextremity yearsofagewithouttherapy, any mostly resolvesby2 R 6.7. cardiovascular diseasestartingatage18 years ( in individualswhohaveatleastoneriskfactorfor R 6.6. age of10 years( HbA1c withorwithoutfastingplasmaglucosestartingat R 6.5. physical activitystartinginearlychildhood( R 6.4. been instituted( density afteradulthormonereplacement therapy has (DXA)scanstomonitor bonemineral absorptiometry R 6.15. ( with inactivevitaminD(ergocalciferol)asnecessary thereafter throughoutthelifespanandtreating years 2–3 yearsofage andevery between 9and11 with aserum25-hydroxyvitaminDmeasurement R 6.14. ( and vitaminDfollowregion-specificrecommendations R 6.13. of estrogenreplacementinbonehealth( counseled onhealthylifestylemeasures,andtherole R 6.12. ( at thestartoftherapyoriftheydevelopduring with orthopediccareifspineabnormalitiesarepresent R 6.11. until growthiscompleted( 6 months annually every duringGHtherapyorotherwise R 6.10. early correctionofrefractiveerrors( the timeofdiagnosis,ifatanolderage,withemphasison gical examination between 12 and 18 months of age orat practice guideline Turner syndromeclinical ⨁⨁◯◯ ⨁◯◯◯ ⨁◯◯◯

We recommendthatalipidprofilebeperformed We recommend lifelong annual measurement of We suggestcounseling on healthy nutrition and We recommend a comprehensive ophthalmolo­ We recommenddental/orthodonticevaluation We recommendthat,whileperipheraledema We recommendclinicalevaluationforscoliosis We suggesttreatmentwithGHbecoordinated We suggestscreeningforvitaminDdeficiency We intakeofcalcium recommendthatdietary We recommendusing DXAscanstomonitor We recommendthatallpatientsshouldbe ). ). ). We suggestusingdualenergyX-ray ⨁⨁◯◯ ⨁⨁◯◯ ⨁⨁◯◯ ⨁◯◯◯ ). ). ). ⨁◯◯◯ ). ⨁◯◯◯ 177 ). www.eje-online.org :3 ⨁⨁◯◯ ⨁⨁◯◯ ⨁◯◯◯ ⨁⨁◯◯ ). ). G5 ). ). ). European Journal of Endocrinology www.eje-online.org R 6.21. of diagnosis( R 6.20. for improvementofliverfunction( for theinitiationoffemalehormonereplacementtherapy publication ( important advanceshave beennotedsincetheir Previous guidelines have highlighted this, but numerous approachtocare. life, necessitatingamultidisciplinary and can involve multiple organs through all stages of Turner syndrome(TS)affects 25–50per100 Introduction ( may beadaptedtomeettheneedsofgirls/womenwithTS cognitive orpsychosocialproblemsinotherpopulations R 7.6. psychosexual adaptation( impairment tofacilitatepositivepsychosocialand and aggressivemanagementofpredictorshearing R 7.5. performance issues( adjustments ifindicated,toaccommodatelearning/ R 7.4. ( assessments atkeytransitionalstagesinschooling R 7.3. indicated ( behavioral screeningsuntiladulthoodwithreferralsas R 7.2. girls andwomenwithTS( isintegratedintothecarefor behavioral healthservices R 7.1. 7. Neurocognitive andbehavioralaspects ( clinics forhealthsurveillance ormultidisciplinary attend specialistinterdisciplinary R 6.19. ( years yearly throughoutthelifespanstartingatage10 (including AST, ALT, GGTandalkalinephosphatase) R 6.18. ( childhood andwithsuggestivesymptomsinadulthood 2–3 years 2 years ofageatafrequency ofevery throughout measurement of transglutaminaseantibodies beginning at R 6.17. ⨁◯◯◯ ⨁⨁◯◯ ⨁⨁◯◯ ⨁◯◯◯ Clinical PracticeGuideline

We for suggestthatevidence-basedinterventions We recommendaimingforon-timepuberty We recommendacademicandoccupational We suggestconductingneuropsychological We recommendannualdevelopmentaland We recommendthatneuropsychologyandallied We recommend monitoring liver function tests We recommend appropriate timing (see We recommendarenalultrasoundatthetime We recommendthatgirlsandwomenwithTS We recommendscreeningforceliacdiseaseby ⨁⨁⨁◯ ). ). ). ). ⨁⨁⨁⨁ 1 , 2 ). Theseadvancescoverall specialty ⨁⨁⨁◯ ). ). ⨁⨁◯◯ ⨁⨁⨁◯ ). ⨁⨁◯◯ C HGravholtandothers ⨁⨁◯◯ ). ). ). 000 females ). R 2.8 ) therapy. Theseguidelineswereinitiatedanddevelopedby infertility, hypertensionandhormonalreplacement efficacy andmostoptimaltreatment of shortstature, of theliterature( Evaluation) evaluation with a separate systematic review of Recommendations, Assessment, Development and questions weresubmittedforformalGRADE(Grading for the present guidelines. Additionally, four pertinent neurocognitive issues.Thesegroupsproducedproposals transition andadultcare(5)othercomorbidities (3) congenitalandacquiredcardiovasculardisease,(4) and developmentduringchildhoodadolescence, TS care:(1)diagnosticandgeneticissues,(2)growth meeting, fivegroupseachaddressedimportantareasin in Cincinnati,Ohio,USAJuly2016.Priortothis the USAandculminatedwithaconsensusmeetingheld meetingsin2014bothEuropeand with exploratory This paperisbasedonaninternationaleffortthatstarted fields involvedinthecareofgirlsandwomenwithTS. ESHRE, SfE,andESCsupported theirowndelegates and co-sponsoredbyPES, ESPE andES.Furthermore, Endocrine Society. andthe Society ofHumanReproduction andEmbryology European SocietyforPediatricEndocrinology, theEuropean for Endocrinology, thePediatricEndocrine Society, the has been formally endorsed by the European Society and theEuropeanSocietyofCardiology. The guideline American HeartAssociation,TheSocietyforEndocrinology, Society ofHumanReproductionandEmbryology, The Pediatric Endocrinology, TheEndocrineSociety, European Society, incollaborationwithTheEuropean Societyfor Society forEndocrinologyandthePediatricEndocrine The guidelinesprojectwasinitiatedbytheEuropean Guideline developmentconsensusworkinggroup Methods pre-meeting discussionsandintheconsensusmeeting. groups appointedrepresentativeswhoparticipatedin delegates fromothersocietiesalsoparticipated.Advocacy Society forPediatricEndocrinology(ESPE).Several the SocietyforEndocrinology(SfE)andEuropean Cardiology (ESC),theAmericanHeartAssociation(AHA), the EndocrineSociety(ES),Europeanfor (ESHRE), of HumanReproductionandEmbryology with importantcontributionsfromtheEuropeanSociety and bythePediatricEndocrineSociety(PES)inUSA, the EuropeanSocietyofEndocrinology(ESE)inEurope, practice guideline Turner syndromeclinical These guidelines were sponsored primarily by ESE, 2 ). Thesefourquestionsrelatedtothe 177 :3 G6 European Journal of Endocrinology specialists), aswellspecialists, suchasspecialist providers (pediatricians, family doctors, internal medicine providers ofpatientswith TS,i.e.,bothprimary-care This guidelinedocumentwas developedforhealthcare Target group summarized in working/writing group.Responsestothecommentsare were discussedandimplementedasappropriatebythe the professionalsocieties.Allcommentsandsuggestions with/without endorsement by review and commentary A draft of the guideline was submitted for external the endofthisarticle). ( All participantscompletedconflict-of-interestforms individuals providedavaluableandnuancedperspective. from Turner syndromeadvocacycommunity. These Each working group included atleastone member account intherationalebehindrecommendations. upon discussion;minoritypositionsweretakeninto all memberswerepresent).Consensuswasreached some of the participants present, and July 2016, where had twoin-personmeetings(September2015,with Woelfle (pediatricendocrinologist).Theworkinggroup van derVelden (pediatricendocrinologist)andJoachim Stochholm (adult endocrinologist), Janielle A van Alfen- Soderstrom-Anttila (fertilityspecialist),Kirstine Michael Silberbach(pediatriccardiologist),Viveca psychologist), TheoCJSas(pediatricendocrinologist), (pediatric endocrinologist),DavidESandberg(clinical A Quigley(pediatricendocrinologist),Karen Rubin Karen OKlein(pediatricendocrinologist),Charmian geneticist), NellyMauras(pediatricendocrinologist), (pediatric endocrinologist),AngelaELin(clinical Olaf MDekkers(epidemiologist),MitchellEGeffner cardiologist), GerardSConway(adultendocrinologist), and writinggroupareNielsHAndersen(adult PES respectively. Othermembersoftheworking were appointedbytheESEClinicalCommitteeand group, Claus HGravholtand Philippe F Backeljauw, Resource Network).Thechairsoftheconsensusworking United States,theTSGlobalAllianceandTurner as wellseveraladvocacygroups(TSSocietyofthe Children’s HospitalMedicalCenter’s TSFoundation, Center forAdvancingTranslational Sciences,Cincinnati and HumanDevelopment(NICHD),theNational from theAHA,NationalInstituteofChildHealth for themeeting,andadditionalsupportwasobtained Appendix 1 Clinical PracticeGuideline , seesectionon Appendix 2 . supplementary data supplementary C HGravholtandothers givenat systematic literaturesearch. Afterincludingrelevant first stepwastodefinethesequestion(s),followedbya a methodologicalbaseforfourclinicalquestions.The previously ( The methodsusedhavebeendescribedinmoredetail development Summary ofmethodsusedforguideline previous guidelines. to addressthosehealthcareissuesnotaddressedinthe recommendations fordailymanagement.We alsoaimed practical clinicalguideline,withfocusonoperational The overall purpose of the guidelines is to provide a Aims fertility doctorsandspecialistsininternalmedicine. pediatricians, geneticists, endocrinologists, cardiologists, recommendation) and The recommendationsarewordedas explaining whyspecificrecommendationsweremade. all recommendationsprovidedareaccompaniedbyatext this isacknowledgedinthemanuscript.Fortransparency, group, but,ifmembershadsubstantivedisagreements, majority consensusoftheguidelinedevelopmentworking Fig. 1 Supplementary Evidence tablesareprovidedin practice were graded based on expert opinion(5). (4). Additionalrecommendationsbasedongood inconvenience, feasibilityofimplementation,etc.) (patient preferences,goalsforhealth,costs,management and undesirableoutcomes,(3)valuespreferences (1) qualityoftheevidence,(2)balancedesirable graded onlyforthesequestions. evidence. Formalevidencesyntheseswereperformedand outcomes (ifpossible);and(2)ratedthequalityof articles, we(1)estimatedanaverageeffectforspecific practice basedonthelimited availableevidence. of theworkinggroup,andas suchrepresentgoodclinical the workinggroupandaccepted bytheremainingmembers recommendations wereproposed byselectedmembersof classifications’ notformallysubmittedforGRADE,the used forallotherrecommendationsaswell.For‘all ( low( classified asvery The qualityofevidencebehindtherecommendations is practice guideline Turner syndromeclinical ⨁⨁⨁◯ All other recommendations were derived from All otherrecommendationswerederivedfrom For the GRADE questions we took into account: ) and strong ( 3 ). Inshort,theguidelinesusedGRADEas ⨁◯◯◯ . ⨁⨁⨁⨁ suggest ), low( (weak recommendation). (weakrecommendation). ) ( 6 ⨁⨁◯◯ ). This approach was ). This approach was 177 Appendix 2 recommend www.eje-online.org :3 ), moderate ), moderate (strong (strong and G7 European Journal of Endocrinology www.eje-online.org individuals. Therefore,two questions were formulated: have advocated for stricter blood pressure control in TS strikingly increasedfrequency inTS.Someexperts with of aorticdilationoreven AoD –bothobserved hypertension, whichhasbeenlinkedtothedevelopment Turner syndromeisoften accompaniedbyprimary clinical outcomesinTS?(GRADEquestion3) What are effects ofbloodpressure treatment on pregnancy withdifferentprotocolsforoocytedonation. that comparedtheeffectivenessofachievingaviable and aorta dissection). We alsosearched for studies risk of abortion and complications (e.g., pre-eclampsia Outcomes consideredimportantwerelive-bornchildren, birth orviablepregnancyafteroocytedonationinTS. for studiesthatreportedontheprobabilityofalive oocyte donationiftheydesirepregnancy. We searched ovarian insufficiency. Women withTS canbe offered Usually, TSisaccompaniedbyinfertilityduetopremature after oocytedonationinTS?(GRADEquestion2) What istheprobability ofachievingviablepregnancy of onedrugandcrossovertrials. reporting height,studiesonlycomparingdifferentdoses were not eligible: non-randomized studies, studies not (due tooxandrolonetreatment).Thefollowingstudies mortality, cardiovascularsideeffectsandmasculinization outcomes wereconsidered:height,qualityoflife(QoL), or without theaddition of oxandrolone. The following (RCTs) publishedafter1990ontheeffectsofGHwith systematically searched forrandomizedclinicaltrials androgen), withthegoalsofincreasingadultheight.We with GH, with/without oxandrolone (a non-aromatizable Short stature,presentinmostindividualswithTS,istreated TS? (GRADEquestion1) What istheeffect ofgrowth-promoting treatment in search strategyandmainfindingsaredescribedbelow. each question, the eligibility criteria, endpoint definition, and for which available evidence was synthesized. For which aseparatesystematicliteraturesearch wasperformed, The guideline panel formulated fourclinicalquestionsfor eligibility criteria Clinical questions,endpointdefinitionsand Clinical PracticeGuideline C HGravholtandothers

uterine growth(forpossiblepregnancylater)andcantoday sex characteristics,attainingpeakbonemass,normalizing induction of pubertyand later for maintaining secondary need hormonalreplacementtherapy(HRT)–firstfor amenorrhea.MostTSindividualswilltherefore secondary or hypergonadotropic hypogonadismandprimary Turner syndromeisusuallyaccompaniedby Estrogen replacement inTS(GRADEquestion4) series wereineligible. considered; cohortstudieswithoutcontrolarmandcase Randomized aswellnon-randomizedstudieswere and mortalitywereconsideredrelevantendpoints. blood pressuretreatments.Cardiovasculardisease comparing different blood pressure targets and different treatment ismosteffectiveinTS?We searched forstudies in TSbetreatedand(2)whatanti-hypertensive (1) atwhatbloodpressurethresholdshouldhypertension ( over theageof50 years with lessthan5%45,Xmosaicism distal toXq24ontheotherX chromosome,andinwomen of TS in females with one X chromosome and a deletion R 1.2. typical clinicalmanifestationsofTS( second sexchromosome,associatedwithoneormore X chromosomeandcompleteorpartialabsenceofthe containing one in phenotypic females with a karyotype R 1.1. 1.1. DiagnosisandgeneticsofTurner syndrome 1. Recommendationsandtheirrationale ( inclusion ofeligiblearticlesareshownintheflowchart number of articles retrieved, exclusion of articles and final CINAHL, Academic Search Premier and ScienceDirect. The (OVID version),Web ofScience,COCHRANELibrary, following databasesweresearched: PubMed,EMBASE was composedforallfourclinicalquestions.The In cooperationwithatrained librarian, asearch strategy Description ofsearch andselectionofliterature dosing throughoutadolescenceandadulthood? question: WhatistheoptimalHRT, mainlyfocusingon be offeredoocytedonation.Thisleadstothefollowing practice guideline Turner syndromeclinical ⨁⨁◯◯ Fig. 1 Supplementary

We recommendagainstconsideringadiagnosis We recommend considering adiagnosis of TS ). ). ⨁⨁⨁⨁ 177 :3 ). G8 European Journal of Endocrinology or microarraystudies. Xp22.3 deletionsdetectedonly bymolecularcytogenetic this maynotbethecasefor girlswithsubmicroscopic cytogenetically visibledeletions ofXp22.3( deficits typicalof45,XTSarecommoningirlswith ( and a45,Xkaryotype failure, whichareoftenpresentinwomenwithTS cardiac anomalies,neuropsychiatricissuesorovarian ( stature and other TS-associated skeletal anomalies stature homeobox)generesides,frequentlyhaveshort the Xchromosome(Xp22.33)where Females withsmalldistaldeletionsoftheshortarm of features andarenotincludedinthedefinitionof TS. celiac disease( more commoninTS,includinghypothyroidismand profile, andaconstellationofotherdisordersthatare and renalanomalies,aparticularneurodevelopmental loss, distinctivecongenitalcardiovascular, skeletal,digital insufficiency (pubertal delay),early sensorineural hearing include otherfeatures,suchaslineargrowthfailure,ovarian clinical manifestationsofTSshouldbebroadenedto webbing andlymphedema( such asthecharacteristicfacialappearance,withneck definition of TS implies the presence of physical features manifestations ( chromosome in association with one or more clinical and completeorpartialabsenceofthesecondsex phenotypic Turner syndromeisachromosomaldisorderthataffects 1.1.1. Definition ( karyotype management guideline apply to TS patients with any R 1.3. 46,X,idic(X)(q24) 46,XX,del(q24) X-autosome translocation,unbalanced 46,X i(Xq);46,X,idic(Xp) 46,XX, del(p22.3);46,X,r(X)/46,XX 45,X/46,XY 45,X/47,XXX; 45,X/46,XX/47,XXX 45,X/46,XX 45,X Karyotype Table 1 11 Clinical PracticeGuideline , Smaller Xchromosomedeletionscausedistinct 12

). Theydonotappeartobeathigherriskfor Type andfrequencyofchromosomeabnormalitiesinTurner syndrome. We suggestthatthenewgeneralsurveillance ⨁⨁◯◯ females 2 , 9 al 1 Table , whohaveoneintactXchromosome 10 ). ). 13 ). Although the traditional ). Incontrast,neurocognitive 7 , 8 C HGravholtandothers ), wesuggestthatthe 14 SHOX ), although (short

(10%) 10–12 15–25 40–50 Rare % 3 over the age of 50 years withless than5%45,Xcellsare over theageof50 years are excluded from the diagnosis of TS ( Phenotypic maleswith45,X/46,XY(orothervariant) referred toashavingprematureovarianfailure(POF). without shortstatureorotherTSfeaturesandshouldbe amenorrhea orsecondary frequently haveprimary regarding theextentofmosaicismindifferenttissues( of theclinicalfeatures,andgeneraluncertainty differences inpatientages,variabilitythedefinition in TSisdifficult,eventhelargeststudies,due to andphenotypesComparative analysisofthekaryotypes or an abnormal second (or third) cell line in a female. in whichthereisanormal(46,XXor46,XY)cellline in TS ranges from complete 45,X to forms of mosaicism TS maybediagnosedacrossthelifespan.Thekaryotype short statureisalsonotubiquitous( features;who havenoapparentorminimalobservable appearance withmanyphysicaldifferencestoindividuals The broadclinicalspectrumofTSrangesfromaclassic 1.1.2. Karyotype–phenotypeanalysis ( for 45,X that defines TS, although many have used 5% ofage,thereisnospecificlowerlimit less than50 years older womenaspartoftheagingprocess( also excluded,because45,Xmosaicismmaydevelopin Nevertheless, severalgeneralizations canbemadeabout doesnotalwayspredictthephenotype. specific karyotype experience showingthat,in anindividualpatient,the ( the body, althoughthishasnotbeenproven conclusively mosaicism’foranormalcellline somewherein‘cryptic tobirthhave somedegreeofindividuals whosurvive 19 practice guideline Turner syndromeclinical 18 24 , , , 21 Females whohave a deletiondistaltoXq24 There aresufficientcase seriesandanecdotal 19 25 , , , 22 20 26 , ). ). 23 ). Ithasbeenhypothesizedthatall45,X Not TS;isodicentricXq24 Not TS;prematureovarianfailure Various Isochromosome Xq;isodicentricXp Ring Xchromosome Deletion Xp22.3 Mixed gonadaldysgenesis Mosaicism with‘Triple X’ Monosomy X Description 177 10 www.eje-online.org ). Becauseofthis :3 15 17 , 16 ). Inwomen ). Women G9 9 ,

European Journal of Endocrinology www.eje-online.org and aorticstenosis;markedly elevatedfollicle-stimulating especially coarctation of the aorta, bicuspid aortic valve set ears and micrognathia; left-sided cardiac anomalies, epicanthal folds,downslanting palpebralfissures,low- or hypoplasticnails);characteristicfacialfeaturessuch as nuchal fold,neckwebbing,lowhairlineandhyperconvex lymphedema sequence(edemaofthehandsorfeet, pubertal delay, withorwithouttheconstellation of the in anyfemalewithunexplainedgrowthfailureor female withtypicalsigns( R 1.4. 1.1.3. Indicationsfortesting genotype–phenotype associations. to provideamoreevidence-basedanalysisofthe registries withconsistentdataenrollmentareneeded 45,X ( can beomittedforthosewiththelowestlevelsof although long-termechocardiographicsurveillance guidelines applytoTSpatientswithanykaryotype, We management suggestthatthesegeneralsurveillance • • • • • • with a45,Xkaryotype: subgroups.Comparedtopatients the differentkaryotype • • • • • • Clinical PracticeGuideline (X-inactive specifictranscript)( presence ofasmallringXortotheabsence disability ispresent,itdoesnotalwayscorrelatetothe variable intellectualdisability, andwhenintellectual A ringXchromosomeissometimesassociatedwith associated withanincreasedriskofgonadoblastoma( orFISH(fluorescent karyotype The presenceofaYchromosomedetectedbystandard 45,X/47,XXX mosaicismhasamilderphenotype( advanced maternalage( for other indications, such as for due to karyotyping prenatally, asmanyofthesearefoundincidentally a moreseverepresentationthanwhenidentified 45,X/46,XX mosaicismdiagnosedpostnatallyhas miscarriage ( Although morefertile,theyexperiencefrequentearly are morelikelytohavespontaneouspregnancies. 45,X/46,XX andvariousotherformsofmosaicism ( Mosaicism varieswithtissuetypeandpatientage congenital heartdiseaseandlymphaticabnormalities. phenotype, including less prevalent and less severe 45,X/46,XX mosaicism is associated with a milder 19 The diagnosis of TS should be a foremost consideration The diagnosisofTSshouldbeaforemostconsideration ,

20 27 We recommendtoconsidertestingforTSin a ). Collaborative studies involving large TS ). 18 , 28 ). Table 2 22 , 29 C HGravholtandothers ) ( , in situ 33 30 ⨁⨁⨁⨁ ). ). hybridization) is hybridization)is ). XIST 31 32 ). ).

nonverbal skillsandothertraits( learning disabilities,especiallyaffectingvisuospatialor OM andconductiveorsensorineuralhearingloss metatarsal, Madelungdeformityandscoliosis;chronic nevi; boneanomaliesincludingshortfourthmetacarpal/ hormone (FSH);cubitusvalgus;multiplepigmented Sex chromosomeabnormalities,ingeneral,canbe 1.2. Prenatal diagnosis a teamofspecialistswithsuchexpertise. clinicdedicatedtoTS,orattheleastby multidisciplinary care becoordinated and performedinthesettingofa early adulthood( and during late adolescence/ prepubescence (8–12 years) age groups,withpeaksduringfetallife,infancy, late forsuspectedTS( karyotype suggest anewapproachtoguidecliniciansinordering Therefore, chromosome analysis should be repeated are uncertain,especiallyin patientswithmosaicism. of individuals with prenatally diagnosed 45,X karyotype analysis, thepostnataloutcome and obligatory. confirmation ofTSis are notdiagnostic,andkaryotype thickness ( be perfectlynormaltogetherwithnuchalfold also suggestthediagnosisofTS( gonadotropin, inhibinAandunconjugatedestriol)may serum screening(alpha-fetoprotein,humanchorionic retardation ( polyhydramnios, oligohydramniosandgrowth fetal echocardiography),brachycephaly, renalanomalies, cardiac defects(whichshouldbefurtherimagedby of TS are coarctation of the aorta and/or left-sided TS more likely ( frank cystichygroma,however, makesthediagnosisof the autosomaltrisomysyndromes.Thepresenceofa in is commoninfetuseswithTS,butalsoobserved TS. In the first trimester, increased nuchal translucency an importantrolethatsuggestsincreasedlikelihoodof prenatal diagnosticprocedure.Ultrasonographycanplay genetic counselor should be provided or specific result, genetic counseling by a geneticist or anomalies. Regardlessoftheindication,testprocedure age, abnormalserummarkersorthepresenceofmultiple amniocentesis, whether performedforadvanced maternal detected prenatallybychorionicvilloussamplingor practice guideline Turner syndromeclinical Turner syndromeisoftendiagnosedindistinct Because an amniocentesis karyotype reflects fibroblast Because anamniocentesiskaryotype 42 40 ). Ultrasoundandmaternalserumscreening ). Abnormaltripleorquadruplematernal 39 34 ). Other ultrasoundfindings suggestive , 35 , 36 , Table 3 37 , 38 41 Table 2 ). We recommendthat ). ), butthesetestsmay 177 before and after :3 ) ( 2 constitutional , 9 , 10 G10 ). We any

European Journal of Endocrinology a Emotional immaturity Renal aplasia Horseshoe kidney Kidneys Aortic dilation/aneurysm Coarctatio aorta Heart Madelung deformity Scoliosis Genu valgum Cubitus valgus Skeleton Alopecia Vitiligo Nail hypoplasia/dystrophy Inverted nipples Thorax Neck High-arched palate Mouth Hearing defects Ears Ptosis Strabismus Nearsightedness Epicanthus Eyes Phentypic charateristics Gastrointestinal andhepaticdisorders Hypertension Endocrinopathies Failure tothriveduringfirstyearoflife Growth failureandreducedadultheight Feature (see also Table 2 The dataareinconsistent,andthegiven percentagesshouldbeviewedwithcaution. Clinical PracticeGuideline Neurocognitive andpsychosocial issues Skin, nails,andhair Micrognathia (smallmandibularbone) Inflammatory boweldisease Celiac disease Elevated hepaticenzymes Android bodycomposition Thyreoiditis andhypothyreosis Type 1diabetes Type 2diabetes Glucose intolerance Psychological andbehavioralproblems Specific (nonverbal)learning disorder Abnormal positioningorduplicationofrenalpelvis,ureters vessels Bicuspid aorticvalve Congenital hipluxation Short fourthmetacarpal Decreased bonemineralcontent Bone agedelay Multiple pigmentednaevi Lymphedema ofhandsandfeet Increased skinridgecount Broad chest(shieldchest) Pterygium colli(webbedneck) Broad short-appearingneck Low posteriorhairline Abnormal dentaldevelopment Deformity ofexternalear Infection ofmiddleear Table 7 Detailed listofmorecommonabnormalitiesassociatedwithTurner syndromeandtheirapproximateprevalence ). C HGravholtandothers a practice guideline Turner syndromeclinical 15–30, ann.incidence~3% Frequency 95–100 50–80 15–50 14–34 50–80 3–42 7–14 ~25 ~40 ~40 2–3 30 60 10 15 20 20 50 10 50 15 10 10 20 35 35 50 85 10 25 25 30 30 25 40 40 35 60 15 8 3 5 5 5 5 ? ? ? (%) 177 www.eje-online.org :3

G11 European Journal of Endocrinology www.eje-online.org now arebeingdiagnosedwith TS,whichmeansthatpre- pregnancy ratesinallwomen undergoingIVF. Embryos selection to increase being used as a method of embryo pregnancy lossorrepetitive implantation failure.Itisalso 48 programs, and pregnancy rates continue to be studied ( used withincreasedfrequencyin evaluation. for fetalkaryotype the investigationofchoicecontinuestobeinvasivetesting cfDNA analysiswererelatively low ( detection rate(90%)andpositivepredictivevalue(23%) of blood. Arecentmeta-analysisof37studiesshowedthatthe array analysis of cell-free fetal DNA (cfDNA) in maternal sequencing orSNP(single-nucleotidepolymorphism) is insufficientevidencetorecommendNIPTforTSby fetal echocardiographyandgeneticcounseling.There amniocentesis, testing isofferedsuchasmaternalkaryotype, may includeTSinthefetusormother. Additional ( testing (NIPT)havehadimplicationsfordiagnosingTS ofaviablenewborn( with delivery spontaneously abort, these findings are also compatible 45,X fetuseswithpleuraleffusionorcystichygromaoften chromosome constitutions ( of TSmaybeseenwithvirtuallyanythecommon postnatally membranous. defect, secundumtype;andventricularseptaldefects,muscularor webbing. anomalous pinnae,micrognathia,narrowpalate,shortbroadneck,and syndrome. bicuspid aorticvalve),mitralvalveanomalies,andhypoplasticleftheart a Turner syndrome. Table 3 Typically bicuspidaorticvalve,coarctation,stenosis(with/without At leasttwoofthefollowing: As theonlyclinicalfeature: 44 Clinical PracticeGuideline ). Such PGS is currently offered to women with recurrent ). SuchPGSiscurrentlyofferedtowomenwithrecurrent Hearing impairment Other congenitalheartdefects Dysplastic orhyperconvexnails Multiple typicalormelanocyticnevi Neuropsychologic problems,and/orpsychiatricissues Madelung deformity Renal anomaly(horseshoe,absence,orhypoplasia) Characteristic facialfeaturesinafemale Couple withinfertility Unexplained delayedpuberty/menarche Obstructive left-sidedcongenitalheartdefect Idiopathic shortstature Fetal cystichygroma,orhydrops,especiallywhensevere ). When TS is suspected, the possible interpretations ). WhenTSissuspected,thepossibleinterpretations Pre-implantation genetic screening (PGS) is being Pre-implantation geneticscreening(PGS)isbeing The recentdevelopmentsinnon-invasiveprenatal stature c Partial anomalouspulmonaryvenousreturn;atrialseptal b Indications forchromosomeanalysistodiagnose Down-slanted palpebralfissures,epicanthalfolds,low-set in allpatients < 40 years ofagetogetherwithshort . Ingeneral,anyofthefeatures 2 , c 10 C HGravholtandothers in vitro ). Although non-mosaic 43 45 ). , b 46 fertilization (IVF) fertilization(IVF) ). In such cases, ). In such cases, a 47 , challenges are common. Of course, the discussion should challenges arecommon.Ofcourse,thediscussionshould specific typesoflearningdisabilitiesandpsychological intelligence scoresinthenormalrange,althoughmany should beemphasizedthatmostindividualswithTShave short statureandovarianfailuretheirmanagement.It should includevariabilityoffeatures,thepossibility of thedifferentcomorbiditiesinperspective.Thediscussion follow-up ofTSpatientswillbevaluabletoputmanagement input ofaphysicianwithexperienceinthelong-term as wellofrecentadvancesinmanagement( complications and QoLof individuals affectedwithTS, counseling needtobefullyinformedabouttheprognosis, genetic counselorsinvolvedinpre-andpost-diagnostic information is provided to parents. Physicians and are difficult,anditiscriticalthatthebestavailable could haveasignificantimpactontheprevalenceofTS. and counseling.Ifusedmoreextensivelyinthefuture,this implantation hasbecomean additional timefor diagnosis standard karyotyping ( standard karyotyping individuals withYchromosome materialidentifiedon R 1.5. past or(4)whennooriginal reportisavailableforreview. performed inthedistant (3) individualswithakaryotype the findings,(2)thosediagnosedbyabuccalswabonly, toconfirm prenatally shouldhaveapostnatalkaryotype shouldberepeated:(1)allinfants diagnosed karyotype orlow-level mosaicism. despite anormalbloodkaryotype may beexaminedifthereisastrongclinicalsuspicionofTS mucosa cellsorpossiblyurineforbladderepithelialcells, adequate, asecondtissue,suchasskinfibroblasts,buccal ( metaphases maybecountedorFISHstudiesperformed additional not demonstrated with standardkaryotype, ( least 10%mosaicismwith95%confidenceintheblood College ofMedicalGenetics,asthiswillidentifyat asrecommendedbytheAmerican 20-cell karyotype All individualswithsuspectedTSshouldhaveastandard 1.3. Postnataldiagnosis contact withTSsupportorganizations. helpful.Thisisoftenaccomplishedthrough can bevery 51 the presenceandseverityofanabnormalphenotype( decisions regardingterminationareofteninfluencedby be tailored to thespecificfindings of thatfetus, because practice guideline Turner syndromeclinical 26 52 ). Discussion with families of girls and women with TS ). DiscussionwithfamiliesofgirlsandwomenTS , , Decisions regarding pregnancy termination Decisions regardingpregnancytermination There areseveralsituationsinwhichaformal 52 53 ). Although a peripheral blood karyotype is usually isusually ). Althoughaperipheralbloodkaryotype

, We recommendgonadectomy inallfemale 54 ). If mosaicism is strongly suspected, but ⨁⨁◯◯ ). 177 :3 49 ). The ). The G12 50 ,

European Journal of Endocrinology were not identified by karyotyping ( were notidentifiedby karyotyping chromosomes and13large copy-numbervariantsthat than 90%ofthecases,and identifiedtwoderivativeY were comparabletoconventional cytogeneticsinmore of 187TSpatientsusing SNPmicroarraygenotypes supplemental. Xchromosomestructuralclassifications differences, butitsroleinTSiscurrentlyconsideredtobe appearance, multipleanomaliesand/orneuropsychological the studyofpeoplewithgrowthdisorders,unusual using PCR. adjacent totheYcentromereshouldbeamplified FISH analyses.Intheseindividuals,multiplesequences negative forYmaterialbyconventionalcytogeneticand only Y-chromosomal sequencesiscurrentlyrecommended 1%). Forthesereasons,molecularscreeningtodetect without Y chromosome sequences, is low (approximately gonadoblastoma amongallTSpatients,includingthose size and potential selection bias ( in riskestimates,possiblyrelatedtomethodology, sample gonadoblastoma, althoughthereisconsiderablevariation all datatogether, approximately10%maydevelopa long-term outcomeofthiscohortareincomplete.Putting FISH variedfrom4to60%in14studies,anddataonthe Y chromosomesequences that weredetected by PCRor ( Y mosaicismthatisnotdetectableinperipheralblood Ymaterial;FISHofbuccalcellsmaydetect for cryptic essential totestatleasttwothreetissuessearch required ( not includethe mapped adjacent to the centromere to a region that does Ymaterial.Thegonadoblastomalocuswas exclude cryptic longer clinically indicated to use FISH with or smallmarkerchromosomes.We proposethatitisno probes arerecommendedtodeterminetheoriginofring TS cases( than FISHandcandetectYmosaicisminupto12%of (PCR) withmultipleY-specific probesismoresensitive has increased.Real-timepolymerasechainreaction methods, thedetectionrateofY-chromosomal material sequences. With theavailabilityofnewermolecular least 10%offemales with TSharborYchromosome and thedegreeofmasculinization(phenotype).At of Ychromosomematerialandmosaicism(genotype), The riskofmalignancyisdeterminedbythepresence noted inTSindividualswithYchromosomesequences. 61 Clinical PracticeGuideline , inTSindividualswithmasculine features who are Chromosomal microarrayanalysishasrevolutionized The rate of gonadoblastoma among TS patientswith An increasedprevalenceofgermcelltumorshasbeen 62 ). 55 59 , , 60 56 ). Whenvirilizationispresent,itremains , SRY 57 , gene;therefore, 58 ). FISHwithXandYcentromere C HGravholtandothers 56 SRY , 63 64 probesarenot ). The rate of SRY ). Long-term probes to

remaining Xmightexertanimpactonheight,growth premature toconcludewhetherthepaternaloriginof heterogeneity( explains partoftheobserved 74 phenotypical features,withconflictingresults( imprinting effectsmightbeassociated with distinct 68 preferential lossofpaternalsexchromosomes( 45,Yandaslight to thenon-viabilityofkaryotype TS, reportapredominanceofthematernalX,largelydue Most ofthestudiesanalyzingparent-of-origineffectsin variance( as apotentialexplanationfortheobserved with monosomyX,animprintingeffecthasbeenproposed greatly,in TSsubjectsvary evenwhenfocusingonwomen into routineclinicalpractice. microarray databeforethesemethodsareincorporated studies areneededtodeterminetheprognosticutilityof learning disabilities,thusimproving QoL.Itmayalso cardiac abnormalities,hypothyroidism, celiacdiseaseand for problemssuchasstrabismus, hearingloss,renaland diagnosis allowsfortimely screeningandintervention initiation oftherapiesfor pubertal development.Early likelihood ofnormaladultstatureandage-appropriate initiated, thegreaterheightdeficitandlower ( sometimes whenlittleornogrowthpotentialremains is oftenmadeyearsaftergrowthfailureapparent,and infancy with lymphedema and webbed neck, diagnosis problem. ForgirlswithTSwhoarenotidentified in Missed anddelayeddiagnosesofTSremainamajor screening1.4. Newborn not indicatedinroutinecareofwomenwithTS. detect theparentaloriginofremainingXiscurrently chromosome ( reasoning with lower scores in subjects with a paternal X rather reported a subtle difference in visual perceptual imprinting on neurocognitive/socialization function, but another studyfoundnoconvincingeffectofgenomic with amaternallyderivedXchromosome( studies describedamoreseverephenotypeinsubjects individuals whoinheritedamaternalorpaternalX.Some features, moststudiesdescribedthedifferencesbetween and function, including certain neuropsychological system(CNS)morphology Regarding centralnervous (response) orthefrequency of organanomaliesinTS. practice guideline Turner syndromeclinical 34 ). Lackofstatisticalpowertodetectsubtledifferences , , 69 Based onthecurrentlyavailabledata,itseems Based on the observation thatphenotypicalfeatures Based ontheobservation From aclinicalperspective,geneticwork-upto 35 , , 70 36 , 71 , 37 ). SeveralstudiesanalyzedwhetherX-linked 76 , 77 ). ). Ingeneral,thelaterGHtherapyis 177 www.eje-online.org :3 75 Table 4 ), although 72 66 G13 ). , , 65 73 67 ). , , European Journal of Endocrinology www.eje-online.org In contrast,arecentstudy estimated thateachreal-time technology havebeenrapid, butitremainsexpensive. greatest promise( pyrosequencing andreal-time PCRappeartoholdthe been proposedforneonatal screeningofTS,which personnel. However, severalmolecularmethodshave processing time,highcostandrequirementforspecialized has majorlimitationsasascreeningtoolgivenitslong to bethegold-standardtechniquefordiagnosingTS, considered newborn screeningprograms.Karyotyping, and/or populationscreening. greater recognitionofthedisorderthrougheducation of toomanyfollicles.EarlierdiagnosisTSwillrequire before the death for oocyte or ovarian tissue harvesting improve fertilityinsomeindividualswithTSbyallowing standard deviationscore. ADHD, attention-deficithyperactivitydisorder;GH,growthhormone;IQ,intelligencequotient;Mat,maternal;ns,notsignificant;Pat,paternal;SDS, Excludes studieswith50orfewersubjects. Skuse Sagi Hamelin Gould Devernay Chu Author, year Table 4 Clinical PracticeGuideline Ideally, screening for TS would be part of existing et al et al et al et al et al ., 1994(65) ., 2007(449) Influence oftheparentaloriginremainingXchromosomeonphenotype. et al ., 1997(75) ., 2013(518) ., 2006(351) ., 2012(546) 78 ). Advancesinpyrosequencing 161 180 80 80 54 63 n

Mat X 116 128 C HGravholtandothers 55 60 35 43

Pat X 25 20 19 45 52 20

Executive functiontasks Special educationalneeds Cognitive function Biochemistry Growth Clinical phenotype Growth Marital status Employment Education Growth Pooled dataonclinicalphenotype Clinical phenotype Phenotype parameter

normal, experienceminor or noclinicalconsequences, that somegirlsidentified with TSwillbephenotypically diagnosed willneedtobedeveloped. for follow-up,treatmentand supportofthenewborns disorders diagnosedonnewbornscreening,infrastructure confirmation. Likeallother findings willneedkaryotype Y material( with low-levelmosaicism,isochromosomeXqandcryptic was showntoaccuratelydiagnoseTS,includingcases ( karyotypes 95%, andonly0.6%ofthenewbornsrequiredrecallfor with mosaicismweretested)foradetectionsensitivity of patient withTSwasdetected(albeitonly10patients PCR testforTSdetectioncosts$15US.Allbutone practice guideline Turner syndromeclinical (s) Possible drawbackstoscreening includethelikelihood If molecular screening for TSisoffered, positive 80 79 ). ). Mostrecently, whole-exomesequencing Hypertension Cardiac Hearing impairment Response toGH Baseline heightSDS Birth length(cm) Birth weight(kg) Baccalaureate degree Adult heightSDS Height gain Height beforeGH Birth weightSDS Birth lengthSDS Renal Webbed neck Cardiac Renal Webbed neck Cardiac Specific parameter Planning ability Behavioral inhibition Nonverbal IQ Verbal IQ Fasting glucose Triglycerides Cholesterol (with GH) Height velocitySDS BMI SDS Height SDS Birth weight(kg) Renal (s) 177 Stat. analysis :3 P P P P P P P P P P

<

< < < < < < < < < 0.005 ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns 0.05 0.05 0.05 0.01 0.05 0.05 0.05 0.05 0.05 (Xm vsXp) G14 European Journal of Endocrinology attainment ofheightsduring childhoodandadulthood The goalsofgrowth-promoting therapiesaretofacilitate 2.1. Growth-promoting therapies should guidefurtherGHdoseselection( IGF-I valuebetween+2SDSand+3SDS,clinicaljudgment above +3SDS,aGHdosedecreaseiswarranted.Foran above themeanforage.IfanIGF-Ivalueismeasured the measuredIGF-Ishouldideallybenogreaterthan2SDS R 2.5. annually ( promoting therapybymeasurementofIGF-Iatleast R 2.4. 6 monthsthereafter( every 4–6 months during the first yearof treatmentand atleast treatment bymeasurementofheightatleastevery R 2.3. potential issubstantiallycompromised( increasing to68 1.3–1.5 mg/m or R 2.2. already pubertalatthetimeofdiagnosis)( (e.g., shortparentsandpredictedadultheightor is already short or has a strong likelihood of short stature absence ofothertreatablecausepoorgrowth),thechild monthsinthe 50th percentile over6 HVobserved child alreadyhasevidenceofgrowthfailure(e.g.,below years)inthefollowingcircumstances: the before 12–13 ofage,andpreferably treatment early(around4–6 years R 2.1. 2. Growth andpuberty considered after additionalimprovementsin methodology. We conclude that newborn screening for TS should be molecular techniquesfordiagnosisneedstobeestablished. benefits ofnewborndiagnosesTSandthefeasibility years( within 3 screening programswouldbeabletoimplement has high-to-moderatefeasibilityandthatmoststate would leadtoasignificantnetbenefit,thatscreening a highcertaintythatscreeningforthetargetedcondition Recommended UniformNewbornScreeningPanelrequires also bediagnosedandwillneedappropriatefollow-up. (if bothphenotypicmalesandfemalesaretested),may chromosome abnormalities,suchasKlinefeltersyndrome and, thus, may be needlessly concerned. Other sex Clinical PracticeGuideline In the United States, nomination of a condition to the In theUnitedStates,nominationofaconditionto

We recommend using a GH dose of 45–50 We recommendmonitoringthesafetyofgrowth- We recommend initiating growth hormone (GH) We suggestthatforTSpatientstreatedwithGH We recommend monitoring growth-promoting ⨁⨁◯◯ 2 81 µg/kg/day (2.0 /day (4.0–4.5 IU/m /day ). Studies are needed to quantitate the ). Studiesareneededtoquantitatethe ). ⨁⨁⨁◯ mg/m C HGravholtandothers 2 /day) in most instances, /day) inmostinstances, 2 ). /day) if adult height /day) ifadultheight ⨁⨁⨁⨁ ⨁◯◯◯ ⨁⨁⨁◯ µg/kg/day µg/kg/day ). ). ). fashion with a concurrent non-treatment or placebo in whichGHtreatmentwascomparedarandomized 2007 CochraneCenterreview( Despite theplethoraofstudiesGHtreatmentinTS,a 2.2. Efficacy ofGHtreatment most women at completion of growth-promoting therapy. for femalepopulationstandardsisthelikelyoutcome therefore, on adult height (AH). AH within the lower range growth (seesectiononestrogensupplementation)and, and escalationtempowillhaveanimpactonpubertal completion oflineargrowth,theestrogenroute,dosage replacement toeitherinitiateorcompletepubertyprior patients ( and resultsinmodestincreasesadultstatureformost growth-promoting therapyisGH,whichincreasesHV to beginatanagesimilarpeers.Thecenterpieceof that minimize physical restrictions and allow puberty control foratleast1 year ( a RCT. In addition, the use of a run-in period to exclude loss tofollow-upmayintroduce selectionbias–evenin original studypopulation( effects wereonlystudiedin approximately62%ofthe considerable loss to follow-up. For example, long-term were not.Long-termdataoftencharacterizedby five studieswereadequatelyblinded,whiletheremaining considerable riskofbiasintheincludedstudies.Only follow-up durationandreportedendpoints.Thereis a patients, treatmentschedules(doseandduration), large heterogeneity with respect to design, included published between1991and2011.Studiesdisplayed (both GHandoxandrolone)( on theeffectofgrowth-promotingtherapiesinTS the present guideline included 14 randomized studies projected AH( much moredramaticgainsof15–17 using highGHdosesatyoungageshavedemonstrated therapy is a reasonable expectation. Two European studies indicate thatheightgainofabout1 the morerecentplacebo-controlled trial ( years( 7.6 from about 5 to8 predicted/projected heightorhistoricalcontrolsranging AH hadaveragegainsvsconcurrentcontrol( North AmericanGHregistrationtrialstreatedto(near-) AH havebeenpublished( age 4 years, and adouble-blind,placebo-controlledtrialto a 2-yearRCTevaluatingtheimpactofGHinitiationbefore RCT thatfollowedparticipantstoAH( practice guideline Turner syndromeclinical 82 89 ). However, asmostgirlswillrequireestrogen , 92 90 , , 93 cm over periods ranging from 5.5 to 91 , 94 ); similar results were observed in ); similarresultswereobserved ). AformalGRADEevaluationfor 83 87 95 , , 84 82 ). Suchpost-randomization 88 Appendix 2 , ) identifiedonlyfourtrials ). PatientswithTSinthe 85 , cm (mean)vsbaseline 86 177 cm peryearofGH 83 ), andonlyasingle www.eje-online.org :3 ). Morerecently, 87 ). Studieswere ). Thesedata 83 ), baseline G15 European Journal of Endocrinology resulted inagreatergrowthrate( oxandrolone therapytoGH,thisadditionof Additionally, in studies comparing the added value of 88 low-dose estrogenarediscussed inthefollowingsections. strategies andadditionofsupplemental oxandroloneor such asage at theinitiation of GHtreatment, GH dosing of treatmentoutcomes.Factors thatcanbeinfluenced useful informationtofacilitaterealisticexpectations difference fromMPH,whilenotmodifiable,mayprovide and durationofGHtreatment( height SD score ( baseline heightSDscoreandMPHscore;maternal baseline includeyoungage;differencebetween the magnitudeofshort-orlong-termheightgainfrom ( of puberty, longdurationoftherapyandhigher GHdose of therapy, longerperiodoftreatmentbeforeinduction (i.e., mid-parental height (MPH)), young age at initiation tall heightatinitiationoftherapy, tallparentalheights www.eje-online.org Factors predictiveof 2.2.1. Factorsinfluencingtheefficacy ofGHtreatment with TSstandards. height SDscoreshouldstillcontinuetoincreasecompared SD scoreiscalculatedaccordingtogeneralstandards,but GH-treated girlswithTSmaylosegroundwhenheight of endogenousGHandestrogen.Duringthisperiod, growth spurtresultingfromthesynergisticactions pubertal age range because girls with TS lack the pubertal for HVandheightSDscoremaybeunreliableduringthe However,observed. comparisonwithpublished ranges normal range(aboveabout152 adequate pubertalgrowth,andthenAHwithinthelower maintained closetothemeanforage,andtherewas occurred withinthefirsttwoyearsoftreatment,HVwas SDS ( patients, withreporteddifferencesrangingfrom0.5to1.5 was tallerinGH-treatedcomparedtonon-GH-treated comparison of GH to no treatment or placebo ( year orchangeinheightSDS.Instudiesthatenableda underpowered ( was notwelldefined.Finally, manysmallstudieswere endpoint the results.Inalmostallstudies,primary non-compliance ( 85 Clinical PracticeGuideline , , 89 Factors such asthe patient’s baseline height and If catch-upgrowth to within the normalrange Most studiesreportedonHV, expressedaseithercm/ 93 83 ), the GH-treated group had a greater growth rates. , , 94 87 , , 100 88 ). , 97 105 101 96 ), andnostudyreportedonmortality. ); weight SD score and dose, frequency ) mayhamperthegeneralizabilityof , taller adultstature 102 , 103 , 104 88 C HGravholtandothers , 95 cm or60 ). Factorspredictiveof 94 , , includearelatively 96 100 , 97 ). , inches) was inches) was 98 , 99 83 ). AH , 87 ,

transition periodafterthecompletionofpuberty. physiological rationaleforcontinuingGHtreatmentintothe remains (boneage girl issatisfiedwithherheightoruntillittlegrowthpotential puberty canbeachieved.Therapymaycontinueduntilthe that thegoalsforbothoptimaladultstatureandtimingof allow for age-appropriate induction of feminization, such likely toresultingreaterheightgainsduringchildhoodand treatment initiation( registries reportasimilarpositiveeffectofyoungerageat in national or pharmaceutical company-sponsored treatment effect.Analysesoflargecohortstudiesfollowed to puberty( 104 indicate thatyoungerageattreatmentinitiation( been firmlyestablished,butvariouslinesofevidence The optimal age for initiation of GH treatment has not 2.2.2. AgeatGHinitiation data indicate that girls with TS appear to be at increased data indicatethatgirlswith TSappeartobeatincreased assessment ofthelonger-term safetyofGH.Observational adverse outcomes( studies thathaveadequatepatient numberstodetectrare equivalent toevidenceofitsabsence.Largeobservational endpoints and absence of evidence of a safety signal is not recognize thatclinicaltrialsarenotpoweredforthesesafety OM andhearingloss( ( 118 115 and risk factors for cardiovascular disease ( generally beenreassuringwithrespecttobloodpressure Safety ofGHtreatmentinTSlong-termclinicaltrialshas 2.2.4. SafetyofGHtreatment following carefuldiscussionofpotentialrisksandbenefits. prognosis, withintheauthority-approveddoserangeand poorheight dose maybeconsideredingirlswithvery routinely recommended,butanincreaseintheGH days/week.HigherGHdosesarenot in divideddoses7 4.5–9.5 mg/m 4.3 IU/m 50–54 at a dose of 0.350–0.375 GH therapyforTSinNorthAmericaisgenerallyinitiated 2.2.3. GHdoseandfrequencyofadministration practice guideline Turner syndromeclinical 119 ), bodycomposition( ), carbohydrateandlipidmetabolism( , Relatively early GH initiation, around 4–6 years of age, is Relatively earlyGHinitiation,around4–6 years ofage,is ), bodyproportions( 106 µg/kg/day), inEuropeat1.3–1.4 , 2 /day; 45–50 107 101 ), includingatleast4 years oftreatmentprior 2 we (0.6–1.4 mg/m /week , 105 ≥ 14 years andHV 122 , 100 108 µg/kg/day) andinAustralasiaat 121 , , 123 , 113 103 109 ). However, itisimportantto 112 mg/kg/week (equivalent to , , , ), isassociatedwithgreater , 124 104 117 120 ) provide more robust ) providemorerobust < , ), bone mineralization ), bonemineralization 106 2 2 ) and prevalence of ) andprevalenceof /day), administered 177 cm/year). There is no cm/year). Thereisno , mg/m :3 110 113 112 , 111 2 , , /day (4.0– 116 113 ). 83 , G16 , , 117 114 85 , , ,

European Journal of Endocrinology modest synergisticincreases ingrowthresponseby with thestandardGHdosealone ( delayed, and/orAHoutcome islikelytobeunsatisfactory diagnosis ofTS(andthereforeGHtreatmentinitiation) is kg/day andmaintainedbelow0.05 oxandrolone fromtheageof10 years orolderat0.03 R 2.6. steroid oxandrolone 2.3. Concomitanttreatment withtheanabolic databases( other observational while noincreaseswerereportedinanalysesfromtwo reported anincrease vs generalpopulationrates( study open question,asanalysisfromoneobservational (T2DM) isincreasedbyGHtreatmentinTSremainsan antagonism ( regional fatdepositionmayoutweighGH-inducedinsulin suggesting thatbeneficialeffectsonbodycompositionand tolerance inGH-treatedvs-untreatedgirlswithTS, abdominal adiposityandsignificantlybetterglucose metabolism. Incontrast,anotherstudyfoundreduced underscores theneedforcarefulfollow-upofcarbohydrate yearsafterdiscontinuationofGHinonestudy( 5 134 in patients with TS havebeen reassuring ( regarding exacerbationofsuchproblemsbyGHtreatment secretion ( and have a specificdefectin glucose-stimulated insulin disorders ofcarbohydratemetabolism( neoplasia inGH-treatedpatientswithTS( registries providenoevidenceofanincreaseinrisk in GH-treated patients with TS ( Although therehavebeenrarecasereportsofneoplasia event thanGH-treatedchildrenwithothergrowthdisorders. girls withTSmaybeatgreaterriskofthisspecificadverse about10%oftheoverallsubjects,suggestingthat registry with TS,thetotalnumberofpatientsTSinthis same study, 3 of10 reported casesof pancreatitis were ingirls increase inlineargrowthstimulatedbyGH( ( in girlswithTSthanchildrenothergrowthdisorders development orprogressionofscoliosiswasmorecommon ( with idiopathicGHdeficiencyorshortstature epiphysis duringGHtreatmentcomparedwithchildren risk ofintracranialhypertensionandslippedcapitalfemoral 122 123 Clinical PracticeGuideline , Patients with TS are inherently at increased risk of Patients withTSareinherentlyatincreasedriskof Although well-controlledstudies havedemonstrated ). Both problems may be exacerbated by the rapid ). Bothproblemsmaybeexacerbatedbytherapid study,). Inanalysesofanotherlargeobservational 135

, 136 We suggestconcomitanttreatmentwith 131 , 117 137 , ). Whether the risk of type 2 diabetes ). Whethertheriskoftype2diabetes 133 ), persistently reduced insulin sensitivity ), persistentlyreducedinsulinsensitivity ). Although most long-term data ). Althoughmostlong-termdata 122 126 C HGravholtandothers , ⨁⨁⨁⨁ 124 , 127 mg/kg/day, ifthe ). 122 ), data from GH ), data from GH 130 113 ). , 125 128 , , 131 116 ). In this ). Inthis ,

129 , , 138 132 116 118 mg/ ). ), ), ) ) ,

addition ofoxandroloneduringtreatmentwithGH( promoting treatmentscheduleinTS. a finalevidence-basedverdictontheoptimalgrowth- prevents performingaformalmeta-analysisandprohibits group (16vs5%)( oxandrolone and GH group compared to the GH only In onestudy, virilizationwasmoreoftenreportedinthe show agrowtheffectofadditionoxandrolonetoGH. GH-treated only ( oxandrolone- andGH-treatedpatientscomparedto cm higher in further that AH was approximately 2–5 than 0.05 at adoseof0.03 initiated should notbedoneuntilaroundage10 years, therapy. If thedecision is madeto add oxandrolone, this and acne) prompts the need for caution in the use of this virilization (e.g.,clitoromegaly, voicedeepening,hirsutism effects ofdelayedbreastdevelopmentanddose-dependent 97 preferred estrogenandthat itbeadministeredbya R 2.9. adult dosingover2–3 years ( ofageincreasingto should startbetween11and 12 years R 2.8. 2.5. Sexhormonereplacement currently notrecommended. estrogen replacementasagrowth-promotingtherapy is has notbeenassessed.Theadditionofvery-low-dose estrogen havenotbeenoptimized,andlong-termsafety this approach, the dosing and administration of childhood windows ( withinspecificdevelopmental cognition andmemory one-quarter ofthegirls,andmodestimprovementsin AH, normalizationofthetimingthelarche forabout with GHdemonstratedamodestsynergisticincreasein promoting agentduringtheprepubertalperiodcombined ultra-low-dose oralethinylestradiolasagrowth- further promotegrowth( estrogen supplementation in the prepubertal years to R 2.7. ultra-low-dose estrogen 2.4. Concomitanttreatment withchildhood practice guideline Turner syndromeclinical , 139 However, nootherindependenttrialshaveevaluated One double-blind,placebo-controlledtrialusing

,

We suggest to notroutinelyadd very-low-dose 140 We suggest that low-dose estradiol (E2) is the We recommendthatestrogenreplacement 87 mg/kg/day. TheGRADEevaluationshowed , , 143 141 mg/kg/day andmaintainedatnogreater , , 95 144 142 139 , 139 , ), thepotentialforunwanted ). Heterogeneitybetweenstudies 145 ⨁⨁◯◯ , 140 ). ⨁⨁⨁◯ ). Thus, existing literature ). 177 ). www.eje-online.org :3

G17 95 , European Journal of Endocrinology E2, 17 *See discussionofhowtoapplypatches below;**notavailableintheUSasmonotherapy;***not inEurope. Depot E2*** Ethinyl estradiol(EE)** Micronized 17 Transdermal E2 Preparation Table 5 www.eje-online.org reaching thesystemiccirculation. ofE2into Thus,delivery by thelivertoestroneandothermetabolitesbefore the body. Orallyadministeredestrogensare metabolized the livertoagreateramountofestrogenthanrest of system andaftermetabolismbytheliver, thusexposing circulation onlyafterabsorptionintotheportalvenous contrast, estrogengivenorallyreachesthesystemic isphysiologic( replacement estrogendelivery as othersomatictissues,andasystemicrouteof circulation; thus,theliver receivesthesameconcentration the postmenopausalsetting( pro-coagulable state( the oralroute( after accumulation ofnon-physiologicestrogensobserved first-pass effectthroughtheliver, therebyavoidingthe withoutthe include: a more physiologicrouteofdelivery studies andtheoreticalconsiderations.Theoreticalreasons we presentdatainsupportofTDusebasedonavailable from initiationofpubertyuntiladulthood.Therefore, choice. However, thereisnostudytodateofTDuse use oftransdermal(TD)preparationsasthepreferred but, sincethepreviousguidelines( to inducepubertaldevelopmentisstillbeingevaluated, and normalizinguterinegrowth. sexcharacteristics,attainingpeakbonemass secondary for inductionofpubertyandmaintainingfemale 6% ofthesesubjects( ( thelarche, occurringmostofteningirlswithmosaicism Approximately one-thirdofgirlswithTShavespontaneous amenorrheaduetogonadaldysgenesis. secondary or hypergonadotropic hypogonadismandprimary treatment ( ofestrogen breakthrough bleedingoccursorafter2 years R 2.10. ( systemic routeandthatthetransdermalispreferred 146 ⨁◯◯◯ Clinical PracticeGuideline Estradiol (E2)isnormallysecretedintothesystemic The optimalestrogen replacement therapyregimen Most patientswithTSwillthereforeneedHRT– Turner syndromeisusuallyaccompaniedby , β -estradiol. 147

Recommended estrogenreplacementoptionsforfeminization inadolescentTS. , 148 ). We recommendaddingprogesteroneonce ⨁⨁⨁⨁ β oralE2(E2) ). Regularmenstrualcyclesoccurinatmost 149 ). Thelatterrouteisassociatedwitha ). 148 150 ). ) andincreasedriskofstrokein 151 ). C HGravholtandothers 2 ), studiessuggest Pubertal initiationdose 152 0.2 mg/month 0.25 mg/day 3–7 µg/day* ). In 2 µg/day estrogen replacement optionsaredepictedin estrogen preferred bymostpatientswhenaTDoptionisavailable. girls, andparenteraladministration(injection)isnot A transvaginalrouteisnotrecommendedforprepubertal administration more closely mimics normal physiology. the systemiccirculation byTD,transvaginalorparenteral symptoms ofhypogonadism. is alsobasedonuterineandbonehealth,aswell supplementation ofendogenoushormones.Adultdosing is forestrogenreplacementofadeficientstate,not important to remember that the recommendation Itis inanorexianervosa. uterine health,asobserved estrogen replacementmaybedeleterioustoboneand puberty andprotectionofgrowthpotential.Delaying initiation doseisbasedonanaverageprogressionof of pubertyinanaveragegirlandminimizerisks.The The goalsofreplacementaretomimictheprogression oeeey6 monthsusing 4–6 dosechangesbetween 6 dose every This theoreticallytranslatesintoa25–100%increase in until adultdosingisreachedovera2-to3-yearperiod. monthstomimicthenormalpubertaltempo 6 every preparations arepreferableforinitiationofpuberty. growth response( yearsmaydecreasethe day administeredpriorto14 152 interfere with the growth response to GH therapy ( (EE), TDE2,oralE2andsystemic(depot)donot ethinylestradiol been initiated,becausevery-low-dose height potentialwhetherornotGHtreatmenthasalready 154 B canalsobeusedtopredictovarianfailureinTS( anti-Müllerian hormone(AMH)andundetectableinhibin future replacementtherapyifgonadalfailureoccurs.Low forspontaneouspubertyisappropriate,with observation orearlier. Ifgonadotropinsarenormalforage, 11 years and FSHmaybemeasured annually starting atage gonadotropins areelevated.Luteinizinghormone(LH) years,aslong treatment shouldbeginat11–12 practice guideline Turner syndromeclinical , , To mimicnormalphysicalandsocialdevelopment, Timing, routeanddose of somerecommended Incremental doseincreases can occurapproximately 155 156 ). Using low doses of estrogen is crucial to preserve ). Usinglowdosesofestrogeniscrucialtopreserve , 157 ). ItshouldbenotedthatEEdoses 140 , 158 ). Therefore,thelower-doseE2 25–100 µg/day 10–20 µg/day Adult dosing 2 mg/month 1–4 mg/day 177 :3 al 5 Table 87 ≥ G18 3 µg/ 153 , 94 , , . European Journal of Endocrinology ( Assessment of risk must be individualized for each woman the benefits,around averageageofmenopause. should persistuntiltherisk ofcontinuationoutweighs various progestinoptions. this risk( However, norpregnane derivativeswerefoundtoincrease and pregnane-ornortestosterone-derivedprogestins. showed noincreasedriskofstrokewithprogesterone sequential progestationalagent.Arecentpublication treatment with17 and adult women with TS should preferably continue each monthforwithdrawalbleeding, added for10 days not seem to induce breast cancer ( ( ( breast cancerrisk,butthedataforthisarerelativelyweak or medroxyprogesterone,ispreferredbasedondecreased progesterone,e.g.Prometrium(100–200 crystalline unopposed estrogen( of endometrialcancerassociatedwithprolonged yearsoftreatment,duetotherisk occurs, orafter2 progestin mustbeaddedoncebreakthroughbleeding and ingirlsgeneral( seen inTSgirlswithspontaneouspuberty(1.9 year) ( in approximately2.25 year, whichissimilartothetempo Each oftheseregimensresultsinTanner stage4breasts onset and for oral E2 slightly faster onset ( The startingdosesfordepotE2leadtoslightlyslower inmostgirls( within 6 months until adultdosingmaybeshortened. If girlsarealreadyolderatinitiation,thedurationoftime possible, girlsmayremainonlowerestrogendoseslonger. for adoseincrease.Ifpotentialtallerstatureisstill determinants residual growthpotentialaretheprimary assessment, patientsatisfaction,ageandoften for optimalgrowthremaintobedetermined( allows titrating dosage, if desired, though E2 concentrations given. Estradiolmeasurementusinganultrasensitiveassay hypogonadal womenuntilhigherdosesofestrogenare as concentrations remain elevated in hypergonadotropic or FSHisnotrecommendedduringestrogentreatment different preparations.RoutinemonitoringofserumLH outcomes inrelationtotherateofdoseincreasefor However, nostudiestodatehaverigorouslystudied the initiationand adult dosesportrayedin 164 166 164 Clinical PracticeGuideline Once adultreplacementdosesarereached,treatment Girls withTStypicallyhaveanormaluterus,and Studies oftheregimensreportonsetbreastbuds , , , 165 167 170 151 ). However, theriskofbreastcancerislowinTS , ). Screeningforthromboembolic riskshould 168 ). StudieshavenotbeendoneinTScomparing ), andlong-term treatment withHRTdoes β -estradiol incombinationwitha 163 161 ). Inadultwomen,micronized ). C HGravholtandothers 94 169 , 159 ). Progestin can be , 160 156 149 , , 161 159 ). Clinical al 5 Table , , 162 160 158 mg) ). ). ) . to postponeestrogentherapy( screening isdoneonlytoeducatethefamilyonrisks,not However, routinescreeningisnotrecommended,and be performedingirlswithapersonalorfamilyhistory. the applicationofa14–25-µgpatch,lowestdoses that cyclicaladministrationofpatches,commencingwith application ( and includepracticalguidelinesforcuttingthepatch or breastdevelopmentwithuseofafractionatedpatch, labels, twostudiesreportpubertalE2concentrationsand/ peak ( overnight mimicsthenormalearlymorningserumE2 dose (one-quarterofa25-µgpatchorabout6.25 have not been directly compared. A fractionated patch girls overdepotinjections,althoughthesetwomodalities treatment ( pubertal growth and development in conjunction with GH low-dose, depotE2monthlyinjectionsinitiatednormal published between1995and2013.Two studies( TD hormonereplacementtherapiesinTS.Studieswere randomized studiesonthedifferencesbetweenoraland the bestapproachforpatchapplication. needed before recommendations can be made regarding without estrogenexposureisunknown,furtherdataare similar results( commercially available, for 1 weekmonthly, mayachieve ( TG werenotdifferentacross routesofadministration. concentrations oftotalcholesterol, LDLcholesteroland difference −8.09;95%CI−12.7,−3.5).Theplasma oral estrogenasshownin a decreaseinHDLplasmaconcentrationscompared to concentrations ( provided in GRADE scoringperoutcomeandevidencesynthesis is included studiesareshownin studies included a small number of subjects. Details of the included studies.Allstudieswerenon-blindedandseveral endpoints. Overall,thereisaconsiderableriskofbiasin (dose andduration),follow-updurationreported studies comparedoralvsTDE2),treatmentschedules design, includedpatients,choiceoftreatment(only3 studies displayedlargeheterogeneitywithrespectto on differencesbetweenroutesofadministration.Included were excluded because they did not report sufficient data practice guideline Turner syndromeclinical 149 A randomized controlled trial showed that early, very The GRADEevaluationofHRTfoundseven In twostudies,bonemineral densitywasstudied Five studiesreporteddataonHDLcholesterol , 160 162 ). Both studies showed a somewhat better lumbar ). Althoughnotrecommendedbytheproduct 156 Appendix 3 162 ). Transdermal E2islikelytobepreferredby , 149 156 172 , ). Becausetheeffectofweeks ). Thereisalsoapublishedopinion 160 . , 172 Appendix 4 , 171 Supplementary Fig. 1 Supplementary 175 ). , 176 177 www.eje-online.org (weightedmean :3 ). TDE2showed µg) applied 173 G19 , , the 174 ) European Journal of Endocrinology www.eje-online.org effects onlipidsorbinding proteins causeanappreciable epidemiological studies( withoralestrogenin thromboembolic riskobserved This isconcerninginthecontextofincreased such asestronesulfateandserumestrogenicbioactivity. a markedincreaseinconjugatedestrogenprecursors, both groups.However, oralestrogenwasassociatedwith titrated tothoseofnormallymenstruatingadolescents in or plasmalipidswhentheE2concentrationswere no differencesinbodycomposition,bonemineralization ( girls withTSfollowedfor1 year administration inadolescence,oralvsTD,usingE240 morning administration( injections ofGHmaybepreferablecomparedwith administration oforalestrogentogetherwithevening of administration.BasedonlyononeRCT, evening individualized dose( pubertaldevelopmentnotinferiortoan a satisfactory RCT concludedthatalowfixeddoseofestrogenproduces dose compared with the low-dose estrogen group ( alkaline phosphatasewassignificantlyhigherinthehigh years,althoughbone-specific find differencesduring5 bone mineraldensityoranthropometricmarkersdidnot study ontheeffectofdoseadministrationE2 (FSH, alkalinephosphatase,osteocalcin)( cross-links) andsomerequiredhigh-dosepreparation deoxypyridinoline unaffected byeitherofthem(urinary 1,25-dihydroxyvitamin D,liverenzymes),somewere low orhighdose(hypotrophicendometria,insulin,PTH, and foundthatsomeparameterswereaffectedbyeither one studycomparedconjugatedandethinylestradiol 178 fixed andindividualized doseof estrogentherapy ( and onerandomizedstudyonthedifferencebetween of administration (morning oreveningadministration) with high-dosetherapy, onestudyontheeffectoftiming that comparedlow-doseestrogenreplacementtherapy affect glucoseorinsulinconcentrationsinanystudy. bone density. was tooshorttodrawmeaningfulconclusionsregarding However, samplesizesweretoosmallandfollow-up (weighted meandifference0.93;95%CI0.68,1.19). Z-score after TD usecompared with oral administration Clinical PracticeGuideline , Only one study has directly compared the route of Very littleevidenceisavailableonthetiming With regardtothedoseofestrogenadministration, Additionally, weincludedonerandomizedstudy The typeandrouteofestrogenadministration did not Current evidencedoes not indicate that the hepatic 179 ). 178 ). 181 179 , ). 182 C HGravholtandothers , 149 183 ). Thestudyfound ). 177 ). ARCT 180 177 ). A , insulin concentration,proteinturnover, lipolysis( in glucose( low-dose TDE2.Therewerenosignificantdifferences clinical differencebetweenlow-doseoralestrogensvs route ( estrogen-progestin administeredorallyorviatheTD TS ( therapy ( evidence oflivertoxicityfromestrogenreplacement administration ( lipids betweengroupswithdifferentroutesofestrogen oral E2( reporting significantlyhigherHDLcholesterolafter ( (0.3–0.5 mg/day) to belowerfollowingeveningoralE2administration (during anOGTT)aswellinsulinresistancetended vs oralestrogen treatment. Glucagon and insulin levels waist-to-hip ratio( osteocalcin, highlysensitiveC-reactiveprotein,BMIor pubertal induction and maintenance, but 20–30 that EE treatmentregimen gives rise to satisfactory treatment all influence uterine growth. One studyshowed as route,dose,ageatonset of treatmentandduration estrogen therapyonuterinevolumearestillinconclusive similar concentrations( study in which TDand oral E2 doseswere titrated to girls ( spine bonemineraldensity(BMD)inonestudyofTS been reportedasbetterthanCEE(0.3–0.45 forms ofestrogen( suppression. Dose–responsestudiesarelackingformost with somesuggestingnoeffectandothers concentration inGH-treatedsubjectsareinconsistent, influence ofdifferentroutesestrogentherapyonIGF-I patients ( 182 women withexistingriskfactorssuchasobesity( of treatment in the oral group, and more pronounced in increased thromboembolicrisk,especiallyinthefirstyear replacement inthepostmenopausalsettinghaveshown looking atoralconjugated estrogens (CEE) vsTDE2 raise bloodpressuresignificantly( unless containingananti-mineralocorticoidprogestin, contrasts with EE-containing contraceptives, which, although E2 causes salt and water retention ( oral orTDroutes,lowersbloodpressure( practice guideline Turner syndromeclinical , Data concerningtheinfluenceofdifferentroutes Transdermal E2 administration (25–37.5 EE exerts dose-related suppression of IGF-I in GH-naïve 174 183 160 190 , ). 186 ), while no differences were observed in another ), whilenodifferenceswereobserved 172 187 196 ). Replacement therapy with E2, by either 149 ). Liver enzymes were elevatedin untreated ), therewerenosignificantdifferencesin , , 188 ), insulintolerance( 149 197 179 149 184 , , ). However, dataconcerningthe ). With theexceptionofonestudy 175 189 , , 172 149 185 , ) and reduced by exogenous 176 , ). 174 ) betweengroupswithTD , , 177 175 195 ). There was also no 177 , 179 177 ). Severalstudies :3 191 ). , 184 mg/day) for µg/day) has , 194 192 ), fasting µg daily ). This , G20 193 175 181 ), ), ,

European Journal of Endocrinology women. Spontaneouspregnancies occurin4.8–7.6% are fertileoftenentermenopause earlierthannormal with theirowneggs,and the fewTSindividualsthat age ( should begiventoofferingfertilitytreatmentatayoung rapidly with age, if at all present, and consideration their probabilitytoconceivespontaneouslydecrease R 3.1. 3.1. Spontaneouspregnancies of thegreatestissuesaffectingtheirQoL( are infertile.Women withTSreportinfertility tobeone Due toearlyovarianinsufficiency, mostwomenwithTS technologies andpregnancy 3. Fertility, reproductive assisted replacement ( ovarianfunctionoradequateestrogen despite preserved demonstrate characteristicneurocognitiveprofiles data indicate that, on average, adult women with TS sexual functioninpatientswithTS( both estrogen use and age of puberty did not influence the patient'ssexlife( optimize self-esteem,socialadjustmentandinitiationof should beinducedataphysiologicallyappropriateageto positive influenceonseveralHRQoLscales( satisfaction withbreastdevelopment(andheight)hada reported normalhealth-relatedqualityoflife(HRQoL); height and had age-appropriate pubertal development therapy isinitiated( short TSgirls,as suggested above,and until estrogen very adjunctive treatmentwithoxandrolonebeconsidered in that are minorand/ortransient.Areasonablesuggestionis menarche and increase clitoral size slightly, but these effects progression inresponsetoestrogenreplacement,delay maximum 2.5 reported inpostmenopausalwomen( view ofthromboembolicandcardiovasculardiseaserisks been nostudiesinchildren,wesuggestagainstCEE Fertility sectionforoptimaldosing).Althoughtherehave related todoseanddurationoftherapy( affected bythetypeofestrogenused( ( failed toinduceafullymatureuterusin50%ofthegirls 198 Clinical PracticeGuideline Only fewTSwomenwill be abletogetpregnant The youngwomenwithTSwhoreachednormal Low-dose oxandrolone (0.03–0.05 ). Moststudiesreportedthatuterinevolumewasnot ⨁⨁⨁⨁

We recommendcounselingfemaleswithTSthat 208 ). mg/day) may modestly slow pubertal ). 95 205 , 139 , , 206 141 ). Onestudyshowedthat , C HGravholtandothers 158 , 150 203 199 ). 49 207 ). 201 ). , 204 ). Available 200 mg/kg/day; , ). Puberty 202 ), butis ) (see

to behigh:30.8–45.1%( miscarriages afterspontaneouspregnancywasreported of women with TS ( with the reference group, women with a TS karyotype with thereferencegroup,womenaTSkaryotype and AoDoccurredinoneTSwoman( women withTScomparedto3.0%inthecontrolgroup, of 10womenwas45,X.Pre-eclampsiaoccurredin6.3% unknown in52%atthetimeofpregnancy. Thekaryotype were conceivednaturally, andtheTSdiagnosiswas of thegeneralpopulation( obstetricaloutcomeswerecomparedwiththose karyotype, 8–20% ( rate ofearlypregnancylossinthegeneralpopulationis remaining etiologiesweremultifactorial( these, two-thirds were TS or Down syndrome, and the 34% werecomplicatedbyafetalmalformation.Of women foundthat,ofthe58%resultingina live birth, 28 without unnecessary delay.without unnecessary (includingstandard IVF)atayoungageand treatment consideration shouldbe given toofferingfertility with autologousoocytes decreases rapidlyandthat vital tocounselthattheirchanceofpregnancy young age, it is from a very decreasing ovarian reserve rates ( resultsinlower IVFpregnancy decreased ovarianreserve live birthratewas5.7%( mosaic TS. The clinical pregnancy rate was 8.6%, and standard IVFinatotalof35cycles22womenwith in womenwithTS,Doger of 12 years( ofyoungTSgirlsbeforetheage for fertilitypreservation R 3.3. ( option hyperstimulation isapossiblefertilitypreservation aftercontrolledovarian that oocytecryopreservation with persistentovarianfunctionshouldbecounseled R 3.2. autologous oocytes 3.2. Assistedreproductive technologies(ART) with between thetwogroups( the control group. Therate of birthdefects did notdiffer vs11.8%in rate was35.6%inwomenwithTSkaryotype with alowermedianbirthweight.Thecesareansection gave birth to children at an earlier gestational age and practice guideline Turner syndromeclinical ⨁◯◯◯ ). Astudyof160spontaneouspregnanciesin74TS In a retrospective study of 115 women with a TS In theonlypublishedstudytodateofIVFstimulation

215

211 We recommendagainstroutineoocyteretrieval We suggestthatyoungmosaicTSwomen , ). ). ⨁◯◯◯ 216 ). GiventhatTSwomen have rapidly 18 ). , 212 28 214 upeetr al 1 Table Supplementary 212 t al. et , ). 209 ). Itiswellestablishedthat ). Mostofthepregnancies ), but the frequency of reportedoutcomesof 177 www.eje-online.org :3 213 210 ). Compared ). Therisk G21 ) ( 18 ,

European Journal of Endocrinology www.eje-online.org incidence ofpre-eclampsia rangedbetween18%and ( pregnancies andashigh100% inmultiplepregnancies pregnancy has been reported to be 35–67% in singleton Table 3 high riskforobstetricalcomplications( contraceptive-based regimens( based regimensresultinbetteruterinedevelopmentthan mature uterinesizeandconfiguration( treated withoralorTDE2CEEmayattainanormal abortion ratesinwomenwithTS( term hypoestrogenismmayalsoincreasespontaneous and/or diminishedendometrialreceptivityduetolong- structurally abnormaluterus,autoimmunemechanisms 222 loss inTSfemalesrangingfrom16to80%( was 28%(95%CI23–34%)( transfer effects model)ofclinicalpregnancyperembryo 224 donated oocytes( 40% ( outcomes). (i.e. inclusionofpatientsbecausespecificallypositive to smallsamplesizesandthepotentialofselectionbias 1990 and2011.Riskofbiaswasmoderate,mainlydue line andXdeletions.Studieswerepublishedbetween other variantssuchasmosaicismwith45,Xinonecell totaling 179patientswitheithermonosomy(45,X)or size ofTSwomenperstudyvariedfrom3to30subjects, on eligibilitycriteriaandendpointdefinition.Sample After GRADEevaluation,11studieswereincludedbased 1990, butthenumberofpatientstreatedhasbeensmall. clinical pregnanciesinoocyterecipientswithTSsince achieve aviablepregnancy. Therehavebeenreportsof women withTS( specialists andcardiologistswithexpertiseinmanaging teamincludingmaternal–fetalmedicine multidisciplinary pregnant womenwithTSshouldbeundertakenbya R 3.5. ( after thoroughscreeningandappropriatecounseling R 3.4. oocyte donation(OD) 3.3. Assistedreproductive technologieswith ⨁⨁⨁⨁ 222 Clinical PracticeGuideline , , Women withTSwhoconceiveOD are at Previous studieshavefoundthatwomenwithTS Initial studiesfoundhighratesofearlypregnancy The clinicalpregnancyratevariedbetween16and For mostpatientswithTS,ODistheonlywayto , 223 225

upeetr al 2 Table Supplementary 224 ). InTS,theincidenceofhypertensivedisorders We recommendconsideringODforfertility, only ,

, 224 ). , We recommendthatmanagementof 226 225 ), likelyrelatedtoinadequateHRT(228).A , , 227 ⨁⨁⨁◯ 18 226 ). Thepooledproportion(random , 217 , 231 , ). 218 Supplementary Fig.2 Supplementary , ), likeotherrecipientsof 232 199 , 219 C HGravholtandothers 229 , ). , 233 220 ). ). Thereported , 230 Supplementary Supplementary 221 219 ). Estradiol- , ,

222 220 ). , , 221 223 , , between 0 and 11% in published studies ( difficult. Theperinatalmortalityratehasbeenreported not reportedseparately, whichmaketheirinterpretation the outcomesofsingletonandmultiplepregnanciesare weight 12–40%( has beenreportedtobe9–33%andthatoflowbirth section rateis31–85%insingletonpregnancies( disorders ofpregnancyis13–39%,andthecesarean oocyte recipientswithoutTS,therateofhypertensive ( while thecesareansectionrateisashigh82–100% 44% insingletonpregnanciesand75–100%multiples, in 44%oftherecipients.Ten womenhadaknowncardiac wasobserved of 7.4%.Inthiscohort,the45,Xkaryotype ( gave birthaftertreatmentwithODbetween1992and2011 232 they tendtoexperienceearly menopause( have folliclesformanyyears thereafter, eventhough until theirlateteens,andsomewomenwithmosaicTS with TS,asmanygirlsTShaveovarianfollicles ispotentiallyfeasible inwomen Fertility preservation 3.4. Fertilitypreservation inTurner syndrome ( reactions fromageneticallyforeignembryo abnormal placentationduetomaternalimmunological pregnancies in TS women is postulated toberelated 235 increased comparedwithconventionalIVF/ICSI( section, prematurebirthandlowweightarealso intracytoplasmic sperm injection (ICSI). Rates of cesarean afterconventionalIVF/ threefold higherthanobserved for hypertensionduringpregnancyisalreadytwofoldto the knowledgethatwithODinnon-TSwomen,risk statistics needtobeviewedwithcautionconsidering was 3150 were reported.Themeanbirthweightofthesingletons occurred infourpatients(3.3%),butnomaternaldeaths in 20.5%.Potentiallylife-threateningcomplications disorderof pregnancy,hypertensive includingpre-eclampsia In total,35%ofpregnancieswereassociatedwitha 29% hadanechocardiogramorCMR during pregnancy. evaluation withintwoyearsbeforepregnancyandonly defect beforepregnancy, 49%hadapre-pregnancycardiac hyperstimulation is a possible fertility preservation option hyperstimulation isapossible fertilitypreservation aftercontrolledovarian Oocyte cryopreservation practice guideline Turner syndromeclinical 233 222 ). The higher risk of hypertensive disorder of with OD risk higher The ). , In singleton pregnancies in TS, the risk of prematurity A large Nordic cohort study of 106 women with TS who A largeNordiccohortstudyof106womenwithTSwho ) reported 122 deliveries and a multiple delivery rate rate ) reported122deliveriesandamultipledelivery , 233 224 ). , g andthatoftwinsis2200 225 , Supplementary Table 4Supplementary 226 , 231 , 232 , 233 ). Incomparison,in 177 ). Inmanystudies, g. These outcome g. Theseoutcome :3 225 236 , 237 ). 226 234 , G22 , 238 ). 231 234 ). , ,

European Journal of Endocrinology diagnosis orscreening,although theymaynothave prenatal geneticdiagnosisand pre-implantationgenetic Patients should be counseled about the availability of must be prepared and accepting of this potential outcome. This mayresultingriefandhardship, and thepatient pregnancy lossorbirthdefectsusingautologousoocytes. many factors,includingtheapparentincreasedrisk of decision toproceedwithtreatmentshouldconsider orfertility treatment.The with fertilitypreservation patient toconsidertheethicalimplicationsofproceeding treatment, itisimportantforboththephysicianand Priortoinitiating investigationor fertility preservation. time toconsideritsimplicationsandthepossibility of allow thepatientandherparent(s)/guardian(s) to have fertility aspectsshouldbeginatthetimeofdiagnosisto fertility treatmentatayoungerage.Counselingregarding rapidly andconsiderationshouldbegiventooffering that theirchancestoconceivespontaneouslydecrease youngage,itisvitaltocounselthem fromavery reserve ( be mentioned during preconception counseling such as adoption or using a gestational carrier should R 3.6. fertility preservation orfertilitytreatment 3.5. Counselingandethicalconsiderationsabout 12 years ( ofyoungTSgirlsbeforetheage fertility preservation date, thereisnotenough evidence torecommendroutine but notexclusive,prognosticfactorstofindfollicles. To pubertal stagewerepositiveandstatisticallysignificant, and normal FSH and AMH concentrations for age and follicles ( small ovaries with no old, but she had very was 8 years of folliculardensityinTSgirls,theyoungestgirlstudied ages, butitrequiresanoperationandanesthesia.Inastudy TS ( may befeasible,butsofar, therearenoreliabledatain oocytes at an evenyounger age, perhaps about 12 years, and havenotattemptedpregnancyyet.Vitrification of and thawinginTS,asthesewomenarestillyoung there arenopregnanciesreportedafteroocytefreezing years( in TSwomenaged14–28 mature oocytesaftercontrolledovarianhyperstimulation of8–13 function. Casereportsdescribecryopreservation in youngmosaicTSwomenwithpersistentovarian ⨁◯◯◯ Clinical PracticeGuideline 239 As womenwithTShaverapidlydecreasingovarian Biopsy ofovariancorticaltissueisfeasibleatyounger

, 240 We suggest that other options for motherhood 237 237 ). , ). Signsofspontaneouspuberty, mosaicism, , 249 238 ). ). C HGravholtandothers 239 , 240 , 241 ). Sofar,

In thisscenario,thephysicianmustconsider but whowishestoproceedwithfertilitytreatment. the patientwhohasidentifiableriskfactorsforAoD, rupture ( the possibilityofmaternaldeathfromAoDoraortic before pregnancy, butnormalresultsdonotpreclude mortality. Intensivecardiacscreeningisrecommended regarding theincreasedmaternalmorbidityand oocytes, thepatientneedstobefullycounseled seems warranted. different countries,carefuladditionalethicalcounseling implications determined by different practice rules in such intrafamilialdonationcomeswithuniquepractical vitrification anduseofaknownoocytedonor. Giventhat ( freeze theirownoocytesforfutureusebythedaughter Mothers ofdaughterswithTSmight be willingto availablefromIVFfortheseprocedures. adequate embryos gestation ( weeks of once duringpregnancy, atapproximately20 aortic valve,coarctation, atleast previousaorticsurgery) dilatation or other risk factors (hypertension, bicuspid cardiography (TTE)inwomenwithTSwithoutaortic R 3.11. center anddeliverbycesareansection( closely ataspecialist these womenshouldbefollowedvery should beadvisedagainstpregnancy. Ifalready pregnant, R 3.10. of theaortaandhypertension( aortic valve,elongationofthetransverseaorta,coarctation associated riskfactorsforAoD,whichincludebicuspid > should beavoidedincaseofanascendingASI R 3.9. ART inallwomenwithTS( and CT/CMRwithin2 years beforeplannedpregnancyor and heartwithatransthoracicechocardiography(TTE) R 3.8. pregnancy ( counseled abouttheincreasedcardiovascularriskof R 3.7. 3.6. Cardiovascular risksduringpregnancy carrier shouldalsobementioned. motherhood suchasadoptionorusingagestational rights. In preconception counseling, other options for safety ofthepatientaswellherreproductive practice guideline Turner syndromeclinical 250 2.5 cm/m Whether conceivingwithautologousordonated ). Thisisanoptiononlyincountriesallowingegg

We suggest that ART or spontaneous conception We suggestthatallwomenwithTSshouldbe We recommendimagingofthethoracicaorta 228 We suggestperformingtransthoracicecho We of AoD suggest that women with a history ⨁◯◯◯ 2 oranascending ASI 2.0–2.5 ⨁◯◯◯ , 231 , 251 ). ). , 252 ⨁◯◯◯ , 253 ⨁◯◯◯ ). Morechallengingis 177 ). ⨁◯◯◯ www.eje-online.org :3 ). cm/m ). 2 with G23 -

European Journal of Endocrinology www.eje-online.org dissection riskwasreported ( women withMarfansyndrome, aneightfoldincreased factor ( ofAoDdidnotrevealpregnancyasarisk largest registry remain undetermined,duetoinconsistentevidence.The also leadtoanincreasedriskofAoDinpregnantwomen in cardiacoutputandcirculating bloodvolume( pregnancy ( Aortopathy andaorticdilationincreasetherisks of 3.6.1. Pregnancyandaorticdisease transfer( singleembryo OD hasamandatory that anywomanwithTSundergoingtreatmentIVF or associated withasingletonpregnancy( literature tobeapproximatelyfivetimeshigherthanthat risk ofAoDduringamultiplegestationisestimatedinthe women withTS( cardiac complicationstobe0–4%inODpregnancies imaging beforepregnancy( cardiac examinationswithechocardiographyorCMR and 106women, only 38% and 49%respectivelyhad Table 3 to 100%beforefertilitytreatment( transfer. from0%cardiacevaluation Publishedstudiesvary these womenhadanycardiacevaluationbeforeembryo estimated tobe2%( rupture duringpregnancyinwomenwithTShasbeen 253 deaths afterAoDrelatedtopregnancy( were published( complications anddeathsinpregnantwomenwithTS increase indiameter( isreasonableincaseofadilatedaortawithrapid surgery R 3.15. (135/85 R 3.14. arch ordescendingaorta( suspicion ofdiseasethedistalascendingaorta,aortic should beperformedduringpregnancywhenthereis R 3.13. first 6 monthspostpartum( during pregnancy and during the at 4- to 8-week intervals shouldbemonitoredfrequently,surgery) includingTTE bicuspid aorticvalve,coarctation, previousAoDor ascending ASI R 3.12. Clinical PracticeGuideline ). Theriskofmaternaldeathfromaorticdissection/ In 1997,thefirstreportsofseriouscardiac Additional studies have estimated the risk of maternal Additional studieshaveestimatedtheriskofmaternal ). Inthetwolargeststudies to date,including 93

258 mmHg) inallpregnantwomenwithTS(

We recommendthatbloodpressurecontrolisstrict We suggestthatCMR(withoutgadolinium) We suggestthatwomenwithTSan We suggestthatduringpregnancyprophylactic ). However, inastudyof278pregnancies in 256 > 2.0 cm/m ). Whether pregnancy-induced changes 254 222 231 ), followedbyadditionalreportsof , ⨁◯◯◯ 224 , 2 oranyriskfactor(hypertension, 255 ⨁◯◯◯ , 231 225 ⨁◯◯◯ ). However, only38–49%of 259 , , ). 233 226 C HGravholtandothers ). Intheinternational ). ). , 232 231 ). 228 ). It is imperative ). Itisimperative , Supplementary Supplementary , 232 231 233 ⨁◯◯◯ , , , 233 251 255 ). The ). The , ). 257 252 ). ) ,

without TSwithcardiovasculardisease( The guidelinesforcarearesimilartothosewomen such asaorticvalvestenosisorcoarctation oftheaorta. with TS may have other cardiovascular abnormalities high riskforAoD.ApartfromtheofAoD,women beforepregnancy.surgery studies thatconsidertheadvisabilityofelectiveaortic ( to answer the questionof dissection risk in TS pregnancy that includesallcasesofTSpregnancywillbeessential significant complications( as opposedtospontaneouspregnancy, isariskfactorfor that founda25-foldincreaseinnon-TSwomen( convincing evidencecamefromaSwedishbirthregistry number hadconnectivetissuedisorders(73%).Themost pregnancy orpost-partum(0.4%),adisproportionate (IRAD)ofallthosewhosufferedAoDduring AoD registry multiple gestationandpre-existing hypertension( chronic renal disease, anti-phospholipid antibodies, older age,elevatedBMI,pre-existingdiabetesmellitus, ofpre-eclampsia, nulliparity,including afamilyhistory pregnant populationisassociatedwithseveralriskfactors, eclampsia ( risk of hypertensive disorders of pregnancy, including pre- congenital heartdisease,womenwithTSareatincreased ( a high riskofAoD advised thatpregnancywouldcarry coarctation oftheaorta and/orhypertensionshouldbe bicuspid aorticvalve,elongationofthetransverseaorta, R 3.18. especially inwomenwithcoarctation ( can beusefultorevealexercise-induced hypertension, R 3.17. ( high pumpflowandavoidanceofvasoconstrictors performed undernear-normothermia,pulsatileperfusion, section first,followedbyaorticsurgery, whichshouldbe If thefetusisviable,itreasonabletoperformcesarean understandingthatfetalviabilitymaybeatrisk. surgery AoD beforethefetusisviable,toperformemergencyaortic R 3.16. 3.6.2. Cardiovascularrisksbeyondtheaorta complications duringpregnancy. may contributetothehigher incidenceofhypertensive Hypertension ismorecommon inwomenwithTS,which practice guideline Turner syndromeclinical 261 ⨁◯◯◯ ⨁◯◯◯ After aorticsurgery, womenarestillconsideredat In addition to the potentially increased risk ofAoD and ). InTScaseswheretheaortaisdilated,thereareno

We suggest that exercise testing before pregnancy We suggestthatwomenwithaorticdilatation, We suggestthatincaseofanacuteascending ). ). 226 , 231 , 233 ). Pre-eclampsiainthegeneral 232 ). A comprehensive registry ). Acomprehensiveregistry 177 ⨁◯◯◯ 262 :3 ). 260 ). ). ART, G24 263 ). European Journal of Endocrinology women withTSanascendingASI is preferredoracesareansectionmaybeconsidered.In with epiduralanesthesiaandexpedited second stage ascending ASIof2.0–2.5 R 3.20. ( women withTSanascendingASIbelow2.0 R 3.19. and TS 3.6.4. Modeofdeliveryinwomenwithadilatedaorta given insuchpregnanciesawomanwithTS( factor, butconsiderationtoprescribingaspirinshouldbe for aspirinuse( factors, suchasafirstpregnancy, becomesanindication on theknowledgethathavingtwoormoremoderaterisk at riskofpre-eclampsia.Thisrecommendationisbased daily from12 weeks forwomen ofgestationuntildelivery Health andCareExcellencerecommends75 has beendescribed( fetal abnormalities;still,someeffectonbirthweight may beconsideredduringpregnancyanddonotcause blockers arecontraindicatedinpregnancy. Beta-blockers syndromes (suchasMarfan),butangiotensinreceptor receptor blockersareadvisedinwomenwithaortic have aorticdilatation.Beta-blockersandangiotensin medication duringpregnancyinwomenwithTSwho not haveTS.Thereisnoclearevidenceforprophylactic do notdifferfromthoseforpregnantwomenwho dilation. Anti-hypertensivetreatmentrecommendations prophylactic medication to prevent (further) aortic health, comprises anti-hypertensive treatment and Medical treatment,specificallyregardingcardiovascular 3.6.3. Medicaltreatmentduringpregnancy cesarean sectionwasnotsuperior toavaginaldelivery of pregnancy andcardiacdisease(ROPAC),registry most women,basedonthe availableliterature.Inthe Vaginal in isthepreferred modeofdelivery delivery the contextofmaternalheartdiseaseand/oraortopathy. and anesthesiologist,allwithexpertiseinpregnancy team consisting of at least an obstetrician,cardiologist ( ofAoD,acesareansectionshould beperformed history R 3.21. considered ( epidural anesthesiaandexpeditedsecondstagemaybe with cesarean sectionisreasonableoravaginaldelivery ⨁◯◯◯ ⨁◯◯◯ Clinical PracticeGuideline A delivery planshouldbemadebyamultidisciplinaryA delivery

We isreasonablein suggestthatvaginaldelivery We recommend that inwomenwithTSa We suggestthatinwomenwithTSan ). ). ⨁◯◯◯ 266 ). ODisnotgivenasaspecificrisk 264 ). , 265 cm/m ). TheNationalInstitutefor C HGravholtandothers 2 , a vaginal delivery , avaginaldelivery > 2.5 cm/m mg aspirin 267 cm/m ). 2 , a 2

increased mortalityandmorbidity( of congenitalandacquiredcardiovasculardisease,with Girls andwomenwithTSfacealifelongheavyburden 4.1. Background Turner syndrome 4. Cardiovascular healthissuesin section followedbyemergencyaorticsurgery. fetus isviable,itrecommendedtoperformcesarean isrecommended.Ifthefetus, emergencyaorticsurgery dissection happensinearlypregnancywithoutaviable immediate attentiononahighspecialistlevel.Ifthe highriskandneedsduring pregnancyiswithvery although italsoleadstohemodynamicchanges.AoD with adilatedaorta,cesareansectionisreasonable, was seen( for themother, whileanincreaseofadversefetalevents or postnatal cardiac examination was normal ( the timeofdiagnosis,even ifthefetalechocardiogram examined with transthoracic echocardiography (TTE) at R 4.1. enlargement andaneurysm 4.2. Medicalandoperativemanagementofaortic safely attemptpregnancy. practitioners andobstetriciansunderstandwhomight TS. Accordingly, itisimperativethatreproductive health increasing thepotentialforchildbearingwomenwith may be beneficial. The rapidly evolving field of ART is toclarifywhenmorefrequenthealth monitoring serve regarding participationincompetitivesportsand(3) (2)helpindecision-making for operativeintervention, aortic dimensionsthat(1)maywarrantconsideration in TS( (stroke) arethemajorfactorsthatreducelifespan ischemic heartdiseaseandcerebrovascular cardiovascular conditionssuchassystemichypertension, published, ithasbecomeincreasinglyapparentthatother attention sincepreviousinternationalguidelineswere thoracic aorticdilation( ( aorta. Inaddition,ageneralizedarteriopathyisobserved to rare but often fatal dissection or rupture of the thoracic coarctation oftheaorta and anaortopathythatcanlead TS, includingahighincidenceofbicuspidaorticvalve, heart diseaseoccursinapproximately50%ofgirlswith practice guideline Turner syndromeclinical 269 ), and TS alone is an independent risk factor for

268 We recommend that aninfantorchildis ). Thisconsensusstatementproposesspecific 265 ). Basedonexpertopinion,inwomen 270 ). WhileAoDhasreceivedmore 37 177 , www.eje-online.org :3 268

). Congenital ⨁⨁◯◯ G25 ). European Journal of Endocrinology www.eje-online.org cases, anabsoluteascending aortadiameterof4 littlerelativetotheirheight.Intheseweigh very short-statured butobese individuals orthosewho made withcaution.This is particularlyimportantin decisions baseduponeitherZ-scoreorASIshouldbe because BSAcalculationsalsoincludebodyweight, consistently apredictorofaorticsize( determined byechocardiography. Although BMIisnot corresponds toaTS-specificZ-scoreof equivalent toanascendingASIof an absoluteascendingaorticdiameterof could beused.InawomanwithaverageBSAforTS, those patientsagedbelow16 years, TS-specificZ-scores Because theascendingaortaASIisagedependent,in yearsofageandatanascendingASI 16 Limited datasuggestthatAoDusuallyoccursabove making itausefulindexbeyondtheageof15 years. teenage years and remains relatively stable thereafter The ASIdecreaseswithbodygrowthandageuntilmid- predict riskforAoDinTS( body surfacearea(BSA))hasbeenproposedtobetter index orabsoluteaorticdiameterincmdividedby ( suggesting thepresenceofanunderlyingvasculopathy present evenintheabsenceofstructuralheartdisease, of thebrachiocephalicandcarotidarteriesmaybe 273 of theaortaand/orhypertensioniscommon( valve, elongationofthetransverseaorta,coarctation a cardiovascularabnormalitysuchasbicuspidaortic aortopathies ( likeotherswithgenetically triggeredrange 4–64 years) addition, AoDalsooccursatanage(median29–35, genetically triggeredaortopathies( ascending aorticdiametersthaninthosewithother for women with TS, AoD appears to occur at smaller (Type B)( 10%) originateinthedescendingthoracicaorta aorta (Type A), whilea smaller percentage (around population ( compared to6per100 occurs inapproximately40per100 sudden inonsetandsevere( shoulder, backorflankdiscomfort,particularlyifitis symptoms consistentwithAoD,suchaschest,neck, seek promptevaluationiftheyareexperiencingacute dilatation and/orbicuspidaorticvalvebecounseledto R 4.2. 275 Clinical PracticeGuideline , Aortic dissectioninTurnerAortic syndrome , 274 276

We recommendthatgirlsorwomenwithaortic , , 271 277 275 271 , 273 ). UsingascendingASI(ASI ). Aortic dilatation and enlargement 272 ). MostAoDoriginateintheascending ). Furthermore,inwomenwithAoD, , 273 000 person-yearsinthegeneral ). Itisimportanttonotethat ⨁⨁◯◯ 270 C HGravholtandothers , 271 272 ). 000 person-years , > 272 , 2.5 cm/m 279 : InTS,AoD 273 > ≥ , = 4 ( , 2.5 cm/m 273 aortic size , 280 > 274 279 m is 4 cm , 2 ) and and 278 ). In ), as 272 cm 2 ). ). . , R 4.3. 4.2.1. Medicalmanagement when determiningAoDrisk. in someone events ( of normalbloodpressuremaylessenriskaortic documented inresectedaortictissueofwomenwithTS. medial degenerationlikeotheraortopathieshasbeen of clinicaltrialstoguidepharmacologicaltherapy. Cystic aortic dilatationisapragmaticone,recognizingtheabsence surgical consultation( period, needanoptimizationofmedicaltreatmentand aortic diameteroranincreaseof demonstrating anincreaseinTS-specificZ-scoreof1 thoracic aortic aneurysms anddissections( thoracic aorticaneurysms care arenotdifferentfrom those forotherpatientswith coarctation of the aorta and/or hypertension) ( bicuspid aorticvalve,elongationofthetransverseaorta, ≥ and forwhomtheirascendingaortaTS-specificZ-score is considered forwomenwithTS,whoare of theaorticrootand/orascendingaortamaybe R 4.6. factors forAoD( with anascendingASI considered forwomenwithTSwhoare of theaorticrootand/orascendingaortamaybe R 4.5. ( or hypertensionaccording to standard definitions of thetransverseaorta,coarctation oftheaortaand/ for AoD, including bicuspid aortic valve, elongation ascending ASI for women with TS who are of theaorticrootand/orascendingaortaarereasonable R 4.4. aortic dissection 4.2.2. Operativerepairofaorticaneurysmsand recommended forotherpatientgroups. prophylactic medicaltherapiesearlierthanwhathasbeen smaller absolute and ASI in TS, it is reasonable to begin practice guideline Turner syndromeclinical ⨁◯◯◯ 4.0, withorwithoutassociatedriskfactorsforAoD(i.e., Because hypertensioniscommoninTS,maintenance An approachtomanagingindividualswithTS The generaltechnicalconcept andperi-operative

281 We suggest that elective operations for aneurysm We suggest that elective operations for aneurysm We suggest that elective operations for aneurysm We recommendthatwomenwithTS ). , ≥ 282 16 years ofagemaybe preferable toASI 16 years ≥ ⨁◯◯◯ , 2.5 cm/m 283 ⨁⨁◯◯ ≥ ). SinceAoDappearstooccurat 2.5 cm/m ). 2 andassociatedriskfactors ≥ ). 6 years of age with an 16 > 2 , andnoassociatedrisk 0.5 177 cm overaone-year :3 < ≥ 16 years ofage, 16 years 16 years ofage 16 years 284 ⨁◯◯◯ ,

285 ). G26 ). European Journal of Endocrinology hypertension; TSZ,Turner syndromespecific Z-scoreoftheaorta(seetextforexplanation). cardiac magneticresonanceimaging; ECG,electrocardiogram;CoA,coarctationofaorta;BAV, bicuspid aorticvalve;HTN, Suggested monitoringprotocol forgirlswithTSfrominfancyto16 yearsofage.TTE,transthoracic echocardiography;CMR, Figure 1 should beperformed( or hasbeenconfirmedprenatally, afetalechocardiogram R 4.10. based onpublishedguidelines( to anticipatedpregnancy(seeR3.8)evaluatetheaorta 10 years in adults or 5 yearsprior in children, every every studies should be performed TTE or CMR surveillance valve orothersignificantdiseaseattheinitialscreening, R 4.9. is areasonableoption( an adultorchildcannottolerateaCMRstudy, aCTscan soon asitisfeasiblewithoutneedinggeneralanesthesia.If R 4.8. diagnosis isthepreferredapproach( TS cardiovascular screening with TTE and CMR at time of R 4.7. Figs 4.3. Cardiac imaging(seemonitoringprotocols Clinical PracticeGuideline B B TTTE: transthora AV: bicuspida 1 Re pr

and every 5year e

rimary man peat T

We recommend,intheabsenceofabicuspidaortic We recommendthataCMRscanisperformedas We recommendthat in adolescents and adults We recommendthat,ifTSishighlysuspected Low risk clinicia TSZ 2 ) TE or ≤ cic echocardiog c orc valve.H o 3 No n ag s CMR C ging by b Co ⨁⨁◯◯

⨁⨁◯◯ A,

B T AV N N raphy. CMR:c : hypertension. , HT ⨁⨁◯◯ ). C HGravholtandothers TN ). pediatric car p Re ⨁⨁◯◯ every 1ye peat T Mode TSZ > a ). . TSZ:Turnersy rdiac magnec ra TE o Ca te ar diologist d ). or CMR 3 3 ar b a ris diology In

k y fa ncy – n ndrome specifi resonance imag ex EC am 1 16 yea G G m, TTE,CMR, ( of aortic dilatation diseases as well as in the surveillance bicuspid aorticvalve( 290 modalities includeTTE,CMRandCT( and riskassessment( cardiac imagingiscrucialfordiagnosis,management acquired cardiovasculardiseaseinTS,non-invasive management plan( andpostnatalmultidisciplinary and modeofdelivery and physiologyofthespecificdefect,recommendedsite fetus withTStoprovide counseling regarding the anatomy when congenitalheartdiseaseisdetectedprenatallyina R 4.12. ( fetus orchildshouldpromptageneticevaluationforTS aortic valveoraleft-sidedobstructivelesioninfemale R 4.11. practice guideline Turner syndromeclinical 290 ⨁⨁◯◯ pediatri Re ever , Because ofthehighprevalencecongenitaland ). However, the high prevalence of undiagnosed rs peat T Mode 291 : c c ging. ECG:elect Z-scoreofthe

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TSZ , 1- c We recommendreferraltoapediatriccardiologist We recommendthatdiagnosisofabicuspid 292 ). ca c ra r 2 ye 2 T TE orCMR

≤ 3 te r rd , ar iologist 293 is s by k CoA, B ). TTEisusefulinthediagnosisofa ⨁⨁◯◯

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2 , 294 BA 9 , V, 286 ) andothercongenitalheart and/ ). , Re 287

CoA: coarctao C every for explana year or H pe ). Themostcommon ca 177 a High ris H rd TSZ > T by pediatric TN t TTEorCMR T 6 www.eje-online.org :3 iologist months 275 3 o k n n , n n ofaorta. ). 288

- 1

, G27 289 , European Journal of Endocrinology www.eje-online.org in individualswith45,Xcompared toXmosaicismor early mortality( individuals withTSandis themostfrequentcauseof Congenital heartdisease occursin23–50%of 4.4. Congenitalheartdisease ( TS, whooftenhavelimitedechocardiographicwindows particularly beyondtheaorticrootandinadultswith CT aremoresensitivethanTTEtochangesinaorticsize, involve radiationexposure.Inaddition,bothCMRand ( CT isanotheroption,butserialsurveillance with TSforthediagnosisofbicuspidaorticvalve( CMR hasalsobeenshowntobebetterthanTTEinadults tool( as ascreeningandsurveillance venous returninTShasledtoincreasedutilityofCMR arch, aorticcoarctation andpartialanomalouspulmonary abnormalities suchaselongationofthetransverseaortic hypertension; ASI,aorticsizeindex(seetextforexplanation). CMR, cardiacmagneticresonanceimaging;ECG,electrocardiogram;CoA,coarctationofaorta;BAV, bicuspidaorticvalve;HTN, Suggested cardiacmonitoringprotocolforgirlsandwomenwithTSabove16 yearsofage.TTE,transthoracicechocardiography; Figure 2 295 Clinical PracticeGuideline BAV: bicuspida TTE: transthorac B T ev Re , AS e 296 peat T p S r r ca y 5-10 I ≤ Low ris rd ). 2.0cm/ iologis TE orCM ye k ar t cic echocardio orc valve.HTN o m 21 s by 2 R R N No CoA,BA , y 297 , 298 Re ev ASI 2.0 N g V, pe ery Mo raphy. CMR:ca : hypertension ca ). Theincidenceishigher H at d de rd TN T 3 3 0 diologis

C HGravholtandothers TT - –2.3 m/m rate 5 E ye or 275 r ar C is t s by k MR , 2 . ASI:Aorcsiz . 289 rdiac magnec

, Card 291 294 Re ASI >2.0– iology e ev , pe Mode ) will 288 293 cardio ery 1 Above at e e T resonance imag index(seetext ). ). xa ra TE

2 y l t t o ogis m, TTE,CMR,E m e ear .3 m/m orCMR e ri 16 y other Xstructuralabnormalities( to bestrongpredictorsofarterial andvenousanomalies anterior–posterior thoracic diameterhavebeenshown arteries ( transverse arch anddilatationofthebrachiocephalic connection, leftsuperiorvenacava,anelongated venousincluding partialanomalouspulmonary havegoneundetected byTTE,that mightotherwise increased incidenceofadditionalvascularanomalies Cross-sectional imagingmodalitieshaveunveiledan be viewedasanindependentmarkerofTS( girls withcoarctation oftheaortahaveTSandshould marker fortheTSdiagnosis.Atleast12.6%ofnewborn bicuspid aorticvalveinafemalemaybeanindependent TS thanthatinthe46,XXfemales,itispossible valve is likely tooccur30–60times more frequently in 7–18% forcoarctation ( prevalence of15–30%forbicuspidaorticvalveand obstructive lesionsaremostcommon,withabaseline sk t practice guideline Turner syndromeclinical by ea

rs 2

: ging. ECG:elec t forexplana 288 C CG Re every 2-3ye , ASI ≤2.3 pe Mode 291 cardio at o T t ). Neckwebbingandan increased n). rocardiogram. ra TE o log t c e e ea or CMR m/ gi ris st 193 CoA, B rs m k by 2 ,

301 AV CoA: coarctao C , an ). Sincebicuspidaortic d/ d 299 6 mo 177 or HTN Repeat CMRe ASI , :3 ca nt 300 High ris ≤ 2.3cm rd hs -1 iologis ). Left-sided n n ofaorta. ye k ev ea st / /m ery r by 2 G28 302

). ).

European Journal of Endocrinology sudden cardiacdeathinthe generalpopulation.Yet, it is associatedwithanincreased riskforarrhythmiasoreven cases thatarenotalreadyknown and(2)QTc prolongation return ( venous with thepresenceofpartially abnormalpulmonary (1) right-axis deviation in an individual with TS is correlated relevance ofthesepotentialabnormalitiesmaybetwofold: consequence ofexcessivesympatheticdrive.Theclinical (due toacceleratedatrioventricularconduction)maybe a autonomic dysfunction( TS canbeattributedtotheunderlyingcharacteristic QTc-dispersion andheartratevariability inwomenwith (30%) ( about 50%,whichishigherthanthatinnon-TScontrols prevalence ofthesechangesinwomenandgirlswithTS is and QT-interval) ontheotherhand.Thereported (PR-interval changes) ontheonehand,andtimeintervals issues (bundlebranchblock,T-wave changesandP-wave population can be roughly categorized into morphological ( weeks after initiation of QT-prolonging drugs 1–2 If theyaredeemednecessary, ECGshouldbeperformed QTc, drugsthatprolongtheQTc shouldbeavoided. R 4.15. > women withTSQTc prolongation(QTc interval exercise testingbeconsidered forriskestimationin R 4.14. QTc ( Hodge’s maybepreferredoverBazett’s formulatoestimate individual withTSatthetimeofdiagnosisandthat (ECG) withQTc measurementshouldbedoneinevery R 4.13. 4.5. Electrocardiogram modifications oftheoperativeapproach. anatomybecauseitmaynecessitateunusual coronary important forthecardiothoracicsurgeontobeawareof malformations increasemortalityriskisunknown.It appear tobecommoninTS( anomalies artery Congenital, morphologicalcoronary anomalies ( artery valveabnormalities,coronary pulmonary ventricular septaldefect,atrioventricular with azygous continuation, cardiac dextroposition, mitral valveanomalies,interruptedinferiorvenacava anomalies includehypoplasticleftheartsyndrome, in TS( ⨁◯◯◯ s ( 460 ms) Clinical PracticeGuideline Differences between the ECG in TS and in the general Differences betweentheECGinTSandgeneral ⨁⨁◯◯ 310 308 303

We suggestthat,inindividualswithprolonged We suggest that 24-h Holter monitoring and ⨁◯◯◯ We suggestthatarestingelectrocardiogram ). ) and should trigger further diagnostics in those ) andshouldtriggerfurtherdiagnostics inthose ). Some changes such as those in P-wave and ). Some changes such as those in P-wave and , 305 304 ). , ). Additionallessfrequentlyoccurring 306 ) andpatentductusarteriosus( ). 309 ). Shortening of the PR-interval ). ShorteningofthePR-interval 306 C HGravholtandothers ). Whethercoronary 307 ). ).

R 4.16. 4.6. Sportsparticipation this population. with theuseofQT-prolonging drugsmaybewarrantedin furtherinvestigation( LQTS genesdeserves of TSisunclear;apotential correlation with variants inthe prolongation shouldbeconsideredasanintrinsicfeature higher heartrateintoaccount( be preferred over Bazett’s formula, because it takes the rate inmanyindividualswithTS,Hodge’s formulamay QTc inTS–viewoftheincreasedintrinsicheart interval define QTprolongation,andcalculationmethodto seen ( to adoseofamiodaronefollowedbycardiacarresthasbeen women withTS,althoughcase-basedQTc prolongationdue far for sudden cardiac death related to QTc prolongation in should beemphasizedthatthereisnopublishedevidenceso in thispopulation.Therefore, considerationofthe in absoluteterms(about40:100 a ‘heart-healthy’lifestylein lightofthelowriskAoD should bemindfulofthesignificant benefitsofhaving the metabolicsyndromein TS,healthcareprofessionals athletics withTS.Giventhepropensityforobesityand regarding cardiovascularandaorticrisksforcompetitive lifestyle in girls and women with TS. Evidence is lacking ( be advised not to participate in any competitive sports Z-score of to severelydilatedaorta,age R 4.20. competitive sportsmaybeadvised( participation inlowandmoderatestaticdynamic Z-score of2.5–3),orage to moderatelydilatedaorta(age R 4.19. to participateinallsports( < normal aorticsize(age R 4.18. be advised( ≥ ≥ R 4.17. athlete withTSandaorticdilation( determining participationrecommendationsforthe disease and/or hypertension should be considered in valve andthepresenceofany other congenital heart practice guideline Turner syndromeclinical ⨁◯◯◯ 2.5 orage 2.0 cm/m with amoderately dilated aorta(ascending ASI 16 years A safelevelofexercise isimportantforahealthy 311

). Additional uncertainties include the threshold to ). Additionaluncertaintiesincludethethresholdto We suggestthatgirlsandwomenwithamoderately We suggestthat,forgirlsandwomenwithamild We suggestthat,forgirlsandwomenwith We recommend that the function of the aortic We suggestthat,forgirlsandwomenwithTS > 2 ). ≥ ), avoidanceofintenseweight-trainingshould ⨁◯◯◯ 3) orage 16 years andASI ≥ ). 16 years (ASI 16 years < ≥ 6 years;TS-specificZ-scoreof 16 16 years (ASI2.0–2.3 16 years ⨁◯◯◯ < 2.0 cm/m < 000 patient-years( 16 years old(TS-specific < 6 years(TS-specific 16 ⨁◯◯◯ ⨁◯◯◯ 312 177 ). > 2.3 cm/m www.eje-online.org ). WhetherQTc 2 :3 ), itisreasonable 313 ). ). ). Caution ). Caution 2 cm/m ) should G29 271 2 )), ))

European Journal of Endocrinology www.eje-online.org women with TS, including a practical algorithm for blood hypertension identification andmanagementforgirls De Groote but none specifically addresses individuals with TS. children, adolescents( ascertainment ofsystemichypertensionininfants, factor intheetiologyofhypertensionforsome( aorta inindividualswithTSwithoutcoarctation canbea pressure gradientsandpossiblytheintrinsicshapeof repair eveninthosewithoutresidualdescendingaortic be idiopathic.Hypertensioncanpersistaftercoarctation renal anomalies that are frequently seen in TS or may adulthood. Systemic hypertension may be the result of may appearatearlyagesandcontinuethrough 60% ofadults( as high20–40%inchildhood( systemic hypertensioninseveralstudieswithfrequency ( systemic hypertension,specificallyforwomenwithTS documented aboutdefinitionsandmanagementof cardiac dysfunctionandaortopathy, littlehasbeen hypertension isaknownriskfactorforprogressive to havesystemichypertension,andeventhough TS-specific Z-scoreis ofageforwhomtheirascendingaorta who are≤16 years or ascendingaortamaybeconsideredforgirlswithTS to reducedilatation of anenlarged aortic rootand/ a beta-blocker, anangiotensinreceptorblockerorboth, R 4.22. ( of ageforwhomtheirascendingASIis the riskforAoDinwomenwithTSwhoare an angiotensinreceptorblocker, orbothtoreduce We suggestmedicaltreatmenttoincludeabeta-blocker, thereof shouldbeconsideredifhypertensionispresent. pressure shouldbeperformedandmedicaltreatment structural heart disease, annual assessment of blood R 4.21. 4.7. Hypertension aortic enlargement. AoD amonggirlsandwomenwithTSwithoutsignificant evidence thatcollisionrepresentsasignificantthreatfor individuals withTS.Inaddition,thereisnopublished encouraging individualizedlevelsofphysicalactivityin risk forAoDshouldbetemperedbytheimportanceof 281 ⨁⨁◯◯ Clinical PracticeGuideline Several guidelinesregardingmeasurementand Although individualswithTSarefrequentlyfound ). IndividualswithTShavebeenconsideredto

We suggestthatmedicaltreatment,including We recommendthat in individualswithout ). t al et 191 . ( , 281 314 ≥ 3.0 ( 317 ) suggestapracticalapproach to , 315 ) andadults( ⨁◯◯◯ , 316 C HGravholtandothers ). Systemichypertension 282 ). ) andinasmany 318 ) areavailable, ≥ 2.3 cm/m ≥ 283 16 years 16 years ). 2

Similarly, nostudiescomparingdifferenttreatment found basedoneligibilitycriteriaandendpointdefinition. on treatment of hypertensionin TS individuals were articles were assessed in full-text. No comparative studies The systematicsearch found313articles,ofwhich12 on clinicaloutcomesinTS?(GRADEquestion3) 4.7.1. Whataretheeffects ofbloodpressuretreatment TS ( diurnal variation in bloodpressurevalueswomenwith has beenconsideredusefulindemonstratingabnormal bloodpressuremonitoring(ABPM) dipping). Ambulatory is relatedtolossofdiurnalvariation(lacknight-time is maskedduringrestingbloodpressureassessmentor This couldbeanend-organeffectofhypertensionthat in TS,eventhosewhoarenormotensive( hypertrophy (increasedLV mass)hasbeenidentified pressure evaluationinadultpatients.Leftventricular reported tobewithinthenormal rangeinothercohorts fibrinogen levels,aswell clottingtimeshavealsobeen ( and proteinsCS were reduced in alargefraction has beenfoundtobeelevatedin65%offemaleswithTS, values ofclottingandfibrinolyticfactors( individual level,manywillhaveincreasedprocoagulant for cohortswithTSwhenassessedintotal,but,onthe stroke. Clottingfactorsandclottingtimesmaybenormal thrombosis andfibrinolysisarerelatedtothromboembolic or otherTS-specificcausesisunknown.Disturbances of related to the increased risk of systemic hypertension the general population ( Cerebrovascular accidents (strokes) occur in excess of 4.8. Thecoagulationsystem of theaorta. as renalanomalies,obstructiveuropathyandcoarctation obesity. Itisessentialtodiagnoseunderlyingcausessuch of healthylifestylechoicesandaggressivemanagement like thatinotherindividuals,includingencouragement definitive treatmentforsystemichypertensioninTSis could bedefined. We concludethatrecognitionofand most effectiveanti-hypertensivetherapeuticintervention strategies. Thus,neitherbloodpressurethresholdnor of bloodpressuretreatmentor these reviewsdonotrefertooriginalarticlesoneffect are commonlydescribedinreviews( targets were found. Two different treatment strategies practice guideline Turner syndromeclinical 323 191 ). Conversely, clotting factors,fibrinolyticfactorsand , 314 , 321 , 322 ). 268 ), but whether this is simply 177 193 :3 , 323 281 ). Fibrinogen ). However, 319 , G30 320 ). European Journal of Endocrinology time topromotethedevelopment ofindependentself- priority overhealthcare( romantic relationshipsand financialconcerns maytake including pursuitofeducation, employment,socialand competing developmentaltasks ofemergingadulthood, is increasinglyrecognizedasavulnerabletimewherein to patientautonomyandfrompediatricadultcare chronic conditions,transitionfromparentaloversight to childduringthistime( conditions, healthmanagementtasksmovefromparent habits areestablished( health outcomes( recognition andtreatmentofcomorbiditiessuboptimal age-appropriate screening,leadingtoreportsofunder- TS arelosttofollow-upanddonotreceiverecommended remains elusive.Asaresult,manyyoungadultwomenwith decade ( transition toadultcarehasbeenrecognizedforovera staged andseamlesstransitiontoensureuninterrupted endocrinologists inprovidingtheirTSpatientswitha health needs.Althoughthecriticalimportanceofpediatric visits areoftenlessfrequentdespitepersistenceoflifelong psycho-behavioral conditions.AsgirlswithTSgrowolder, and forscreeningreferralassociatedmedical for initiation of GH therapy,intervals induction of puberty and monitoredbyapediatricendocrinologistatroutine adolescence fortheirpatientswithTS( a plannedandstagedtransitionprocessinearly (or anyotherTScareprovider/coordinator)implements R 5.1. 5. Transition from pediatrictoadultcare few womenwithTScoagulationdisorders. about thromboembolicdiseaseinTSwillhelpidentifythe issued concerningthecoagulationsystem,butawareness been found.Therefore,nogeneralrecommendationcanbe data arelacking,andthecommondenominatorhasnotyet excessively activatedinsomewomenwithTS,outcome (13%) thanthatinthebackgroundpopulation(2%)( polymorphism heterozygosityismoreprevalentinTS One studyshowedthatfactorVLeidenG1691Agene formation are more frequently reported in TS ( The most common mutations associated with thrombus been reportedforsomeprocoagulantfactors( with TS ( Clinical PracticeGuideline In childhood, girls with TS are typically cared for In childhood,girlswithTSaretypicallycaredfor Adolescence is atime when manylifelong health Even though the clotting system appears to be

We recommendthatthepediatricendocrinologist 327 315 ), widespread adoption of this best practice ), widespreadadoptionofthisbestpractice , 324 328 ), though high-normal values have , 329 331 , 333 ) and,forthosewithchronic 330 332 ). Adolescenceisanideal ). C HGravholtandothers ). Forindividualswith ⨁⨁◯◯ 325 325 ). , , 325 326 326 ). ). ).

talking with providers and managing daily activities ( keeping, trackinghealthissues,managingmedications, reported health-relatedskillsinareasofappointment- validated measure that examines knowledge and self- Assessment Questionnaire5.0(TRAQ)isa20-item outcomes ( management competenciesarepredictorsofadulthealth readiness skillsthatincludehealthnavigation,andself- the spectrumofchronichealthconditionssupportthat TS duringthisstageoflife. alleviate someofthechallengesforyoungwomenwith preparation fortransitiontoadultcareovertimecan medical andpotentialpsychosocialneeds,purposeful to amelioraterisk.Giventhedualaspectsofbothchronic into adulthoodandpromotehealthylifestylebehaviors andoftheevolvingimpactTS of herownhealthhistory care behaviors and to make the adolescent with TS aware transition preparation,planning, andimplementationas sharing ofexperiences( reduce stressanddistress and promotethereciprocal organizations toenhance knowledge andconfidence, to-parent) contactwithTSsupportandadvocacy their careteamsencouragepeer-to-peer(andparent- R 5.4. process ( establish a workflow to support acoordinated transition system,thepediatricandadult health careteams delivery R 5.3. Development ofhealthliteracyskills,whichcombine document thecoreelementsoftransition( team uses or adapts available transition tools to track and R 5.2. transition challenge 5.1. UseofgenericandTS-specifictoolstomeetthe health carerecommendations. andongoing adult content for personal health history for adultcare,complementedbyindividualizedTS-specific such asTRAQcanbeausefulwaytoassesspreparedness chronic condition( slightly lowerTRAQscores,comparedtopeerswithouta youth withTShadsimilarhealthliteracyscores,but study oftransitionreadinessacrosschronicconditions, component oftransitionpreparation.Inacomparative health needsandpreferences’( ‘cognitive andsocialskillstocommunicatearticulate practice guideline Turner syndromeclinical Transition research andclinicalcareguidelinesacross Many professionalsocietieshave endorsedhealthcare

⨁⨁◯◯ We suggest that, irrespective of the health care We suggestthatpediatricendocrinologistsand We suggestthatthepediatricendocrinology 334 , 335 ). 339 , ). We suggestthatvalidatedtools ⨁⨁◯◯ 336 ). TheTransition Readiness ). 338 177 ), isanadditional www.eje-online.org :3 ⨁⨁◯◯ G31 337 ). ). European Journal of Endocrinology www.eje-online.org benefit ofexperiencingan appropriate timingofpuberty. documented ovarianinsufficiency thepsychological yearsprovidesmostgirlswithTS by age11–12 more physiological hormonal replacement regimens during adolescence.The induction ofpubertywith yearsofage,withfurtherexplanations patient by9–11 on puberty should be discussed in simple terms with TS Estrogen therapy and reproductive issues: during transition 5.2. KeyTS-specificcontentareas tobeaddressed roles ofeachprovideronheradultcareteam. underscores theneedforTSyoungadulttoclarify approach for transitioning to an adult practice, which for planningpediatricpracticesandarecommended principles forestrogentherapy, arecommendedapproach the customizedsetofTS-specifictoolsincludesguiding In additiontothethreecoreelementsmentionedpreviously, following threecoretransitionelements: condition-specific setoftoolsincludes,ataminimum,the to achieve optimal self-care as an emerging adult. Each transition_tools.pdf pediatric_adult_care_transitions/endo_turner/endo_ts_ information/high_value_care/clinician_resources/ www.acponline.org/system/files/documents/clinical_ and AmericanCollegeofPhysicians(ACP)( Hormone Health Network, Turner Syndrome Foundation Transition Toolkit, co-producedbytheEndocrineSociety, of condition-specifictoolsistheTSPediatrictoAdultCare Transition are availableattheAmericanAcademyofPediatrics a keycomponentofqualityhealthcare.Generictools Clinical PracticeGuideline that needtobeaddressed. gaps inself-careknowledge,skillsoradditionalissues the receivingadultcareteamtoassessanyremaining Self-care assessment: and family, andsenttoreceivingadultcareclinician(s). be completedbypediatricclinician(s),sharedwithyouth communication betweenpediatricandadultclinicians,to record elementsoressentialinformationneededfor Transfer summary: adult care. is mastered by the time a young adult is transferred to as ateachingandtrainingaidtoensurethateachitem to beusedfordocumentationandrevisitedovertime manage theirspecificcondition.Thetoolisintended conversation abouttheyouth’s neededskillsto to beusedbythepediatriccareteambegin Transition readiness assessment: Website ( ) tohelptheyoungadultintransition www.go A summary of key medical of key medical A summary Anassessmenttooltobeusedby ttransition.org). An example C HGravholtandothers Anassessmenttool TheimpactofTS https:// Got TS to understand how early prevention or identification TS tounderstandhowearlypreventionoridentification into adulthood. It is essential foreach young adult with develops and( pressure carefullymonitoredandtreatedifhypertension – ( preventive measuresthatcanbetakentostayhealthy These conditionsneedtobespecifiedaswellthreekey yet detectedbythetimeoftheirtransitiontoadultcare. during childhood,thatthereisariskforconditionsnot continued follow-upcareforspecificconditionsidentified to eachyoungadultwithTShow, inadditiontotheneedfor health outcomes: organ andtissueintegrityaretobeemphasized. psychosexual health,aswelltomaintainreproductive long-term estrogentherapytosustainvascular, boneand assisted pregnancyneedtobediscussed.Thebenefitsof is tobereviewed.Serioushealthrisksofspontaneousor The scope of available and emerging reproductive options future health,QoLandlongevity. and treatmentofrelatedcomorbiditieswilldeterminetheir in Europe where each center serves largepopulationsof in Europewhereeachcenter serves vertically integratedcaremodel appearsmoreprevalent patient, andthesameelectronic healthrecords.This care team,afamiliarsite of caretothetransitioning to adultcarebysharingsimilar membersofthehealth and exchangeofhealthcareinformationfrompediatric the advantageofprovidingamoreseamlesstransition programsoffer Joint pediatric-adultcaremultidisciplinary care andguidingprinciples 5.3. Transition care modelsfrom adolescenttoadult counseling asneeded.SeealsoSection 7. individual TSyoungwomanandtoprovideappropriate educational andcareergoalsalignwiththeabilitiesof It isalsoimportantforpediatricproviderstoascertainthat that, ifnotaddressedduringtransition,canimpactQoL. inTSposepsychosocialrisk social adjustmentobserved neurocognitive profile,personalitytypeanddifficult ensure fullpotentialandhighqualityoflife and areductioninmorbiditylosstomedicalfollow-up. emphasized withtheaimofensuringguideline-drivencare of preparationforadulthoodcardiovascularcareis to discuss.Duringthistransitionperiod,theimportance heart disease. cholesterol, diabetes,hypertension,strokeandischemic Girls withTSareatincreasedriskofobesity, elevated practice guideline Turner syndromeclinical 1 Associated needsandlifestylerequirements toensure optimal Psychosocial, educationalandvocationalissuesto Cardiovascular healthcare from childhoodtoadulthood ) liveahealthyandactivelifestyle,( al 6 Table 3 Pediatric providers need to articulate clearly Pediatricprovidersneedtoarticulateclearly ) continue to take sufficient estrogen well ) continuetotakesufficientestrogenwell is a list of topics that are helpful isalistoftopicsthatarehelpful 177 :3 2 : Thetypical ) have blood ) haveblood G32 : European Journal of Endocrinology pediatric endocrinology care team to fulfill. Establishing pediatric endocrinologycare teamtofulfill.Establishing clinicians tobestmeettheirneeds isanessentialroleforthe family identify an adult endocrinologist and other adult support transition.Helpingthe individualwithTSandher to each coreelementandtodesignanofficeworkflow the pediatriccareteamis(are)responsibleforimplementing recommended. Itisessentialtodefinewhichmember(s) of to overseetheimplementationoftransitionactivities is Identifying anofficeandclinical‘transitionchampion’ core elementsoftransitionasdetailedaboveisfollowed. as longastagedtransitionprocessthatincludesthe the caremodel,itdoesnotprecludeaqualitytransition outside oftheirhealthcaresystem( others needtotransitiononeormoreadultproviders using thesameelectronichealthrecords(EHR),while adult careproviderswithinthesamehealth care system careprogram.Somehaveaccessto adult multidisciplinary young adultsdonothaveaccesstoanintegratedpediatric- In theUnitedStates,similarmodelsexistinfewplaces. when youngadultsleavethepediatricphaseoftheircare. TS patientsandreportlowratesoflosstofollow-upcare *When 9–12 monthsold; see text. The recommendationsareforscreeningonly. Aclinicalsuspicionofactivediseaseshouldalwaysleadtorelevantinvestigation.Fordetails,please Skeletal assessment Bone mineraldensity Skin examination Clinical investigationforcongenitalhip Dental evaluation Ophthalmological examination Audiometric evaluation Renal ultrasound Celiac screen 25-Hydroxyvitamin D HbA1c withorwithoutfastingplasma Aminotransferase, GGTandalkaline Lipids Thyroid function(TSHand(free)T4) Blood pressure Weight/BMI elsewhere, i.e.cardiacandneuropsychological). Table 6 dysplasia glucose phosphatase Clinical PracticeGuideline Structural requirements:Structural Recommendations forscreeninginTurner syndromeatdiagnosisandthroughoutlife(excludingthosecovered

# when 12–18 monthsold; The reality is that many TS TherealityisthatmanyTS C HGravholtandothers Fig. 3 At diagnosis Yes, innewborns Yes, ifnopreviouscare Yes Yes* Yes Yes Yes Yes At diagnosis

¤ has beenestablished cardiovascular riskfactors:hypertension,overweight,tobacco,diabetes,andphysicalinactivity. ). Regardless of ). Regardlessof # Attention willbegivento: (1)theageofsubjects,(2) comorbidities ofTSnotcovered elsewherewillbemade. In thissection,management recommendationsfor (from childhoodtoadulthood) 6.1. ComorbiditiesinTurner syndrome throughout thelifespan 6. Healthsurveillanceforcomorbidities to yetanothertransitionstrategyinthenearfuture. Leveraging oftelemedicineplatformsmayopenthedoor patient successfullytransferredtoheradultprovider(s). ensure asuccessfultransitionandascertainthattheTS and receivingadultendocrinologistmaybebeneficialto period ofsharedorco-managementbetweenthepediatric document mayberequired.Insomesettings,abrief transition andaprintedratherthandigitalhealthsummary providers usingdifferentEHRswillassistinaseamless of healthinformationbetweenpediatricandadult encouraged andneeded.Overcoming non-interoperability a goodpartnershipwiththereceivingadultprovidersis practice guideline Turner syndromeclinical Every 3 years Starting at2 years;thereafter Every 2–3 yearsafter Annually after10 yearsofage Annually after10 yearsofage Annually Every visit Every visit After diagnosis 5–6 years and12–14 years Annually every twoyears 9–11 years ofage (see 6.1.10.) (childhood)

Every 5 years With suggestivesymptoms Every 3–5 years Annually Annually Annually ifatleastone Annually Every visit Every visit After diagnosis Every 5 yearsandwhen Annually

regional recommendation cardiovascular riskfactor discontinuing estrogen 177 www.eje-online.org :3

(adults) G33

¤ or

European Journal of Endocrinology www.eje-online.org risk ofisolation,depression and, possibly, dementia. are crucial to avoid hearing-related speech pathology and management ofhearingimpairment infemaleswithTS myringotomy tubesasindicated ( ear diseaseandOMwithantibioticsplacement of R 6.2. measures ( early andadequatetechnicalotherrehabilitative a mid-frequencysensorineuralhearingloss,toassure and/or presenceof hearing thresholdlevels,karyotype regardlessofinitialageatdiagnosis, initial 5 years every R 6.1. 6.1.1. Otolaryngologyproblems of recommendedscreeningssee recommendations beyondexpertopinion.Forasummary There existslittleevidenceformanyofthefollowing in normal populations) and (3) cost–benefit ratios. as hyperlipidemiaandvitaminDdeficiency(asoccur geographical differencesinmanagementofissuessuch Transition modelsfrompediatrictoadultcare. Figure 3 Clinical PracticeGuideline Early recognition,evaluation andappropriate

We recommendaformalaudiometricevaluation We recommendaggressivetreatmentofmiddle- ⨁⨁◯◯ ). Table 6 C HGravholtandothers ⨁⨁◯◯ . ).

external auditory canal ( external auditory protruding pinnae, cupped auricles and narrowing of the to 34%ofpatientsandincludelow-setabnormally Anomalies oftheexternalearhavebeendescribedinup early-onset sensorineuralhearing loss(SNHL)( malformations, increaserisk forOMandcontributeto as alackofgrowth-regulating genes mayinduceauricular single orabsentshortarmof the Xchromosome( chronic OM( T-cells, mayinduceanimmunedeficit predisposingto with haploinsufficiencyoftheX-linked helper-cell frequenciesinperipheralbloodthat,together contributory. Femaleswith TS havedecreasedT-follicular related factors(estrogendeficiency)mayalso be increased rate of OM and the effects of X chromosome- and abnormalorientationoftheEustachiantubes. canal skeleton, adownwardslopeoftheexternalauditory morphology, includingdelayeddevelopmentofthecranial abnormalities arelikelyrelatedtoabnormalcraniofacial practice guideline Turner syndromeclinical The rateofhearingproblems ismuchhigherwitha A subnormal immune response, leading to an The reasonsforhearingimpairmentaremultifactorial. 342 ). 340 , 341 ). In addition, hearing 177 :3 UTX 344 340 genein ). , G34 343 ), European Journal of Endocrinology and impairedhearing,particularly CHL,areatincreased term effectsonhearing( or previous estrogentherapy. Oxandrolone has no long- possible effectsoftheX-chromosomal origin( TS patients ( typically presentinindividuals30 yearsandolder( hearing losswasfoundin3%ofthepatientsand in one-thirdoffemaleswithTS( in life.SomedegreeofSNHLhasbeenreportedtooccur accelerated hearingloss.Thisrequiresaidsearly SNHL, whichaddstothealreadyexistingdipandcauses early presbycusis( high-frequency region( decline, especiallyifassociatedwithimpairmentinthe is astrongpredictoroffuturehighratehearing years of age and in 11% of females between 11 and 20 deeper andmorebasin-shapedovertime.Itwaspresent can occurasearly6 years. Itisprogressiveandbecomes clearly understood.Amid-frequencysensorineuraldip middle-ear pathology( with TS,occurringandwithoutprevioussignificant necessity ofmoreextensivetympanicprocedures( of myringotomy tubes asindicatedtooffset the future and OMiscrucialincludesantibioticsplacement ( tympanic membrane,persistentotorrheaandolderage ofchronicOM,retraction of the ahistory karyotypes, factors forcholesteatomainclude45,Xand46,XisoXq and recurrentcholesteatomahasahighprevalence.Risk in 9–66% of the patients studied ( younger age( membrane pathologyandismostcommonlyseenin to middle-eareffusion,frequentOMandtympanic bone gapof published literature( third ofpatients with TSandisconsistent throughout ( yearsandolder, nonehadnormalhearing in those50 in younger age groups (7–30 years) ( and short-armmosaickaryotypes females withpreserved SNHL. factorparticularlyin estrogens mightbeacontributory positive effectsonhearing.Thus,lackofendogenous and neurotrophiceffectsonthebrainlikelyhave in the human ear ( 340 346 Clinical PracticeGuideline Variable effectsofGHtherapyonearproblemsin SNHL istheprevailinghearingimpairmentinfemales Conductive hearingloss(CHL),definedasanair- Normal hearing is present in about one-third of Estrogen receptors- , inaboutone- ). Overall,hearinglosswasobserved 348 ). Aggressive treatment of middle-ear disease, 121 359 > 10 , ). Middle-eardiseasehasbeenreported 350 < dB ofhearingloss,iscommondue 345 35 years ofage)withhigh-frequency 35 years 341 ) could be due to the variations in α ). Estrogens have neuroprotective 346 352 and- , 347 346 ). Theexactpathologyisnot ). Women whohave lowBMD ). Patientsmaydevelopan , β 347 havebeenshowntoexist C HGravholtandothers ). 341 341 341 , , 346 346 , 346 , ). In contrast, 347 ). Isolated 351 ). Mixed 349 ) and/ 346 ). ). throughout thelifespan( TSH measurementsbeginninginearlychildhoodand at diagnosisandthenannuallywith(free)T4 R 6.3. 6.1.2. Autoimmunity recurrence rate. becauseofahigh ofcholesteatomasurgery with history Continuous long-termfollow-upisindicatedforthose resolution ofthemiddle-eardiseasetodetectSNHL. even after the throughout the lifespan are mandatory prevent sequelae.Inaddition,periodicexaminations annually, todetectmiddle-eardiseaseand isnecessary in thosewithfractures( balance werealsofoundinwomenwithTSandespecially risk forfractures.Hearingimpairmentandimpairedbody polyglandular syndromeseemsnotincreased( frequency ofAddisondiseaseandtypeIorIIautoimmune alteration thatmaypredisposetoautoimmunity( CD4–CD8 lymphocyteratio,suggestinganimmune predisposition isnotknown,thereadecreaseinthe disease (IBD) ( bowel rheumatoid arthritis,uveitisandinflammatory type 1diabetesmellitus,alopeciaareata, juvenile hypothyroidism), celiacdiseaseand,toalesserdegree, thyroid disease (thyroiditis, hyperthyroidism and development of several autoimmune disorders, including thyroiditis ( between ovarianfailure to theautoimmunity, theremaybeanassociation absence ofasecondXchromosome isamajorcontributor ovarianfailuresuggestthat,whilethe those withprimary unknown. However, datathatcomparewomenwithTSto monosomy give(s)rise to autoimmunity remain(s) adult haveregularfollow-upandscreening. with ageand,therefore,itisimportantthatthechildand development of one or more of these conditions increases course tothatingirlswithoutTS( tends topresentatalaterage,butwithsimilarclinical in childrenand young adultsis1.7–3.0%. However, it with TSis3.2%( annual incidenceofhypothyroidisminadultwomen increases withage( TS. Itmaybegininearlychildhood,anditsprevalence prevalent autoimmunedisorderfoundinpatientswith Hypothyroidism duetoHashimotothyroiditisisthemost practice guideline Turner syndromeclinical Individuals withTShaveanincreasedrateof Careful follow-upduringearlychildhood,atleast The mechanism(s)wherebyX-chromosomal

We recommend screening for hypothyroidism 359 355 ). 359 , 356 355 ). TheincidenceofGraves'disease ). While the genetic basis for the 353 ). Onestudysuggeststhatthe per se ⨁⨁◯◯ , 354 andchroniclymphocytic ). 360 ). 177 , www.eje-online.org 361 :3 ). Theriskfor 357 G35 ). The 358 ). European Journal of Endocrinology www.eje-online.org diabetes shouldpromptassessment ofantibodiesrelated to loweradiposityandless IGT( least onestudysuggeststreatment withGHmaylead diabetes has been noted during GH therapy. In fact, at additional increase in the incidence of insulin-requiring and decreased likely duetobothdiminishedfirst-phaseinsulinrelease secretion andIGT( hyperinsulinemia, insulin resistance, decreased insulin (without overtdiabetes)havebeendescribed,including 356 TS acrossallagesinepidemiologicalstudies( is about10-foldand4-foldincreasedinpatientswith the ageof10 years( HbA1c withorwithoutfastingplasmaglucosestartingat R 6.5. 6.1.4. Diabetes and hypertensionindependentofobesity( have anincreasedriskofimpairedglucosetolerance(IGT) of theseabnormalities( literature ( youth andadultsisunclearwithdiscrepanciesincurrent peers ( percent leanbodymass thanage-andBMI-matched percent bodyfat,larger waistcircumference andlower ( yet, otherresearch suggests anincreasedburdenofobesity with TSreflectsthepopulationmeansinsomestudies; as obesity. Theprevalenceofobesityinyouthandadults management shouldbeinplacetoavoidriskfactors,such cardiovascular disease,aggressivelifestyleandmedical physical activitystartinginearlychildhood( R 6.4. 6.1.3. Obesity for anypregnantwoman. pregnancy shouldfollowlocalclinicalpracticeguidelines ( on ultrasound, not different from the general population and/or withthyroidenlargement.Theglandis, recommended atfirstdetectionofthyroiddysfunction recommended. However, theirmeasurementisusually not altermanagement,soaspecificprotocolcannotbe 363 362 Clinical PracticeGuideline , The riskofbothtype1and2diabetesmellitus Because TSisahigh-riskconditionforearly Regular screeningforanti-thyroidantibodiesdoes , ). Managementofthyroiddysfunctionduring 368 364

363 We recommend lifelong annual measurement of We suggestcounseling on healthy nutrition and ). Various abnormalitiesinglucosehomeostasis ). IndividualswithTShaveahigherBMI, , 364 365 , , 366 366 β -cell responsiveness( , ⨁⨁◯◯ 131 ). ThedegreeofcentralobesityinTS 367 , ). GHtherapymaymitigatesome 117 133 , , ). 119 191 C HGravholtandothers ). Youth with TSmay , 117 367 ). Confirmationof , 369 131 282 ), whichare ⨁⨁◯◯ , , 369 367 166 ). No ). , 268 ). , cardiovascular diseasestartingatage18 years ( in individualswhohaveatleastoneriskfactorfor R 6.6. 6.1.5. Lipiddisorders specialist. to type1diabetes,aswellevaluationbyadiabetes study showednodifferenceinlipidsnon-obeseTS elevations arerarelyreported( LDL cholesterolandtriglyceridesthancontrols,severe While studiesdemonstratehighertotalcholesterol, cardiovascular riskfactorswasnotanalyzed( population. However, the relationshipto BMI and other with TS,whichishigherthanthatinthegeneral has beenreportedtooccurin37–50%ofwomen already elevatedcardiovascularrisk.Hypercholesterolemia in youth( edema therapist( skin atanyagebeassessed and treatedbyaprofessional serious compromiseoffingernails, toenailsorextremity yearsofagewithouttherapy, any mostly resolvesby2 R 6.7. 6.1.6. Lymphatics recommendations forthegeneralpopulation. e.g., hypothyroidism,andtreatmentcouldfollowthe causes, should firstpromptanassessmentforsecondary obtained. Findinganelevatedcholesterolconcentration dL ( transition toadultcare.Ifnon-HDLcholesterolis yearspriorto 9 and11againbetween1721 from totalcholesterol)ontwooccasions:oncebetween cholesterol (calculatedbysubtractingHDL that childrenhavemeasurementofnon-fastingnon-HDL Pediatrics andAmericanHeartAssociationrecommend risk ofmortality. is nonethatthetypeorrouteofadministrationincreases lipid concentrations( 363 influenced byamultitudeoffactorsintrinsictoTS( years( age 45 disease wasraised,butfewdeathsoccurredpriorto that thestandardizedmortalityratioforischemicheart death certificates toidentify causesof mortalityidentified adults comparedtocontrols( practice guideline Turner syndromeclinical ≥ , TS maybeassociatedwithanatherogeniclipidprofile In theUnitedStates,AmericanAcademyof 372 3.7

mmol/L), thenafullfastinglipidprofileshouldbe We recommendthatalipidprofilebeperformed , We recommendthat,whileperipheraledema 375 149 ). Thereisevidencethatestrogenmodifies , 268 176 ⨁◯◯◯ ). Thehypercholesterolemia ispartly , 367 149 , , 370 176 ). 315 , , 371 370 325 ). Adifferentstudyusing ), contributingtoan , , 177 375 372 :3 , , 376 374 ), butthere ⨁⨁◯◯ ). Another 372 ≥ 145 mg/ , G36 373 325 ). ). ). , European Journal of Endocrinology lateral open bite are commonly found. They also have lateral openbitearecommonly found.Theyalsohave large overjetandlateral cross-bite andanterior abnormal palate ( and smallmandible),increased cranialbaseangleand also havearetrognathiclower face(includingarecessed loss especiallyduringorthodontictreatment.Theymay increased riskforrootabsorptionwithsubsequenttooth eruption, changes in crown and root morphology, and an ( care, individualclinicalfindingsandpatientneeds should bebasedonthestandardofdental/orthodontic was established.Future management andfollow-up at diagnosisifnopreviousdental/orthodonticcare R 6.8. 6.1.7. Dentalandorthodontics be donebytheindividualorafamilymember. examination of the nails and skin of feet and toes should to GHtherapyhasnotbeenreported.Ifaffected,lifelong salt-/fluid-retaining therapies(estrogen).Arelationship any laterage,possiblyinassociationwithinitiationof resolves orwasnotpresentatbirth,itmay(re)occur may needtobestartedearly. Evenifthelymphedema or skinarecompromised,professionaledematherapy without therapy, but,ifthefingernails,toenailsand/ yearsofage edema usuallyresolvesorimprovesby2 problems withwritingandbuyingshoes.Theperipheral skin( problems anddry X reportedlymphedemasymptoms,especiallytoenail girls andwomenwithTS,65%ofthosemonosomy of219 hands andfeet.Inalymphedema-focusedsurvey of hypoplasticnipplesanddistortionthenails posterior hairline,rotationofthepinnae,appearance ( a webbed neck and left-sided congenital heart defects deformity). Thereisalsoastrongassociationbetween and feetwebbedneck(resultinginthe lymphedema as peripheral edema, primarily of the hands that dowillusuallydemonstratetheresiduaoffetal ( the severelyaffectedfetusesfailtosurvive women withTSusinglymphangiography( hypoplasia or aplasia has also been demonstrated in adult impaired developmentisunknown.Peripherallymphatic the internaljugularvein( communication betweenthejugularlymphaticsacand malformations andobstruction,primarilyatthe conceptuses withTSasaconsequenceoflymphatic 380 ⨁◯◯◯ Clinical PracticeGuideline Females with TS may present with variations in dental Females withTSmaypresentvariationsindental Cystic hygromaandlymphedemaoccurinmany ). Furtherconsequencesincludeloweringofthe

We recommenddental/orthodonticevaluation ). 382 ). Inaddition,distal molar occlusion, 381 377 ). Otherimplicationsinclude ). Thegeneticbasisforthe C HGravholtandothers 378 pterygium colli pterygium 379 ). Manyof ); those

gives thefalseillusionofincreasedpalatalheight( archmaxillary withthepresenceoflateralpalatalridges that palatalheightisnotaffected,asanarrowerdental have a ‘high-arched palate’. Recent research indicates in linewiththegeneralpopulation( tendtohaveabnormalities with a45,X/46,XXkaryotype have moresevereoralanddentalanomalies,whilethose oral hygienewhencomparedwithcontrols( caries issignificantlylowerdespitethefindingsofpoorer is commonlyfound( than-normal toothmobility( and gingivalindicesareabnormalthereishigher- thinner enamelandabnormaldentin( years). The teeth have months–3.5 controls (range6 monthsearlierthanthatin dentition oftenerupts12 mandibular first and second premolars ( andpermanentteethwithtwo-rooted smaller primary Future managementand follow-up shouldbebased if nopreviousdental/orthodontic carewasestablished. recommend dental/orthodontic evaluationatdiagnosis breathing obstructionand disturbeddigestion.We teeth-crowding, trismus, mastication difficulties, untreated, mayleadtodentaldeformities,bruxism, growthduringfetaldevelopment which,if maxillary is causedbydistortionofpropermandibularand/or skeletal ageandmaturity( malocclusions thatshouldbetreatedaccording to with TSastheyoftenpresentdentalandskeletal develop thecorrectdentaltreatmentplanforfemales dental age.Evaluationofthesefactorsiscrucial to delayed skeletal age, with the paradoxically advanced growth, anabsentordelayedpubertalgrowthspurtand possible neckinvolvement( vertebralmorphologyand to assessabnormalcervical considered, ananesthesiaconsultationmaybeneeded is specialists. Inaddition,iforthodonticsurgery isneeded,andperiodonticprosthodontic surgery orthognathic insufficiencyifmaxillary pharyngeal team becauseofriskhypernasalspeechandvelo- antibiotic prophylaxis)and,asindicated,acleftpalate pediatrician or endocrinologist; cardiologist (for possible ( to minimizeadverseeffectsonspeechdevelopment TS; thus, early diagnosis and treatment are recommended dental pathology( low tongueposition may furthercontribute to oraland practice guideline Turner syndromeclinical 389 Historically, it was believed that females with TS Females with 45,X or with 45,X/46isoXq mosaicism There issignificantdisparitybetweendelayedlinear Cleft palateisoccasionally reported in females with ). Acomprehensiveassessmentshouldinvolvea 388 386 ). ). Paradoxically, theprevalenceof 390 390 385 ). ). Skeletalmalocclusion ). Decreased crown width ). Decreasedcrownwidth 386 177 www.eje-online.org 384 ). :3 383 ). The palatal ). Thepalatal 385 ). Permanent ). Permanent ). 387 G37 ). A European Journal of Endocrinology References arementionedinparentheses. Foot Lower extremities Spine Upper extremities Sternum (548) Craniofacial features(547) Abnormality Table 7 www.eje-online.org melanocytic nevi compared to the general population, melanocytic nevi compared to the general population, Girls andwomenwithTShaveanincreasednumberof 6.1.9. Dermatology refractive errorsarevitaltopreventvisionloss. 35% those with TS ( of males(8%).Multiplevisualdeficitsarefoundinabout prevalence ofred-greencolorblindnessissimilartothat downward-slanting palpebralfissuresarealsocommon.The with TS.Ptosis(16%),epicanthalfolds,hypertelorismand amblyopia eachoccurinroughlyone-thirdoffemales hyperopia andmyopia( and women with TS, with increased prevalence of both early correctionofrefractiveerrors( time ofdiagnosis,ifatanolderage,withemphasison ofageoratthe examination between12and18 months R 6.9. 6.1.8. Ophthalmology clinical findingsandpatientneeds. on thestandardofdental/orthodonticcare,individual Short broadfeet(416) Flat feet(416) Splayed foot(416) Hyperextension ofthegreattoe (558) Hypertrophic medialfemoralcondyle(552) Prominent, abnormallylocatedtibialtuberosities(552) Genu valgum(416,557) Increased upper-to-lower segmentratio(556) Kyphosis (415,555) Scoliosis (414,415,554,555) Short neck(553) Short 4thand/or5thmetacarpals(551,552) Distal radio-ulnarphysicaldisparity(551) Madelung deformity(550,551,552) Cubitus valgus(549) Pectus excavatum Short –leadingtoshieldchest,fusionofbones,orbowing Retrognathia orapparenthigh-archedpalate Clinical PracticeGuideline Short andposteriorlyrotatedmandiblemaxilla Short posteriorcranialbase Refractive errors are present in about 40% of girls Refractive errorsarepresentinabout40%ofgirls

We recommendacomprehensiveophthalmological Musculoskeletal abnormalities. 392 ). Early detection and correction of ). Early detection and correction of 391 ). Importantly, strabismusand C HGravholtandothers ⨁◯◯◯ ). with prevalencerangingfrom15to64%( conditions does not differ by karyotype ( conditions doesnotdifferbykaryotype ( mosaic karyotypes patterns, suchas hypomelanosis ofIto,may accompany though casereportsexist.Whorlingskinpigmentation 400 Prevalence dataarenotavailableforalopeciaareata( or hypertrophicscarsaftersurgicalprocedures( report showedthatonlyabout3%developedkeloids practice suggests that keloids commonly occur, but one prevalence overthegeneralpopulation( a studyof594womenwithTSdidnotfindanincreased Psoriasis isfrequentlyreportedinpatientswithTS,but vitiligo (2.7–6%)( prevalence includepilomatricomas(2.6%)( 168 TS isassociatedwithandincreasedmelanomarisk( 394 and otherskinlesions( No clearrelationshiphasbeenfoundbetweenGHtherapy nor totriggermalignanttransformation( it hasbeenshownneithertoincreasethenumberofnevi practice guideline Turner syndromeclinical , , ). Studies conflict with regard to the question whether Therapy withGHmaytriggermelanocytegrowth,but 403 395 ) andforcutisverticisgyrata( , 396 ). Other skin conditions that have a greater ). Otherskinconditionsthathaveagreater 399 407 , Prevalence 399 400 ). The prevalence of other skin ). The prevalence ofotherskin 23–42, 35 63–86 40–75 12–59 ). ) andhalonevi(18%)( 0–7 65 31 31 78 54 46 97 87 86 79 20 80 60

(%) 177 402 166 399 :3 , 393 , 404 ). 401 19 , 397 , 408 , ). Clinical ). Clinical 405 23 , , , G38 , 409 402 399 398 406 167 393 23 ). ). ). ). ), ) , , , European Journal of Endocrinology ( and vitaminDfollowregion-specific recommendations R 6.13. of estrogenreplacementinbone health( counseled onhealthylifestyle measures,andontherole R 6.12. 6.1.10.2. Osteopenia,fractureriskandvitaminDtherapy independent ofkneemisalignment( compared totheotherandfootabnormalitiesmaybe common. Abnormalitiescanbedifferentinoneextremity knee alignment( dysplasia. Abnormalitiesofthelowerextremity, including specifically forgirlswithTS. of scoliosisoronmanagementapproachesandoutcomes timing ofestrogenreplacementandthenaturalhistory No dataareavailableregardingtherelationshipof Scoliosis mayprogressordevelopduringGHtherapy. is morecommonwithincreasingageandheight( or mimicthepatternofidiopathicscoliosis( scoliosis ismostlikelymulti-facetedandcanbecongenital and scoliosis occurs in patients with TS. The etiology of GH therapy( femoral epiphysishasbeenreportedwithandwithout augment footandhandsize( persists ( rotation ofthemandible,yetpre-existingretrognathia but mayincreasethelongitudinalaxisandanterior craniofacial featuresingirlswithTS( prevalence ofmajorabnormalitiesisnotedin Reported consistently associatedwithspecifickaryotypes. phenotype isdifferentfrompersontoandnot Musculoskeletal abnormalitiesareextensiveinTS.The 6.1.10.1. Hippathology, kyphosisandscoliosis ( at thestartoftherapyoriftheydevelopduring with orthopediccareifspineabnormalitiesarepresent R 6.11. until growthiscompleted( 6 months annually every duringGHtherapyorotherwise R 6.10. 6.1.10. Orthopedics ⨁◯◯◯ ⨁⨁◯◯ Clinical PracticeGuideline Infants mayhaveanincreasedriskofcongenitalhip An increased risk of kyphosis, vertebral wedging GH therapydoesnotappeartocauseacromegaloid

410 We recommendclinicalevaluationforscoliosis We suggesttreatmentwithGHbecoordinated We intakeofcalcium recommendthat dietary We recommendthatallpatientsshouldbe ). ). , 413 412 ). genu valgum ). TherapywithGH,however, may ⨁◯◯◯ ) andarch irregularities,are C HGravholtandothers 112 416 ). ). Slippedcapital ). ⨁⨁◯◯ 410 414 , 411 Table 7 ). Scoliosis , ). 412 415 . ), ), ). with neither BMD nor fracture risk ( 425 is associatedwithhigherBMD( Conversely, endogenousandexogenousestrogenexposure ( vitamin D(ergocalciferol)asnecessary throughout thelifespanandtreatingwithinactive years thereafter 2–3 yearsof age and every 9 and 11 with aserum25-hydroxyvitaminDmeasurementbetween R 6.14. D metabolismmaybeabnormalaswell( lower 25-hydroxyvitamin D concentrations and vitamin increased riskoffracture.Women withTSappeartohave of BMDmaybedifficulttointerpret. tibia and radius ( microarchitecture and lower bone strength in both the high-resolution peripheralQCThasshowncompromised dueto and thedifferencesinbonegeometry due tothesmallbonesizeaccompanyingshortstature may appearfalselyreducedwhenevaluatedbyDXA resulting frominadequateestrogenexposure.TheirBMD not associatedwithBMDorfracturerisk( fracture, hearingimpairmentandolderage( ofparental fracture riskisassociatedwithlowerBMD,history fracture even with normal BMD ( of estrogentherapy(simulatingmenopause)( density inallwomenwhenconsideringdiscontinuation R 6.16. been instituted( density afteradulthormonereplacement therapy has R 6.15. ( childhood andwithsuggestive symptomsinadulthood 2–3 years 2 years ofageatafrequencyevery throughout measurement of transglutaminase antibodies beginning at R 6.17. 6.1.11. Gastrointestinalandliverdisease D therapyingirls,adolescentsorwomenwithTS. no literature supporting the benefits of universal vitamin BMD( replacement, maypreserve those withlow25-hydroxyvitaminD,alongestrogen Vitamin D3supplementation(20 content duetothepartialvolumeeffect( density ( evaluation ofBMDhasshownnormaltrabecularbone deficiency ( practice guideline Turner syndromeclinical ⨁◯◯◯ ). GH therapy is associated with increased bone size, but ). GHtherapyisassociatedwithincreasedbonesize,but Girls and women with TS have an increased risk for Girls andwomenwithTShaveanincreasedriskfor Decreased calciumstatusmayalsocontributetothe Many womenwithTShaveosteopeniaorosteoporosis

428 We recommendusingDXAscanstomonitorbone We recommendscreening forceliacdiseaseby We suggestscreeningforvitaminDdeficiency We suggestusingDXAscanstomonitorbone ). 427 ) withfalselyreducedcorticalbonemineral ). Furthermore,quantitative CT (QCT) ⨁⨁◯◯ 430 ). Therefore, radiographic evaluation ). 180 417 433 μ 426 g or800 , , 177 418 418 ). However, thereis ). Karyotype itself is itself is ). Karyotype ⨁◯◯◯ www.eje-online.org :3 23 , , 419 422 , 166 166 IU daily)in ⨁⨁◯◯ 429 ). Increased ). Increased , , 431 420 ). 423 ), while ). , , G39 , SHOX 432 421 424 ). ). ). ). ,

European Journal of Endocrinology www.eje-online.org administration ( replacement therapy, regardless of the route of or resolutionofliverenzyme elevationwithestrogen cirrhosis)( biliary autoimmunity (e.g.,primary sclerosing cholangitis) and lesions (e.g., primary biliary anomalies, asevidencedbynodularregenerativechanges, 366 and metabolicsyndromeaslikelycontributors( understood, butthoughttobemultifactorialwithobesity necessitate biopsy. fibrosis andsteatosis( as determinedbytransientelastographytoevaluatefor and controlledattenuationparametermeasurements elevations shouldpromptassessmentforliverstiffness portal hypertension or steatosis. Persistent liver enzyme those with biochemical abnormalities to identify nodules, Liver ultrasound with Doppler blood flow may be done in is sixfoldmorethanthatinthegeneralpopulation( threatening complications,althoughtheriskofcirrhosis revert tonormal( tend topersistorprogressivelyincreaseandrarely 2.1–3.4% ( prevalence byage(20–80%)andanannualincidenceof abnormalities areacommonfinding,withincreasing in patientswhomthediagnosisisindeterminate( disease ishighlyunlikely. Thistestingmayalsobeused HLA-DQ8 areboth negative, afuturediagnosis of celiac groups suchasTS.IftestingrevealsthatHLA-DQ2and that HLAtypingbeusedasafirst-linescreeninhigh-risk the necessityoflong-termscreening.Ithasbeensuggested (HLA) typingmaybeconsidered,inordertodetermine positive serologicaltesting.Humanleucocyteantigen with intestinalbiopsyshouldbeconsideredinthose antibody positivityisdetectedin2–16.6%.Endoscopy ( This suggestsincreasingprevalenceinchildhoodwithage ofagerespectively. for thoseunder5andover10 years based onbiopsydataof2and5timesthegeneralpopulation population (prevalenceof4.5%)( for improvementofliverfunction( for theinitiationoffemalehormonereplacementtherapy R 6.19. ( years yearly throughoutthelifespanstartingatage10 (including AST, ALT, GGTandalkalinephosphatase) R 6.18 435 ⨁⨁◯◯ Clinical PracticeGuideline , The mechanismforliverdiseaseinTSisnotwell- Asymptomatic liver test (ALT, AST and GGT) Celiac diseaseismorefrequentlydiagnosedintheTS Several studieshavenowdocumented improvement ). Endomysialand/ortissuetransglutaminase(tTG) 439 .

). Other possiblerisk factors include vascular We recommendmonitoringliverfunctiontests We recommend appropriate timing (see ). 188 , 437 187 439 , , 438 ). Importantly, fewprogress to life- 190 440 , 439 ). Inthecaseofisolated ). Concerningfindingsmay ). Liverenzymeelevations C HGravholtandothers 434 ⨁⨁◯◯ ), witharelativerisk ). 441 ). R 2.8 166 436 186 ). ). ) , β to detect esophagealvarices, which could require either present, uppergastrointestinalendoscopyisrequired should be considered. If liver architectural changes are GGT andalkalinephosphatase),ursodeoxycholicacid cholestatic syndrome(oftenindicatedbyelevationsin evaluation forIBD,vascularmalformationsofthegut or intestinalbleedingbeevaluatedforIBD. abdominal pain,unexplainedweightloss,diarrheaand/ ( an isoXqencompassmorethanhalfofthosewithIBD severe comparedtothegeneralpopulation.Patientswith tends to occur at a younger age and symptoms are more more frequentthanulcerativecolitis.Onsetofdisease (0.15–3%) ( amelioration ofsteatosis( loss hasbeenshowntobeeffectiveforpreventionor renal scarringandresultant sequelae.Congenitalrenal of obstructionorreflux)is critical topreventpermanent antibiotic treatment/prophylaxis orsurgicalcorrection infections isnecessary. (including Properintervention tract Therefore, ahighindexof suspicionforurinary to bemorefrequentasaresultofobstructionorreflux. population ( renal diseaseissevenfoldhigherthanthatinthegeneral e.g., chronicrenalfailure,althoughmortalityrelated to morbidity,with renalanomaliesdonothavesecondary obstructions andhydronephrosis(5–15%).Themajority acquired, arealsocommon,andincludeduplications, duct andureteralanomalies,bothcongenital multicystic ( partially ortotallyduplicated(5–10%),absent(2–3%), ( effects of lymphatic stasis, may be the underlying basis failure in budding or migration or the compressive TS isbroadandaffects24–42%( of diagnosis( R 6.20. 6.1.12. Renaldisease rare causeofgastrointestinalbleeding. malformation isreportedtobe7%,itremainsarelatively described. Althoughtheprevalenceofagutvascular mesentery, largebowelandsmallhavebeen telangiectasias andvenousectasiasinvolvingthe should alsobeconsidered( practice guideline Turner syndromeclinical 445 450 -blocker treatmentorsurgicalligation.Finally, weight While gastrointestinalbleedingshouldpromptan The prevalence of IBD in patients with TS isincreased The spectrumofrenalanomaliesinpatientswith , ). Anomaliesdescribedincludehorseshoe(11%)and 446

). Itisrecommendedthatanypatientwhohas We recommendarenalultrasoundatthetime 443 < 268 ⨁⨁⨁⨁ 1%) orectopic( , ). Urinary tractinfectionsarethought ). Urinary 444 , 445 ). 442 ). Crohn’s diseaseseemstobe ). 447 < 1%) kidneys.Collecting , 448 449 177 ). Hemangiomas, :3 ). Embryological ). Embryological G40 European Journal of Endocrinology Cardiovascular Obesity Table 8 Blood tests Orthodontics Dermatology Audiology Psychological Fertility Diabetes Liver Bone metabolism

Clinical PracticeGuideline Guidelines foradulthealthsurveillance. Blood pressure MRI aorta Echocardiogram Weight Action Celiac screen Thyroid function Teeth inspection Skin inspection Audiogram ENTHistory Review psychological Uterine ultrasound Adoption andoocyte HbA1c Liver ultrasound Liver functiontests Vitamin Dandcalcium DEXA scan issues donation education glucose profile ± atn plasma fasting

C HGravholtandothers Annually As appropriate 3–5 years –yearlyif Annually Suggested frequency With suggestive Annually Annually Annually 3–5 years As appropriate As appropriate As appropriate Annually As appropriate Annually 3–5 years Every 5 years aortic root symptoms > 3 cm practice guideline Turner syndromeclinical Hypertension affects upto50%ofyoungadultsand Some unitsuseechocardiographyforroutinemonitoring Management sharedwithGUCH(Grown-ups Many comorbiditiesareweight-related,e.g.,diabetes, Comments Estrogen replacementrequireduntil~50 years(orolderif Increased risk(4–6%)ofceliac disease. Checktransgluta Increased riskofautoimmune thyroiditis. In Referral recommendedifrequired Assess forkeloidandchangesinpigmentednevi Deafness iscommonandunderreported.Self-reporting Increased riskofsocialisolation,anxiety, andobsessive US oftheuterusshouldtakeplaceonarrivalinadult Spontaneous pregnancyoccursin2–5%.Ovarianfailure Consider OGTTifHbA1ciselevated.Highriskofdeveloping Liver USrequiredformarkedlyraised(GGT),alkaline Liver enzymes,especiallygammaglutamyltransaminase Monitor boneprofileinthosewithlowcalciumand angiotensin receptorblockers.Foraorticroot to normalguidelinesincludinguseofbeta-blockersor age-specific referencedata.Hypertensioncanbetreated contributes totheriskofaorticdissection.Refer depends onexpertiseoftheechocardiographyservice pre-pregnancy assessment.TheplaceofMRIscanning and reserveMRIforambiguousfindingsoraspartof of theaorta,andaorticdilatation malformations includebicuspidaorticvalve,coarctation congenital heartdefects)clinicpreferable.Congenital fitness, sedentarylifestyle,andpoorfoodchoices at annualvisits.Obesitymaybeduetolowphysical management isthemostimportanthealthintervention elevated cholesterol,andliverdysfunction.Weight there havebeenmanyyearsofestrogendeficiency)to tricuspid aorticvalveor and BAV, aimforsystolicbloodpressure minase IgAantibodies(andtotal IgA)andvitaminB12 TPO antibodiesifpreviouslynegative hypothyroidism (24%)orhyperthyroidism (2.5%)include hearing losscommonandprogressiveinadults which canleadtoconductivehearingloss.Sensorineural unreliable. Otitismediaiscommoninchildhood(60–80%) psychology support.SeeSection7and relationships. Problemsareresponsivetoclinical reduced self-esteem.Reviewproblemsinworkplaceor behavior. Higherlevelsofshynessandsocialanxiety, and clinic andagainduringthework-upforpregnancy required pregnancy withregardtoriskofaorticdissectionis occurs in90%.Medicalreviewonadvisabilityof plasmaglucose underestimatesdefectofinsulinsecretion insulin deficiencyandresistance.Fasting impaired glucosetolerance(50%)dueacombinationof defects identifiedonUS measuring fibrosisandsteatosis,biopsyifstructural phosphatase ortransaminases.Considerspecialscans screen foracutechanges(rarelypositive) improves withestrogenandweightloss.Considerviral (GGT), arecommonlyelevated.Slowlyprogressive,but vitamin Dlevels;excludeceliacdisease(seebelow) in othersituations short staturewithDEXA.Osteoporosiscanbetreatedas prevent osteoporosis.Bonedensityofspinereadslowin < 120 mmHg ifbicuspidvalve 177 www.eje-online.org Tables 9 :3 < mg if 140 mmHg > and 3.0 cm G41 10 - European Journal of Endocrinology www.eje-online.org presented inSection 6. Inaddition to assistedreproduction reviewed regularlytaking into account the evidence a coreactivityoftheadultTS clinic. steatohepatitis. Therefore, weight management should be outcomes includingriskofhypertension,diabetesand is acentralfactordeterminingmanylong-termhealth non-attendance. access toteststhatmayberequiredandfollow-upon of contact,bevigilantforpsychosocialissues,ensure A cliniccarecoordinatorcanbehelpfulasthepoint related, sexualfunctionandplansforfuturefertility. issues includingrelationshipsbothpersonalandwork such asexercise, dietandweightcontrol,psychosocial additions totheteam. nutritionists andphysicaltherapistsmakeuseful hepatology). Alliedhealthcareproviders,suchas audiology, dermatologyandgastroenterology(including heart disease),genetics,psychology, otolaryngology, cardiology (preferablywithexpertiseinadultcongenital include endocrinology, gynecology(includingfertility), direct referralsystemforanotherday. Relevantspecialties be accessibleeitheronthedayofvisitorthrougha avarietyofpractitionersshouldhealth surveillance, centered care.Becauseofthemultisystemnature should striveto provide one-stop-shoppingpatient- clinicwithout centralcoordination,amultidisciplinary care whentheyattendmultiplespecialtyclinics increasing withage. affect approximately25–50%ofadultswithaprevalence with TS.Forinstance,hypertensionandhypothyroidism on theincidence of newcomplications arising inadults Recommendations on the frequencyof testing are based of TS.Itemsforamedicalreviewarelistedin clinicfamiliarwiththenaturalhistory multidisciplinary great towarrantanannualassessmentpreferablyina ( health surveillance clinicsfor attend specialistinter-ormultidisciplinary R 6.21. 6.2. Theadultclinic can alsoresultinelevatedbloodpressure. scarring duetoprolongedrefluxorrecurrentinfections increase theriskofhypertension( anomalies have,inasinglestudy, notbeenshownto Clinical PracticeGuideline In commonwiththegeneralpopulation,obesity Clinic participationshouldalsocoverlifestylefactors As womenwithTSfrequentlyreportsuboptimal The burdenofhealthcareissuesforadultsissufficiently Contraception andfertility optionsshouldbe

We recommendthatgirlsandwomenwithTS ⨁⨁◯◯ ). C HGravholtandothers 451 ). However, renal al 8 Table .

TS ( there islittleinformationontheiruseinwomenwith vaginum function mayrequireadditionaltopicalestrogen ovarian insufficiencyinyoungwomen.Improvedsexual should haveaccesstoagynecologistexperiencedin function particularly relating to arousal ( reference data( older atsexualdebutcomparedtoaveragepopulation Women withTSmoveawayfromhomelater, are 6.2.1. Sexualfunctioninadults routine preventativeadultcareishighlyencouraged. providertocareforurgentissuesaswell a primary specialty centermayoccurannually, engagement with pathways toadoption. technologies, theteamshouldbefamiliarwith routine follow-up. ofnevishouldbeincludedin Nevertheless, surveillance the increasedascertainment ratethatmightexist. of pigmentedneviinwomen withTS,considering less thanonemightexpect from theheightenednumber retrospective studies.Theexcessincidenceofmelanoma is reflects lower-than-averageexposuretoestrogen in screening protocol. consensus groupdoesnotrecommendaspecificcancer clarify the cost-effectiveness of routine screening, the increased between12and14.Untilprospectivestudies 4.3- and6.6-foldwiththeSIRratioformeningioma system malignancy increased between the risk of nervous melanoma increasedbetweentwofoldandthreefold, to atleast 30% ofthe population average, the risk of All reportthattheincidenceofbreastcancerisreduced standardized incidenceratios(SIR)between0.9and1.34. cancer ispossiblyslightlyraised(inonestudyonly)with TS ( registries recordingdatafromover5400womenwith undertaken acomparisonofcytogeneticandcancer studieshave Three largeretrospectiveobservational 6.2.2. Cancersurveillance are associatedwithalowerriskofthrombosis( EE arepreferredtohigher-dosepreparationsbecausethey contraceptive pillsarerequired,thosecontaining20 routine adviceoncontraception. If combinedoral practice guideline Turner syndromeclinical 455 Given that multidisciplinary coordinationata Given thatmultidisciplinary The reducedincidenceofbreastcancerprobably Women withspontaneousovarianactivityrequire 167 , , orsystemicandrogensupplements,butsofar, 456 168 ). , 396 206 ) andreportthattheoverallriskof , 452 , 453 ) andshowimpairedsexual 177 :3 454 457 ). They ). G42 μ g of per European Journal of Endocrinology emotional/behavioral problems areincreasinglycalled countries, regular screenings fordevelopmentalor and clinicalpsychologists. associated with TS,include clinical neuropsychologists the educationalandpsychosocialdifficultiessometimes for specialists, trainedtodiagnoseorprovideinterventions attainment andHRQoL( profile, whichmay negatively impacteducational Turner syndrome is associated with a neurocognitive 7.1. Background ( may beadaptedtomeettheneedsofgirls/womenwithTS cognitive orpsychosocialproblemsinotherpopulations R 7.6 psychosexual adaptation( impairment tofacilitatepositivepsychosocialand and aggressivemanagementofpredictorshearing R 7.5. performance issues( adjustments ifindicated,toaccommodatelearning/ R 7.4. ( assessments atkeytransitionalstagesinschooling R 7.3. indicated ( behavioral screeningsuntiladulthoodwithreferralsas R 7.2. girls andwomenwithTS( isintegratedintothecarefor behavioral healthservices R 7.1. 7. Neurocognition andbehavior ( common withlowovarianreserve of endometrialcancerpresumablybecauseanovulationis spontaneous menstruation are not completely free of risk cancer ( ( chromosome shouldcontinuetobemandatory gonadectomy forindividualswithafragmentofY with aYchromosomeisnotexactlyquantified, therapy havebeenidentified( close linkswiththeuseofGHorestrogenreplacement Although meningiomaisinparthormonesensitive,no ⨁◯◯◯ ⨁⨁◯◯ Clinical PracticeGuideline Women withTShavenoincreasedriskofendometrial Although theriskofgonadoblastomainindividuals The causeoftheexcessriskmeningiomaisunclear. Although notyetthestandard ofcareinmany .

We for suggestthatevidence-basedinterventions We recommendthatneuropsychologyandallied 459 We recommendaimingforon-timepuberty We recommendacademicandoccupational We recommend annual developmentaland We suggestconductingneuropsychological ⨁⨁⨁◯ ). ). ); however, thosewomenwhoretain ⨁⨁⨁◯ ). ⨁⨁◯◯ ⨁⨁⨁◯ al 9 Table 458 ). C HGravholtandothers ). 460 ). Behavioralhealth ). ). ). 56 ). neurocognitive function( other chronicpediatricconditionsinvolvingthreatsto Strengths andDifficultiesQuestionnaire multiple languages.Anexampleofsuchameasureisthe administration time,simplescoringandvalidationin ( screening tools ( consider incorporatingpsychometricallyrobust specialists caring for girls and women with TS should arenotdelivered,thensettings wheresuchservices providers.Inpart ofroutinevisitstoprimary-care adult populations( Annual mentalhealthscreeningsarealsomandatedin annual developmentalandbehavioralscreenings( (beginning inthefirstyear)andadolescentsincludes preventive pediatric health care for all children ( for bynationalandinternationalhealthorganizations affected in TS and their potential impact on adaptive affected inTSandtheirpotential impactonadaptive psychoeducational andpsychosocial domainsmostlikely and therapyemployed( ( substantially alteroutcomeisanareaofactiveresearch ( withahostofdevelopmental disorders early intervention literature thatoutcomeisbetterforchildrenwhoreceive communication difficulties.Whilethereisagrowing as wellsubstantialriskformotorandpossible pattern of developmental strengths and weaknesses or atschoolentry, aswarranted, giventheiremerging occupational, physicalandspeechtherapyinearlylife It isalsorecommendedthatchildrenbereferredfor whom a referral can be made (e.g. school psychologists). at identifyingsuchprovidersinthecommunityto team,theneffortshouldbedirected multidisciplinary asa member ofthe psychologist) isnotavailabletoserve arise ( and highereducation,oratanytimethatdifficulties (preschool), atschoolentry, attransitiontohighschool neuropsychological evaluationbeconductedinearlylife assessment. Accordingly, itisrecommendedthata indicationstoconductaneuropsychological necessary and youngadulthood,representbothreasonable associated withpassagethroughchildhood,adolescence the social, emotional and educational environment neurocognitive profileinTS( assessments sensitivetothewell-documented are optimallyaugmentedbyneuropsychological practice guideline Turner syndromeclinical 470 469 2 461 ). Idealmeasureswillsharethecharacteristicsofbrief Following recommendationsandguidelinesin The following sections review the neurocognitive, The followingsectionsreview theneurocognitive, , ), theintensityordosageoftreatmentrequiredto , 468 471 462 ). If a neuropsychologist (or otherwise qualified ). Ifaneuropsychologist(orotherwise ) andcontingentonthedeficit beingtargeted ). IntheUnitedStates,recommended 464 463 ) as a feature of the model of care ). Thesescreeningsareoptimally 472 466 ). , 467 al 10 Table ), behavioralscreenings 177 (SDQ)( www.eje-online.org :3 ). Changesin 465 ). G43 462 ). ). European Journal of Endocrinology www.eje-online.org Perceptual- Executive/ Working Attention Academic Intellectual Domain Table 9 visuospatial motor and control cognitive memory achievement Clinical PracticeGuideline Summary ofneurocognitive,academic,social,andpsychologicalphenotypesinTurner syndrome.

50–75% withdyscalculia 90% withaverageor Summary offindings Sensorimotor findingsless Poorer performanceon Domains mostaffected: Deficits inverbaland Deficits inattentional Inconsistent reading Inconsistent phonological 569, 570) 495, 497,513,567,568, consistent (14,476,494, below themean) (performance −1to−2SD perceptual-motor tests visuospatial and 473, 494,497) ADHD symptoms(14,74, be limitedtothosewith flexibility; problemsmay inhibition, andmental planning, response (14, 74,567) to −2SDbelowthemean) memory (performance−1 visuospatial working 473, 481,494,561) sustained attention(14, inconsistent resultsfor orienting attention,and control, preserved 513, 565,566) comprehension (507,512, reading) hyperlexia (accelerated strength withsome reading, butmostoftena processing andword- processing deficit disorder) andnumerical (mathematics learning 561, 562,563,564) 494, 497,513,559,560, (IQ with intellectualdisability above-average IQ10% < 75) FSIQ

> I (208, PIQ C HGravholtandothers Difficulties with Poor performancein Difficulties withvisual Difficulty with Difficulty with Distractibility, poor Poor performancein Poor adaptiveskills,if Manifestation working memory sequencing, and switching tasks, mathematics in space) and rotatingobjects lost, troubledriving, tasks (e.g.,getting and behaviors inhibiting thoughts flexibly, and planning, thinking ‘in amind’s eye’ holding information calculations, and multi-tasking, mental inability tositstill organization, and reading less efficient in mathematics; maybe is present intellectual disability practice guideline Turner syndromeclinical Specific learning Intellectual disability Associated diagnoses Learning disorders: Increased riskof (dyscalculia) disorder (~10%) reading disorders mathematics and contribute toboth ciencies can deficits orineffi disorder (25%) hyperactivity attention-deficit/ -

Target coredeficitsknownto Referral tooccupationalor Establish academic If intellectualdisabilityispresent, Intervention Referral tooccupational Referral foracademicsupportif Medications forADHDwhen Classroom modificationsto Behavioral therapy, including Neuropsychological testing academic anddailyfunction motor andvisuospatialissuesin physical therapyforperceptual- strengths capitalization onverbal time demands,and interventions, extensionsof and empiricallysupported difficulties, includingtutoring is evidenceoflearning mastery ofconceptswhenthere developmentally appropriate accommodations thatenable attainment and educational/vocational optimize adaptivefunctioning provide appropriatesupportto strategies therapy tolearncompensatory functioning interfering withacademic visuospatial deficitsare indicated enhance in-classbehavior parent managementtraining Graphogame respectively) (e.g., TheNumberRaceor research-supported methods symbols usingneuroscience numerosities withnumber representation and linking exact such asnumericalmagnitude underlie mathematicsdisorders

177 :3 ( Continued

G44 ) European Journal of Endocrinology References arementionedinparentheses. Psychological Social cognition Motor Language Memory Domain Table 9 well-being Clinical PracticeGuideline Continued

Phonological processingmay Average tolow-average Inconsistent. Objectand Summary offindings Limited andequivocal Excessive dissatisfactionwith Distress aboutteasingor Loss ofinterestorpleasure Social withdrawal Adults –experimentaltasks Average/low-average theory Children –average/low- Inconsistent findings Poorer performanceon Pragmatic languagenot Problems withsyntactic Semantic language Enhanced receptiveand Decreased fluency(1–1.5SD 532, 573,574) 526, 527,528,529,530, (49, 205,475,523,524,525, autism spectrumdisorder support forhigherratesof self-concept orself-image bullying in activities 572) states (500,501,503,571, attribution ofmental gaze estimation,and – poorclassificationoffear, of mind recognition) recognition (impairedfear processing/affect average- to-impairedfacial consistent (476) sensorimotor findingsless perceptual-motor tests,but 512, 513) studied (478,490,491,492, processing preserved orenhanced expressive vocabulary naming below themean)and be enhanced 497) (14, 491,493,494,495,496, performance vsdeficits) as statisticaldifferences in facial memory(measured worse thanverbalmemory location memorymaybe C HGravholtandothers Difficulty initiatingor Poor recognitionof Difficulty identifying Difficulties with Delayed motor Clumsiness Strengths invarious Inefficiency (e.g.,slow Manifestation

relationships maintaining peer nonverbal cues facial emotions writing and dressingself) walking, feedingself, milestones (e.g., communication written aspects oforaland diagrams) (e.g., picturesand through visualmeans when learning and moreeffortful) practice guideline Turner syndromeclinical Associated diagnoses Adjustment disorder Anxiety Major depressive Autism spectrum Social Developmental disorder disorder disorder communication disorder coordination

Consider occupationsthatrelyon Use verbalstrengthstoenhance Enhance visuallearningby Use verbalstrengthsin Intervention Medications fortreatmentof Individual psychosocialtherapies Referral topsychologistor Social skillsgrouptherapy Referral topsychologist/ Establish academic Early interventionforpreschool- Referral tooccupationalor science) verbal strengths(e.g.,library knowledge acquired) as ameanstoassessskillor testing orverbalpresentations performance (e.g.,useoral academic andwork using verbalmnemonics describing materialsaloud, educational curriculum when indicated mood andanxietysymptoms Insight-Oriented Therapy) Behavioral Therapyand when indicated(e.g.,Cognitive evaluation psychiatrist forfullclinical provider through schoolorcommunity depression, orlowself-esteem co-morbid issueswithanxiety, poor socialskills,aswell evaluation andtreatmentof psychiatrist forfurther for school-agechildren accommodations asappropriate age children skills and trainingof(specific)motor physical therapyforcoaching 177 www.eje-online.org :3

G45 European Journal of Endocrinology www.eje-online.org Attention Academic achievement Intellect/development Domain Table 10 Adaptive functioning Social cognition Motor Language Memory Perceptual-motor and Executive/cognitive control Working memory demonstration ofadaptivedeficits is requiredforadiagnosisof‘intellectualdisability.’ * States andCanadarankedwithin top15(575,576). currently availableversion/edition.* and different languageswithaccompanyingnorms.Versions/editions ofthemeasuresnotspecifiedtosimplifytable.Examinersshould adoptthemost The assessmentmethodslistedinthistableserveasexamplesofthetools usedtoassesstherespectivedomains.Therewillbesubstitutemeasuresin Psychological well-being ≥ (arithmetic) visuospatial

Clinical PracticeGuideline 10% ofrespondents; Suggested neuropsychologicalandpsychologicalassessmenttools. # < † 10% ofrespondentsforthedomain. Preschoolanddevelopmentalmeasureswerenotincludedinreferences;

NICHQ Vanderbilt AssessmentScales Conners RatingScales NEPSY (AttentionandExecutiveFunction)(3–16 years) Conners ContinuousPerformanceTest Test ofVariables ofAttention(TOVA) Wechsler Individual AchievementTest Woodcock-Johnson Test ofAchievement* Wide RangeAchievementTest* Wechsler Intelligence ScaleforChildren(~6–16 years)* Wechsler Preschool andPrimaryScaleofIntelligence Mullen ScalesofEarlyLearning(birthto~5 years) Child assessment Adaptive BehaviorAssessmentSystem Vineland AdaptiveBehaviorScales Standardized clinicalassessmentswhenappropriate Assess qualityandnatureofsocialrelationships NEPSY TheoryofMind* NEPSY Affect Recognition* Physical andNeurologicalExaminationforSoftSigns Finger-tapping test* Pegboard test* Movement AssessmentBatteryforChildren Assessments ofgrossandfinemotorability Peabody PictureVocabulary Test Controlled OralWord AssociationTest (semanticand Clinical EvaluationofLanguageFundamentals Rey ComplexFigureTest (recall)* Children’s MemoryScale* California Verbal LearningTest (child)* Rey ComplexFigure(ROCF)(copy)* Wide RangeAssessmentofVisualMotorAbilities Motor-Free VisualPerceptionTest Developmental Test ofVisualPerception Developmental Test ofVisualMotorIntegration # NEPSY-Executive Functionsubscales Tower Tests Contingency NamingTest Trails MakingTest* Wisconsin CardSortingTest* Stroop Test/DKEFS ColorWord* Complex spantasks* Test ofPragmaticLanguage Clinical assessment Behavioral RatingInventoryofExecutiveFunction (~2–7 years) (e.g., ADOS) (PANESS) phonemic fluency)* Strengths andDifficulties Questionnaire(SDQ) Children’s DepressionInventory Multi-dimensional AnxietyScaleforChildren Behavioral AssessmentSystemforChildren(BASC) Social ResponsivenessScale(SRS) # specifythosetoolsmostfrequently used inassessmentpracticesofclinicalneuropsychologiststheUnited C HGravholtandothers #

# # #

# # # # practice guideline Turner syndromeclinical #

# # # #

# Conners ContinuousPerformanceTest Test ofVariables ofAttention(TOVA) Wechsler IndividualAchievementTest Woodcock JohnsonTest ofAchievement* Wide RangeAchievementTest* Wechsler Adult IntelligenceScale(~16– Adult assessment Judgment ofLineOrientation* Behavioral RatingInventoryofExecutive Behavioral DyscontrolScale Tower Tests Contingency NamingTest Trails MakingTest* Wisconsin CardSortingTest* Stroop Test/DKEFS ColorWord* Complex spantasks* Conners RatingScales Vineland AdaptiveBehaviorScales Standardized clinicalassessmentswhen Assess qualityandnatureofsocial Warrington Faces Benton FacialRecognition Finger-tapping test* Assessments ofgrossandfinemotorability Peabody PictureVocabulary Test Controlled OralWord AssociationTest Boston Naming* Rey ComplexFigureTest (recall)* Wechsler MemoryScale* California Verbal LearningTest (adult)* Rey ComplexFigure(ROCF)(copy)* Clinical assessment Adaptive BehaviorAssessmentSystem Token Test 90 years)* Function appropriate (e.g.,ADOS) relationships (semantic andphonemicfluency)* Beck AnxietyInventory* Beck DepressionInventory* Social ResponsivenessScale(SRS) # # #

177 # :3

#

† in theU.S., #

# G46 # # # # European Journal of Endocrinology girls withTSandisoftenaccompanied byahighrateof inapproximately25%ofschool-aged ADHD isobserved it andbeginstorespond)is also afrequentfinding( pace atwhichonetakesin information,makessenseof information) ( transient holding,processingandmanipulation of (the inappropriate responses and working memory switching attentionbetweentasks,planning,inhibiting and womenwithTS.Thesemayincludeproblems in Deficits inexecutivefunctioningoccurasubsetofgirls cognitive control 7.3. Attention,workingmemoryand educational attainment( must beprovidedtooptimizeadaptivefunctioningand intellectual disabilityispresent,appropriatesupport the highestriskforintellectualdisability( abilities ( impairments inexecutivefunctionsandvisuospatial higher thanisperceptual reasoning, likelyreflectingspecific intellectual disability( intelligence; nevertheless,approximately10%experience The majorityofindividualswithTSareaverage 7.2. Intellectualfunctioning and theirfamilies. course ofactionforclinicians,girlsandwomenwithTS interpersonal andvocationalgoalsreflectsaprudent of thechallengesthatTScanpresentaroundacademic, Nevertheless, awareness with appropriate intervention. the courseofdevelopmentandmaysignificantlyimprove neurodevelopmental function changes dynamically over Furthermore, (or absence)ofadeficitbasedonkaryotype. women withTS;oneshouldneverassumethepresence cognitive andpsychosocialphenotypesofgirls the highdegreeofindividualvariabilityinsomatic, may beadaptedwithsimilarpositiveeffects( developedfornon-TSpopulations generic interventions coordination disorder( autism spectrumdisorders( learning disorders( deficit/hyperactivity disorder (ADHD)( TS alignwithrecognizeddiagnoses,includingattention- cognitive andpsychosocialchallengesassociatedwith phenotype ofTShaveyettobedeveloped.However, the biological mechanismsrelatedtothecorecognitive function ( Clinical PracticeGuideline As inothergeneticsyndromes,itiscriticaltonote 478 al 9 Table ). AringXchromosomeisassociatedwith 478 , ). Interventions specifically targeting specificallytargeting ). Interventions 474 481 9 ), socialcommunicationdisorder, ). Reducedprocessingspeed (the 476 ). Verbal reasoningisconsistently 479 ), and evidence suggests that ), andevidencesuggeststhat , 480 475 C HGravholtandothers ). ) and developmental ) anddevelopmental

72 479 , 477 473 , 480 ) ( ), specific ), specific Table 10 ). When 478 ). ). appear tobeindependentofvisuospatialdeficits( common ingirlswithTSwithoutADHDbehaviorsand continue inadulthood.Executiveimpairmentsareless hyperactivity symptoms.Itisunclearifthesesymptoms everyday tasksthatinvolveavisualcomponent(e.g., everyday Visuospatial issuesmaymanifestasdifficultieswith girls andwomenwithTSareinthevisuospatialdomain. cognitive challenges in The most frequently observed development perceptual-motor7.4. Visuospatial, andsensorimotor beneficial ( Workplace accommodationsforadultsmayalsobe training andclassroommodifications( approach commonlyincludesparentmanagement behavior therapy( children oradults–canbeamelioratedviacognitive- Problems stemmingfromexecutivefunctionissues–in deficits ( or enhanced( for verbalinformationmay be preserved Long-term memory 7.6. Declarativememory enhance academicandworkperformance. pathologist iswarranted. Verbal strengthscanbeusedto academic performance,referraltoaspeechandlanguage issues arisethatsubstantiallyimpactcommunicationor on spatiallanguage( that incorporate executive demands ( However, weaknesses arereportedinlanguagetasks functioning ( batteries ofreceptiveandexpressivelanguage Average to above-average performance on standardized 7.5. Speechandlanguage additional strategiesforachievingtherapeuticgains( functioning. Occupationalandphysicaltherapiesare support ifspatialdeficitsareinterferingwithacademic be appropriate.Childrenshouldreferredforacademic diagnosis ofdevelopmentalcoordinationdisordermay fine motor function ( difficulties invisuo-motorcoordination,learningand general andspecificmotorimpairments,including motor functionarerelativelylimited,butsuggestboth poor performanceinmathematicscourses.Studieson and/or judgingdistances( aspects of driving, finding one’s wayaround a new place practice guideline Turner syndromeclinical 496 482 , 497 490 493 , 483 ). In contrast, object and location memory ). Incontrast,objectandlocation memory , , 491 494 ). 482 492 ) hasbeennotedingirlswithTS. , 354 , 495 ). Whenspeechandlanguage 483 , 445 ), though some studies report ), thoughsomestudiesreport 476 , , 484 , 487 488 ). Forchildren,this )) andcontributeto 177 ). In some cases, a 490 www.eje-online.org :3 ) or which rely 485 , G47 489 486 473 ). ). ). European Journal of Endocrinology www.eje-online.org TS often choose careers in health care, social services and and TS often choose careers in health care, social services challenging working experiences ( from their level of education and report less positive/ show aloweroccupationalstatus thanwouldbeexpected ( comparison groups;however, retirementoccursearlier TS isequal( 515 attainment comparedtothegeneralpopulation( with TS showa similar or increased level of educational that capitalizeonverbalstrengths. of time demands and utilizing learning/teaching strategies extension tutoring, empirically supported interventions, academic accommodationsshouldbemade,including inconsistent ( processing ( word recognition( aged childrenwithTSdisplayadvancedreadingand 6–10% estimateinthegeneralpopulation( with anestimatedprevalenceofabout50%relativetoa learning disorder(dyscalculia)( The academicphenotypeofTSincludesamathematics satisfaction 7.8. Educationalattainmentandprofessional (PEERS) ( for the Education and Enrichment of Relational Skills developed forindividualswithASD,suchastheProgram provider mayprovehelpful.Socialskillsinterventions skills grouptherapythroughaschoolorcommunity indicated forfurtherevaluationandtreatment.Social training inappliedbehavioranalysisorapsychiatristis present, referraltoapsychologist,specialistwith this remainscontroversial( for autismspectrumdisorder(ASD)( literature suggeststhatindividualswithTSareatgreaterrisk understanding thementalstatesofothers( and emotionrecognition( Girls and women with TS may demonstrate poor facial 7.7. Socialcognition used toenhanceacademicandworkperformance. verbal mnemonics( improved bydescribingmaterialsaloudandincorporating to acceleratedforgetting( are reported as less efficient, which may be secondary 517 Clinical PracticeGuideline ). The employment status of young women with ). Theemploymentstatusofyoungwomenwith Despite these well-documented learning issues, women Despite thesewell-documentedlearningissues,women , 519 506 ). Adult women with TS, especially older cohorts, ). AdultwomenwithTS,especiallyoldercohorts, 512 ), maybeadaptedforindividualswithTS. 452 512 , , , 513 514 490 516 499 ) andreadingcomprehensionare ). Whenlearningissuesarepresent, ). Findingsregardingphonological , ). Strong verbal memory can be canbe ). Strongverbalmemory 517 498 500 ) orhigher( 505 ). Visual learningmaybe , ). Whensymptomsare 501 C HGravholtandothers 519 507 , 480 , 502 , 520 508 , 206 ) anddifficulty 504 ). Women with 511 , , 503 ), although 509 518 ). School- ). Some , ) than ) than 510 206 ), , 7.9. Psychosocialissues various riskgroups. distinguish essentialfromnon-essentialfeaturesin than usethislabeluntilfutureresearch isable,toclearly the patternofstrengthsandweaknessesseeninTSrather learning disability. Assuch,wehaveoptedtodescribe fornonverbal Disorders (ICD-10)offeraspecificcategory International ClassificationofDiseaseandRelated and StatisticalManualofMentalDisordersnorthe ‘formative’ stage( learning disabilityconstructisstillinthescientifically neurocognitive phenotypeofTS.Yet, thenonverbal label nonverballearningdisabilitytocharacterizethe ideally includesvocational/careercounseling( be viewed as a recommendation.Instead,careerguidance teaching ( ( isolation ( women with TS experience higher degrees of social ( cubitus valgusandwebbedneck)socialadaptation relationship betweenthepresenceofTSstigmata(e.g., TS ( adulthood, teasingappearstobeafrequentproblemin without TS.Duringschoolage,butalsocontinuingin experience lowerself-conceptcomparedtogirls/women girls ( outcome measuresandsmallsamplesizes.Ingeneral, conflicting data,possiblyduetoselectionbias,disparate ( Studies ontheincidenceofanxietyordepressioningirls replacement ( ovarianfunctionoradequateestrogen despite preserved (intact verbalabilitiesand impaired visuospatialskills) with TSdemonstratecharacteristic neurocognitiveprofiles Available dataindicatethat,onaverage,adultwomen neurocognition andbehavior 7.10. Impactofhormonaltherapieson adaptation ( predict lower self-esteem andpoorerpsychosocial sexual experience(associatedwithdelayedpuberty) cognition. In addition, hearing impairment and limited may arise, due to difficulties insocialobservations and arelesslikelytocohabitate( practice guideline Turner syndromeclinical 523 526 473 Some researchers andclinicianshaveusedthe 49 , , , 475 531 525 526 , 516 , ) orpsychologicalwell-being( ), marry atlowerrates( ), marry , 206 452 523 527 , 205 529 , 208 , ) andwomen( 515 516 ) andwomen( , , 534 ). These cognitive differences are seen 530 , ). Theyreportfewerclosefriendships 522 518 , 535 ). Studieshavefailedtodetecta ), andneithertheDiagnostic ), but such a finding should not ), butsuchafindingshouldnot , 536 516 ). 205 , 524 515 , 206 177 , 524 , 525 , :3 516 , 532 515 ) withTSshow 528 , ). Girlsand 517 , 521 ) withTS 518 ). These ). , G48 533 ) European Journal of Endocrinology patients accesshealthinformation thoughInternet attend anytypeofhealth careprovider. Increasingly, It isestimatedthatonlya minority ofwomenwithTS tohospitalclinics 8.1. Exploringalternatives 8. Optimizingcare across thelifespan through GHtreatmenthadaneffect( women withTS,neitherAHnorestimatedheightgained degree ofsexualexperiences)adaptationyoungadult and HRQoL)psychosexual(e.g.,sexualmilestones effect onpsychosocial(e.g.,self-esteem,socialadjustment ( 94% ofreportedoutcomessufferedfromahighriskbias a widerangeofsyndromes,includingTS,indicatedthat and cognitive effects of GH treatment for short stature in specificity. Asystematicreviewexaminingpsychological on QoLinindividualswithTSmaylacksensitivityand available forassessmentoftheimpactshortstature with concerns regarding short stature. Furthermore, tools of childrenwhopresenttopediatricendocrinologists population maynotberepresentativeoftheexperiences that target shorter-than-average children in the general psychosocial dysfunction ( the long-standingassumptionthatshortstatureleadsto neurocognition ( women withTS( and depressionwithoxandroloneadministrationinadult no effect on neurocognition and higher reports of anxiety in girlsaged10–14 years ( low dosesofoxandrolonemayimproveworkingmemory youth withTSisconflicting,onestudyindicatingthat puberty. Evidence supportingandrogen administration in 534 adaptation andperceptions ofhealthhasbeenreported( sexual developmentandpositiveself-concept,social windows. Arelationshipbetweenage-appropriatesomatic possible treatmenteffectwithinspecificdevelopmental processing speedandmotorfunction( demonstratedimprovementin in girlsaged10–12 years ( in verbalandnonverbalmemory years,demonstratedmodestimprovements of 5and8 estrogen administrationingirlswithTS,betweentheages much earlierindevelopment.However, atrialoflow-dose impact onmodifyingcognitivedifferencesthatlikelyarise adulthood, endogenousorexogenousestrogenhaslimited of different etiologies ( in comparisontowomenwithprematureovarianfailure 542 Clinical PracticeGuideline , Studies of GH in TS have failed to demonstrate an effect on Studies ofGHinTShavefailedtodemonstrateaneffecton ). In the sole, epidemiologically oriented study of GH ). Inthesole,epidemiologicallyorientedstudyofGH 537 ). These datasupport age-appropriate induction of 539 142 ), andsomeresearch calls intoquestion ). 496 538 540 ), suggesting that, at least by ), while another study found ), whileanotherstudyfound , C HGravholtandothers 541 145 452 ). However, research ) and replacement ) andreplacement 144 , 534 ), suggesting a ), suggestinga ). 49 , that informationregardingaccesstopatientsupport and emotional symptoms ( illness indicatedimprovementinadolescents’ behavioral inadolescentswithchronic peer-support interventions conditions iswellestablished.Asystematicreviewof The valueofpeersupportforadolescentswithchronic 8.2. Roleofpatientsupportorganizations status areavailablewhenacutelyunwell. number oftestsandensurethatvitaldatasuchascardiac access onesetofrecords.Suchasystemcanreducethe of onlinemedicalrecordssothatdisparatespecialistscan women withTSlendsitselftotelemedicineandtheuse alternatives to face-to-face clinic encounters. Care for wider populationofwomenwithTS.Thereareseveral so allteamsshouldhaveastrategytoengagewith up thereis,itcanonlycatertothosewhoattend,and searches andsocialmedia.Howevergoodaclinicset for womenwithTS,andinformation fromthesesources Several countrieshavedeveloped registriesrecordingdata 8.3. Nationalregistries forTurner syndrome women withTS. to important advances in research and care for girls and with TS.Theiradvocacyeffortshaveandcontinuetolead patients, families,adolescents,youngadultsandwomen lead inprovidingeducationalandnetworkingforumsfor increasing theirdevelopmentalautonomy. that offeractivitiesgearedtoadolescentsandtoward local, regionalandnationalpatient/advocacy TS groups addition, itisimportanttolinkpatientsandfamilies to a care network of providers on a national basis. In of TS.Supportorganizationscanalsoassistindeveloping of careersorpartnersindividualswithanewdiagnosis expertise outsideofclinic attendances and for thesupport support frompeers. the riskofisolationandtogetspecificinformation contact alocalTSpeer-supportorganizationtodiminish adolescents andwomenwithTSshouldbeadvisedto impact ontheirlives( belonging toapeer-supportgrouphashadpositive care pathways.ManywomenwithTSindicatethat groups inordertoshareexperienceanddevelopfuture should takepartincombinedmeetingswithpatient TS on a regular basis. Members of each medical care team organizations bemadeavailabletoeachindividualwith practice guideline Turner syndromeclinical Patient andfamilyTSadvocacygroupshavetakenthe Patient supportorganizationsarevitalinproviding 544 ). Parentsofyounggirls, 543 ). We recommend 177 www.eje-online.org :3 G49

European Journal of Endocrinology www.eje-online.org EJE-17-0430. This islinkedtotheonlineversionof thepaperat Supplementary data inthefuture. therefore benecessary numbers ofparticipants.Largecollaborativeeffortswill indeed, in almost all rare conditions, lack sufficient designed andlargestudies.Muchresearch inTS,and, asanimpetus forfuturewell- fact, anditshouldserve on expertopinion.Itisimportanttoacknowledgethis the recommendationsthatwepresentarestillonlybased answered, based on evidence, and consequently, most of be appreciated,mostofthesequestionscouldnot be submittedtoGRADEevaluation.However, ascan and wethereforealsoaskedfourquestionsthatcould We have aimed at presenting evidence-based guidelines was toupdateknowledgeandfocusonallareasofcare. care of females with TS hadbeen published, and ourgoal yearssincethelastsetofrecommendationsfor 10 with astakeinTSCincinnatiJuly2016.Ithasbeen groupofprofessionals gathering ofaninterdisciplinary sides of the Atlantic. This development led to the in EuropeandtheUSAthroughmeetingsonboth This guidelinearosefromtwosimultaneousdevelopments 9. Summary patients (‘stakeholders’). such asAoD.Ideally, dataarecontributedbyprovidersand in ordertodeterminefactorscontributingrareoutcomes at anationallevelandthatdatafromthembecombined psychosocial datafromindividualswithTSareestablished expertise forthecareofTScandevelop. for RareDiseasesunder the umbrellaofwhichspecialist the UnitedKingdomhavedevelopedNationalCenters bias comparedtoclinicalregistries( comparison with clinical data with reduced ascertainment hasbeenvaluableinallowing Cytogenetic Registry since1957( TS karyotype and mortality(allcausesshown)inallwomenwitha that hasrecordeddataonmorbidity, includingcancer the developmentoftheseresources. stratification ofriskforrareeventswillbeachieved with early phase of development, and it is likely that improved ofthiscondition.Elsewhere,registriesareatan history has greatlyexpandedourknowledgeregardingthenatural Clinical PracticeGuideline We recommendthatregistriesrecordingclinicaland Examples ofregistriesincludeonefromSweden 545 ). InDenmark,theCentral C HGravholtandothers 37 http://dx.doi.org/10.1530/ , 517 ). Franceand of Obstetrics and Gynecology, Division of Pediatric and Adolescent School ofMedicine,St.Louis,MO,USA),LesleyLBreech(Department (Cardiovascular Division,DepartmentofMedicine,Washington University (Patient Advocate,Maplewood,Minnesota,MN,USA),AlanCBraverman Hospital ofPhiladelphia,PA, USA),NatalieBrobinBonfig following: Vaneeta Bamba (Division of Endocrinology, Children’s The International Turner syndrome consensus group includes the Acknowledgements States, theTSGlobalAllianceandTurner ResourceNetwork). Foundation, aswellseveraladvocacygroups(TSSocietyoftheUnited Translational Sciences,CincinnatiChildren’s HospitalMedicalCenter’s TS (NICHD grant#1R13HD089663),theNationalCenterforAdvancing the AHA,NationalInstituteofChildHealthandHumanDevelopment delegates forthemeeting,andadditionalsupportwasobtainedfrom by PES,ESPEandES.Furthermore,ESHREESCsupportedtheirown These guidelinesweresponsoredprimarilybytheESE,andco-sponsored Funding perceived asprejudicingtheimpartialityofresearchreported. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest Psychiatry, Eastern Michigan University, Ypsilanti, MI, USA), Kerstin University, Umeå,Sweden),ReneeR. Lajiness-O’Neill (Departmentof Chapel Hill,NC,USA),BeritKristrøm (DepartmentofPediatrics,Umeå (Department ofPsychiatry, University of NorthCarolinaatChapelHill, Fertility, Burlington,Ontario,Canada), RebeccaChristine Knickmeyer Sophia” Children’s Hospital, Athens,Greece),MeganFKarnis(One Medical School, National and Kapodistrian University of Athens, “Aghia Endocrinology, MetabolismandDiabetes,FirstDepartmentofPediatrics, Birmingham, AL,USA),ChristinaKanaka-Gantenbein(Division of Women andInfantsCenter, UniversityofAlabamaatBirmingham, Stockholm, Sweden),Walter HJohnson,Jr. (DepartmentofPediatrics, (Department of Otorhinolaryngology, Karolinska University Hospital, Karolinska UniversityHospital,Stockholm,Sweden),MalouHultcrantz USA), OutiHovatta(DepartmentofScience,Intervention,andTechnology, Adolescent Psychiatry, Stanford University Medical Center, Stanford, CA, Hospital, Cincinnati,OH,USA),DavidSHong(DepartmentofChildand FL, USA),LorenHiratzka(DepartmentofCardiacSurgery, BethesdaNorth Cincinnati, OH,USA),DarleneHay(PatientAdvocate,SouthwestRanches, Gutmark-Little (Department of Pediatrics, Cincinnati Children’s Hospital, Endocrinology, MedicalUniversityofSilesia,Katowice,Poland),Iris (School ofMedicineinKatowice,DepartmentPediatricsandPediatric Michigan, CardiovascularCenter, AnnArbor, MI,USA),AnetaGawlik Ghent UniversityHospital,Ghent,Belgium),KimEagle(Universityof de Backer (Department of Cardiology and Center for Medical Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA), Julie Hospital, StPetersburg,FL,USA),MarshaLDavenport(ProfessorEmeritus, Melissa L Crenshaw (Division of Genetics, Johns Hopkins All Children’s OH, USA),AnneCrawford(PatientAdvocate,SanFrancisco,CA, (Division ofEndocrinology, CincinnatiChildren’s Hospital,Cincinnati, Endocrinology, HospitalSaintAntoine,Paris,France),Sarah D Corathers Center, Oklahoma City, OK,USA),SophieChristin-Maitre (Department of (Department of Pediatrics, University of Oklahoma Health Sciences Children’s MercyHospital,KansasCity, MO,USA),StevenChernausek Fulshear, TX,USA),JosephCernich(DivisionofPediatricEndocrinology, Children’s Hospital, Cincinnati, OH, USA), Nancy Bryant (Patient Advocate, Chicago, IL, USA), Nicole M Brown (Department of Pediatrics, Cincinnati School ofMedicine,AnnandRobertHLurieChildren’s Hospital of Chicago, J Brickman(DepartmentofPediatrics,NorthwesternUniversity’s Feinberg Gynecology, CincinnatiChildren’s Hospital,Cincinnati,OH,USA),Wendy practice guideline Turner syndromeclinical 177 :3 G50 European Journal of Endocrinology References genetics anddiagnosticssectionduringtheconsensusmeeting. Paul Saenger are thanked for their valuable insights respectively, to the contributions totherealizationofthisproject.AdriannaSanRomanand Society oftheUnitedStates,andTSResourceNetworkformany Syndrome GlobalAlliance,andCindyScurlockfromTurner Syndrome with theconsensusmeetingorganization),KellyRonallofromTurner Pediatrics, SeattleChildren’s Hospital,WA, USA). University of Messina, Messina, Italy) and Luciana T Young (Department of Wasniewska (Department ofHumanPathologyandDevelopmentalAge, Pediatric EndocrinologyandDiabetology, Brussels,Belgium),Malgorzata Rotterdam, theNetherlands),FranciskaVerlinde (BelgianSocietyfor Iris MvanHagen(DepartmentofCardiology, ErasmusMedicalCenter, Advocate, Executive Officer of Turner Syndrome Support Society, UK), Cincinnati Children’s Hospital, Cincinnati, OH, USA), Arlene Smyth (Patient Nicole MSheanon(DepartmentofPediatrics,DivisionEndocrinology, Director, Turner SyndromeSociety oftheUnitedStates,Houston,TX,USA), Charlottesville, VA, USA),CindyCScurlock47(PatientAdvocate,Executive (Department ofMedicine,UniversityVirginiaSchool University ofFloridaHealth,Gainesville,FL,USA),RichardJSanten Cité, France),ArwaSaidi(DepartmentofPediatrics,PediatricCardiology, Groupe Hospitalier Paris-Seine Saint Denis,APHP, Université Paris, Paris Dominique Roulot-Marullo(Unitéd’Hépatologie,HospitalAvicenne, University, Nemours-DupontHospitalforChildren,Philadelphia,PA, USA), Chicago, IL, USA), Judith Ross (Department of Pediatrics, Thomas Jefferson Pediatrics andMedicine,UniversityofChicagoPritzkerSchool Center, Rotterdam,TheNetherlands),RobertRosenfield(Departmentof (Department of Cardiology, Erasmus University Medical Center, Thorax University ofHeidelberg,Germany),JolienRoos-Hesselink Gudrun AnnaRappold(DepartmentofHumanMolecularGenetics, President ofTurner SyndromeGlobalAlliance,OverlandPark,KS,USA), Center, Houston,TX,USA),KellyC.Ranallo(PatientAdvocate, Founder/ McGovern MedicalSchoolattheUniversityofTexas HealthScience UPMC, Pittsburgh,PA, USA),SiddharthPrakash(DepartmentofPediatrics, Popovic (DepartmentofPediatrics,Children’s HospitalofPittsburgh Unit, GreatOrmondStreetHospitalforChildren,London,UK),Jadranka Hospital, Bologna,Italy),KristianHavmandMortensen(Cardiorespiratory Endocrinology andRareDiseaseUnit,SOrsola-MalpighiUniversity Pueblo, CO, USA), Laura Mazzanti (Department of Pediatrics, Pediatric Children’s Hospital,Miami,FL,USA),LisaMawson(PatientAdvocate, Angeles, CA,USA),LeoLopez(DepartmentofClinicalPediatrics,Nicklaus (Department ofPediatrics,DavidGeffen SchoolofMedicineatUCLA,Los of NorthCarolinaatChapelHill,NC,USA),BarbaraLippe (Department ofPediatrics,DivisionPediatricEndocrinology, University Sahlgrenska UniversityHospital,Gothenburg,Sweden),JenniferRLaw Landin-Wilhelmsen (Department of Medicine,SectionforEndocrinology,

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European Journal of Endocrinology 67 66 65 64 63 62 61 60 59 58 57 56 55 54 53 52 Clinical PracticeGuideline B. Theparentaloriginofthesingle X chromosomeinTurner Mathur A,StekolL,SchatzD,MacLaren NK,ScottML&Lippe Human Genetics analysis ofsex-chromosomemonosomy. Hassold T, BenhamF&LeppertM.Cytogeneticandmolecular (doi:10.1136/jmg.31.11.840) Turner phenotype. Paterson WF&ConnorJM.Possibleroleofimprintinginthe Chu CE,DonaldsonMD,KelnarCJ,SmailPJ,GreeneSA, syndrome. is equivalenttometaphasecytogeneticsfordiagnosisofTurner Bondy CA.Single-nucleotidepolymorphismarraygenotyping Prakash S,GuoD,MaslenCL,SilberbachM,MilewiczD& (doi:10.1016/S0140-6736(94)91028-6) of gonadoblastomaorvirilisation[letter]. Page DC.YchromosomesequencesinTurner’s syndromeandrisk (doi:10.1016/S1472-6483(10)60387-2) amenorrhoea. occurrence ofgonadoblastomaincasesTurner syndromeand Modi D&BhartiyaD.Ychromosomemosaicismand ejmg.2013.07.008) ofMedicalGenetics Journal derivatives inpatientswithTurner syndrome. high ratesofXchromosomalmosaicismandY GW, HoefslootLH van Alfen-vanderVelden JA,Traas MA,MielooH,vandeZande Freriks K,Timmers HJ,Netea-MaierRT, BeerendonkCC,OttenBJ, (doi:10.1002/gcc.2870140309) the Ychromosome. CA. Molecularmappingoftheputativegonadoblastomalocuson Salo P, KaariainenH,PetrovicV, PeltomakiP, PageDC&dela 1400–1407. chromosome. molecular definitionofthesusceptibilityregiononY Tsuchiya K,ReijoR,PageDC&DistecheCM.Gonadoblastoma: 2003 gonadoblastoma. sequences inTurner’s syndrome:associationwithvirilizationand F, HidalgoS,JaraA,MuzzoPanteonE Mancilla EE,PoggiH,RepettoG,RumieGarcia H,Ugarte BF03345783) of EndocrinologicalInvestigation markers inTurner syndrome:screeningof130patients. Niederland T, KozariA,BertalanR,UgocsaiP Sallai A,SolyomJ,DobosM,SzaboHalaszZ,SagodiL, jcem.85.9.6800) Endocrinology andMetabolism chromosome material:apopulationstudy. of gonadoblastomainfemaleswithTurner syndromeandY Gravholt CH,FedderJ,NaeraaRW &MullerJ.Occurrence 5/s-0034-1387734) Clinical EndocrinologyandDiabetes of YcentromereinTurner syndromepatients. Bettendorf M.AnalysesofGonadoblastomaY(GBY)-locusand Knauer-Fischer S,BesikogluB,IntaI,KneppoC,Vogt PH& (doi:10.1097/GIM.0b013e3181c684b2) for Turner syndrome. Wolff DJ,Van guideline DykeDL&PowellCM.Laboratory (doi:10.1002/ajmg.a.30954) ofMedicalGenetics A American Journal chromosome mosaicisminUllrich-Turner syndromepatients. Wiktor AE&Van DykeDL.Detectionoflowlevelsex ofHumanGenetics Journal 95% and99%confidencelimitscommentsonuse. Hook EB.Exclusionofchromosomalmosaicism:tables90%, 16 1157–1163. Genetics inMedicine American Journal ofHumanGenetics American Journal Reproductive BioMedicineOnline 1988 Journal ofPediatricEndocrinologyandMetabolism Journal et al Journal ofMedicalGenetics Journal Genes Chromosomes Cancer 42 Genetics inMedicine . BuccalcellFISHandbloodPCR-Ydetect 534–541. 1977 2013 2000 2010 2014 29 56 2015 94–97. 497–501. C HGravholtandothers 85 33 14 2005 3199–3202. 222–227. 53–59 123 et al 2010 American Journal of American Journal Lancet Journal ofClinical Journal 138 61–65. . Ychromosome (doi:10.1016/j. 1994 2007 et al European Experimental and 1995 12 259–261. 1994 1995 . Y-chromosome (doi:10.1007/ 52–55. (doi:10.1210/ 31 15 (doi:10.105 14 840–842. 547–553. 343 57 210–214. American Journal Journal

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