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European Journal of Endocrinology -18-0309 Bicêtre, France, Assistance-Publique HôpitauxdeParisandUniversitéDiderot,SorbonneCité,Paris,France, 1 Bruno Donadille strategies. testicular functionattheendofpuberty. Earlymanagementofthesepatientsmaylead to fertilitypreservation Currently, mostpatientsarediagnosedinadulthoodwith azoospermia,consistentwithourobservationsofdecreased untiladulthood,astheypresentsimilarprognosis thanthosebornwithseveregenitalanomalies. Conclusion: B levelsandincreasedFSHlevels). but 71%( suggesting evidenceofpartialgonadaldysgenesis.Moreover, pubertyoccurredspontaneouslyin93%ofpatients two patientshadminorabnormalitiesofexternalgenitalia.Onepatientdevelopedatesticularembryoniccarcinoma, features includingcardiac(6/23patientsinvestigated)andrenalmalformations(3/19investigated).Twenty- 158 stature. Mostpatientshadstuntedgrowth,withabnormalgrowthspurtduringpubertyandameanadultheight of Results: Methods: abnormalities ofexternalgenitalia,notablyintermsgrowthandpubertaldevelopment. The purposeofthisstudywastoevaluatetheclinicaloutcome45,X/46,XYboysbornwithnormalorminor Objective: Abstract Référence desMaladiesEndocriniennesRaresdelaCroissance,Assistance-PubliqueHôpitauxParis,France Lorient, France, Department Department, CHULyon, CentredeRéférencedesAnomaliesduDéveloppementGénital,Lyon, France,Pediatric Endocriniennes RaresdelaCroissance,Assistance-PubliqueHôpitauxParis,France, 8 Centre deRéférencedesMaladiesEndocriniennesRareslaCroissance,Assistance-PubliqueHôpitauxParis,France, Department, CHURennes,France, Référence desAnomaliesduDéveloppementGénital,Assistance-PubliqueHôpitauxdeParis,LeKremlin-Bicêtre,France, Chantal Metz-Blond Blandine Esteva Laurence Dumeige and followedup? genitaliabeinvestigatedanomaly ofexternal Should 45,X/46,XYboyswithnoormild Pediatric EndocrinologyDepartment,CHUNecker-Enfants Malades,CentredeRéférencedesMaladies Pediatric EndocrinologyDepartment,CHURobertDebré,CentredeRéférencedesMaladiesEndocriniennesRareslaCroissance, https://doi.org/ www.eje-online.org Clinical Study ± m i.e. 7.6cm, Twenty patientshadaprenatal diagnosis, whereas20patientshadapostnatalmainlyforshort Retrospectivelongitudinalstudyof40patientsfollowedbetween1982and2017inFrance. n 10 Fewstudiesofpatientswitha45,X/46,XYmosaicismhaveconsideredthosenormalmalephenotype. CHU Nantes,France, 10.1530/EJE

Thisstudyemphasizestheneedtoidentifyandfollow-up 45,X/46,XYpatientsbornwithnormalmale = 3 13 Pediatric Department,CHUAngers,France, 5) ofthoseevaluatedattheendpubertypresentedsigns ofdeclinedSertolicellfunction(lowinhibin CHU Grenoble,LaTronche, France,and − 7 14 , Dinane Samara-Boustani 2.3 DSwithcorrectionfortargetheight.SeventypercentofpatientspresentedTurner-like syndrome -18-0309 , Sophie Christin-Maitre 1 , 11 2 , Livie Chatelais , Catherine Naud-Saudreau 3 © 2018EuropeanSociety ofEndocrinology L Dumeigeandothers 6 11 Genetic Department, CHRU Brest,France, 3 , Claire Bouvattier Printed inGreatBritain 14 14 Endocrinology Department,CHUSt-Antoine,Centrede 8 , Jean-Claude Carel , Delphine Zenaty 7 Pediatric EndocrinologyDepartment,CHUArmandTrousseau, 12 4 , Clémentine Dupuis Pediatric EndocrinologyDepartment,CHUBicêtre,Centrede 12 Centre HospitalierdeBretagneSud, 4 , Marc De Kerdanet not sobenign? 45,X/46,XY phenotypicboys, Published byBioscientifica Ltd. 1 , Marc Nicolino 1 , RegisCoutant 9 Pediatric Endocrinology 13 , Juliane Léger 2 INSERM UMR-S1185,LeKremlin 5 , Capucine Hyon 9 , Sabine Baron 3 and Downloaded fromBioscientifica.com at09/27/202110:51:05PM

Laetitia Martinerie 1 5 , Jean-Pierre Siffroi Pediatric (2018) Endocrinology European Journal of Correspondence [email protected] Email to LMartinerie should beaddressed 179 10 6 179 , , :3 , 181–190

181 1 , 2 –190 6 , via freeaccess European Journal of Endocrinology www.eje-online.org www.eje-online.org neonate, child or adult) with a 45,X/46,XY , neonate, childoradult)with a45,X/46,XYkaryotype, Inclusion criteriawerephenotypically malepatient(fetus, Patients Methods should leadtoabettermanagementofthesepatients. diagnosis, of the necessity of long-term follow-up and characteristics. It underlines the importance of an early growth, pubertaldevelopmentandotherphenotypic or glanular hypospadias), in terms of abnormalities ofexternalgenitalia(unilateral male patientswithnormalorminor 45,X/46,XY to beconsideredforpropermanagement( stature andotherTurner syndrome-likefeaturesthatneed ( early declineoftesticularfunctionwithpubertaldelayand these patientsmayhavedysgenetictestes,responsiblefor anomaly atbirth,sporadiccasereportshavesuggestedthat ( patients areidentifiedinadulthoodbecauseofinfertility or followed after birth. Currently, most of the diagnosed thesepatients are rarelyinvestigated antenatal karyotype, upon diagnosis,notablywhenitisincidentallyfoundonan difficult astheyhavefewassociatedsigns( ofgenitalorgans.Thus,thediagnosisisrather fetal development,allowingMullerianductsregressionand two testes, with secretion of AMHandtestosterone during phenotype ormildgenitalanomaly. Thesepatientsdevelop 10 function, infertilityandreducedadultheight( genital ambiguityfrequentlyhaveimpairedtesticular of thepatientsdescribed( anomalies ofgenitaldevelopmentaccountforonly10% while patientswithanormalmalephenotypeorminor patients withseveregenitalanomaliesintheliterature, patients diagnosedinthepostnatalperiodaremainly external genitalia( assessed thatmorethan90%ofthesepatientshavenormal systematic examination of the genitals at birth have studieswith external genitalia.Antenatalkaryotype ambiguous genitalia( , rangingfromnormalfemalephenotype, ( incidence between1in6000and15000livebirths The 45,X/46,XYmosaicisararecondition,withan Introduction 11 1 , Clinical Study ). However, littleisknownaboutboyswithanormalmale , 2 This studyevaluatestheclinicaloutcomeof ). 45,X/46,XY patients present a large spectrum of ). 45,X/46,XYpatientspresentalargespectrumof 12 , 13 6 ). However, despitetheabsenceofgenital , 14 ). Furthermore, they may also have short ). Furthermore,theymayalsohaveshort 1 , 3 3 ). However, cohortsof45,X/46,XY ) to male phenotype with normal ) tomalephenotypewithnormal 4 , 5 ). 45,X/46,XY patients with ). 45,X/46,XYpatientswith L Dumeigeandothers 15 , 6 16 ). Moreover, 4 , , 6 17 , 7 ). , 8 , 9 , biological data: investigation ofmedicalrecords,growthchartsand The followingdatawerecollectedbyretrospective Data collection with theDeclarationofHelsinki. authority (CNIL,DR-2018-049,N°918051),inaccordance (N°2017/347_2, N°28164)andtheFrenchdataprotection Review CommitteeforBiomedicalResearch Project study was approved by theLocal and National Ethics and nature of all procedures used. This observational from eachpatientafterfullexplanationofthepurpose with anEMS an ExternalMasculinizationScore(EMS) unilateral cryptorchidism orglanularhypospadias,with normal oronlypresentaminorabnormalitysuchas inFrance. External genitalia had tobe urology services followed between 1982 and 2017 by endocrinology or – – not sobenign? 45,X/46,XY phenotypicboys, – – antenatal diagnosis had a postnatal karyotype inorder antenatal diagnosishadapostnatal karyotype Y chromosomerearrangements. Allpatientswithan examined to determine the degree ofmosaicism and blood lymphocytes.At least 30mitoseswere Chromosomal analyseswere performedonperipheral 2 years oftreatment. gathered: duration,doseandstaturegainafterthefirst noted. Informationongrowthhormonetherapywas thereafter anddevelopmentofatesticulartumorwere therapy wasneeded to induce or defined asatesticularsize height SDS).Ageatonsetofpubertaldevelopment(G2 mean, correctedfortargetheight(heightSDS both incentimetersandstandarddeviationtothe adolescence. Height measures are expressed as values were collectedatseveralagesthroughoutinfancyand discrepancy. Foreachpatient,weightandheightdata and orthopedicdefectssuchasscoliosisorleglength posterior hairline,multipleotitismediaordeafness carinatum, multiplenaevi,high-arched palate,low colli,pectus such asfacialparticularities,pterygium features due to 45,X were reported, Phenotypic reason forperformingthekaryotype. stage atdiagnosisandtheendofpuberty sampling),heightandpubertalTannerkaryotype parents +6.5 target height(definedbymeanofthetwo intra-uterine growthretardation(IUGR),parental including obstetrical andneonatalmedicalhistory Clinical data:termofpregnancy, birthparameters, ≤ 10 wereexcluded.Consentwasobtained cm), ageatdiagnosis(definedasof Downloaded fromBioscientifica.com at09/27/202110:51:05PM ≥ 4 mL or25 179 :3 mm), whether > 10. Patients − target 182 via freeaccess European Journal of Endocrinology severe IUGR(3patients) andrenalmalformation fold thickness(4patients), short thighbone(2patients), inTurnersimilar tothoseobserved syndrome: nuchal some cases, features found by ultrasound imaging were 21 markersormaternalage (9patients).However, in abnormalitysuchasanincrease oftrisomy karyotype to amniocentesisweregenerallyunrelatedwiththe 20 patientshadapostnataldiagnosis.Signsleading Twenty patientshadaprenataldiagnosis,whereas Diagnosis from 12centers. Forty patientswereincludedinthestudy, originating Results threshold wassetat0.05. (Graph prism, Graphpad Software Inc.). Significant two groupsandaFisher’s testforqualitativevariables Kruskal–Wallis test for comparisonbetween more than Whitney analyses wereperformedusinganon-parametricMann– results areexpressedasmedianandinterquartile.Statistical Results areexpressedasmean Statistical analysis – – – – Clinical Study and cardiovascularsystem. with regardstothegonads(ultrasoundorMRI),kidney Imaging investigationswerereviewed,particularly the totalabsenceofsperminsemen. noted, whenperformed.Azoospermiawasdefinedas from theonsetofpuberty. Resultsofspermcountwere > dysfunction wasdefinedbyincreasedFSHlevel AMH andtestosteroneconcentrations.Sertolicell points duringfollow-up:IGF1,FSH,LH,InhibinB, plasmalevelswerecollectedatseveraltime genotype correlations. AZF lociinpatients,ordertoanalyzephenotype/ TSPY genepresentaswellpossiblealterationofthe anomaly, thenumberofcopiesSHOXand If not,wededucedfromtheYchromosomestructural loci analyseswerenotedwhenspecifiedbygeneticists. TSPY gene, SHOX geneand Azoospermia Factor (AZF) structural anomalyoftheYchromosome,breakpoints, one patient due to parental refusal. In patients with a to confirmthechromosomeabnormality, apartfrom 10 IU/L and/ordecreasedinhibinBlevel U testforcomparisonbetweentwogroups,a ±

s L Dumeigeandothers . d . Forhormonelevels, < 60 pg/mL

short armsofchromosomesYand181patientwith , 1 patient with a translocation between Y (11Yp and2isodicentricYq), 5patientswitharing the Ychromosome:13patientswithanisochromosome 4–80%). Twenty patients (50%) had a structural defect of plasma percentage ofthe45,Xlineagewas26.1%(range: Themean All patientshada45,X/46,XYkaryotype. Karyotype for infertility. isolated shortstature,andfourpatientsduringadulthood Finally, sixpatientswerediagnosedduringpubertyfor (orchidopexy).incidentally foundduringtesticularsurgery were diagnosedbecauseMullerianductsderivatives genitalia intwopatients.Amongthesetenpatients,three delay inonepatientandminorabnormalitiesofexternal mainly forshortstature,associatedwithpsychomotor (2 patients).Ten patientswerediagnosedduringchildhood patients. Autoimmunitywas notedforthreepatients deafness. Amildpsychomotor delaywasnotedforfour patients, includingtwo suffering fromconductive asymmetry. Multiple otitis media was reported for five eight patientsascubitusvalgus, scoliosisorleglength like syndrome.Orthopedicdefectswerenoted in concerned dysmorphicfeaturesconsistentwithTurner- or growthdeficiency( of 45,Xmonosomy, asidefromgenital abnormality Twenty-one patientspresentedfeaturessuggestive Others characteristics postnatal diagnosis). for 5(42%)ofthesepatients(allwerewith a patients, andMullerianductsderivativeswerereported in12 genitalia wereinvestigatedbyimagingorsurgery patients withapostnataldiagnosis( difference betweenpatientswithaprenataldiagnosisand of genital development ( while the22remainingpatientshadminorabnormalities in18patients Normal externalgenitaliawereobserved genitalia andinternal Characteristics ofexternal tumorigenesis. two copies of the TSPY gene, implicated in testicular that 13patients(thosewithanisochromosomeY)had region, compromising their fertility. Similarly, wededuced Yq, potentially leadingtopartorcompletelossoftheAZF a Yq . Thus,12patientshadadefectconcerning not sobenign? 45,X/46,XY phenotypicboys, Downloaded fromBioscientifica.com at09/27/202110:51:05PM Table 1 i. 1 Fig. ). There was no significant ). Inmostcases,they 179 al 2 Table www.eje-online.org www.eje-online.org :3 ). Internal 183 via freeaccess European Journal of Endocrinology www.eje-online.org qualitative variables,withstatistical significanceasfollows: Comparison betweentwoparameters wasperformedusingnon-parametricMann–Whitney Mean ageatlastevaluation(years Declined Sertolicellfunctionat puberty(definedbyFSH Turner syndromefeatures( Growth hormonetreatment( Mean finalheight(cm Mean pubertalgrowthspurt(cm Height aftercorrectionfortargetheight(DS IUGR Mild anomalyofexternalgenitalia n of thisanomalywasperformedandtherelativepercentage. results areexpressedasthenumberofpatientspresentingwithanomaly, amongthenumberofpatientsforwhomscreening Table 2 ( defects ( a prenataldiagnosis,particularlyconcerningorthopedic patients withapostnataldiagnosisthanin were significantlymore Turner syndromefeaturesin (horseshoe kidneysorunilateralrenalagenesis).There insufficiency) and16%(3/19)hadrenalabnormalities with aorticinsufficiency, atrialseptumdefectoraortic valve, mildaorticdilatation,ventricularseptaldefect (6/23) hadcardiacmalformations(bicuspidaortic one patient). Twenty-six percent of patients investigated positive antiadrenalandanti-GADauto-antibodiesin patient, isolatedHashimotothyroiditisinonepatientand (Pernicious anemiaandHashimotothyroiditisinone Bilateral testicularhypotrophy Association ofcryptorchidism/asymmetry Glanular hypospadias Unilateral cryptorchidismorasymmetryof Normal externalgenitalia genitalia. Table 1 Table 2 and/or inhibinB hypospadias/penile curvature of testicularvolumeandglanular testicular volume (%) Clinical Study Dysmorphism Psychomotor delay Autoimmunity Orthopedic defects ENT defects Cardiac malformation Renal malformation Puberty Infancy Neonatal period ). No difference was observed betweenpatients ). Nodifferencewasobserved Clinical characteristicsofpatientsaccordingtothetimingdiagnosis.Forclinicalandbiologicalcharacteristics, Phenotypic characteristicsofpatientsexternal P

= 0.04) anddysmorphicfeatures( < 60 pg/mL), ±

s . d . n , , %) n n ) n , %) (%) ±

± s . L Dumeigeandothers

d s . . d , . n ) ) ±

s 11 18 . n 2 6 3 d . , a n P )

< P 0.05, =0.03) 15 27.5 45 ≥ 5 7.5 % 10 IU/L b P

< 0.01. height orpubertalgrowthspurtbetweenpatientswitha of 14.1 ( seven patients followed from childhood was 158 until endofpuberty( confirmed forthefivepatientsfollowed longitudinally and adulthood( progressively from the neonatal period to adolescence deviation score (SDS) corrected for target height decreased a prenatalorpostnataldiagnosis.Meanheightstandard betweenchildrenwith significant differencewasobserved than the10thpercentile for22/33patients(IUGR).No investigated duringchildhood.Meanbirthheightwasless Birth parameterswereavailablefor33patients Prenatal andpostnatalgrowth abnormalities ofexternalgenitalia. with normalmalephenotypeandpatientsminor there was nocorrelation between the number of SHOX were notassociatedwithheightvariation;mostnotably, ( was significantly associated with a shorter adult height 166 the mean height of patients diagnosed in adulthood was prenatal andpostnataldiagnosis( not sobenign? 45,X/46,XY phenotypicboys, − P

2.30 DS = 0.032). Conversely, Ychromosomestructuraldefects ±

1.5 − − ± Prenatal diagnosis − 18.8 0.88 0.79 163

1.5 4 cm. Aminorabnormality of external genitalia 13/20 (65%) U 7/20 (35%) 6/20 (30%) 7/20 (35%) cm. There wasnosignificant difference infinal ± 1/4 (25%) testforquantitativevariablesanda Fishertestfor ± 6.5 ± ± ± ±

20 (50) 1.23 DS)withapoorpubertalgrowthspurt .7 ( 0.07 .8 ( 0.28 .7 ( 0.07 ( 1.53 ( 1.13 2/20 1/20 1/20 2/11 3/10 1/2 2/5 ± 6.5 n n n n n i. 2A Fig. =3) =2) =2) =10) =15) Fig. 2B Downloaded fromBioscientifica.com at09/27/202110:51:05PM ). Thisgrowthpatternwas ). Adultheight,evaluatedin − Postnatal diagnosis − al 2 Table − 11.8 1.93 160 2.65 179 1.7 14/20 (70%) 12.69 10/20 (50%) 14/20 (70%) 7/20 (35%) 9/13 (69%) ± :3 ± ± ± 20 (50) ± .7 ( 0.07 9/20 7/20 .5 ( 1.95 .7 ( 1.07 ( 0.97 3/20 2/13 4/12 .6 ( 0.76 3/6 0/9 ). Incontrast, ± 5.17 a a n n n n n =7) =4) =13) =5) b =5) a ± 7.6cm 184 via freeaccess European Journal of Endocrinology puberty ( Gonadal functionwasstudied intenpatientsduring except foronepatientwhorequired testosteronetherapy. occurred spontaneouslyata meanageof12.7 infancy, 15havecurrentlyreachedpubertalage. Puberty level above1.5 years),demonstratedanincreaseintestosterone to 11 test, performed in six patients at various ages (6 months oflife.hCG for twopatientsevaluatedpriorto1 month rising above1.5 adequate increase of testosterone and inhibin B levels, diagnosis atameanageof1.3 Mini-puberty, evaluatedinsevenpatientswith aprenatal Gonadal function patients freeoftestosteronetreatment( treatment didnotseemtomodifypubertalstuntingin patients treatedwithGHandothers( assessment, there was no statistical difference between patients was 0.92 yearsoftreatmentevaluatedin11 height gainafter2 GH therapyisstillongoingforsixpatients.Theaverage day. Meandurationoftreatmentwas4.5 7.4 diagnosis ( prenatal diagnosisandtenpatientswithapostnatal were treatedwithGH,includingsixpatientsa gene copiesandfinalheight( Phenotypic characteristicsinrelationwith45,Xmonosomy. Figure 1 Clinical Study ±

. years,withanaveragedoseof49.7 3.4 Fig. 3 Table 2 ) andlongitudinalfollow-up wasavailable ng/mL. Amongpatientsdiagnosedduring ng/mL and150 ). Meanageatonsetoftreatmentwas ± 0.44 s . d . However, at final height pg/mL respectively, except P .5. ite patients Sixteen =0.25). L Dumeigeandothers ± . mnh, showed months, 0.6 Fig. 2B P .7, n GH and =0.87), ± . er, and 2.6 years, ). ± ± 1.1 years, 1.1 years, 15µg/kg/ treated withGH. treatment wasnotknownforpatient4.Patient1 Arrows indicatetheonsetandendofGHtreatment.End height follow-upoffivepatientsfrombirthtopuberty. correcting fortargetheight adolescence. Resultsareexpressedasmeanof Growth characteristics.(A)Meanheightduringchildhoodand Figure 2 of Sertolicelldysfunctionand allhadazoospermia,while patients diagnosed because of infertility, 50% had signs limit and two patients having increased LH levels. Among half ofthepatientshavingtestosterone levelsatthelower levels remaininginthenormalrangeforage,butwith cell functionseemstobelessaffectedwithtestosterone ( three patientshadaninhibinBleveloflessthan60 concomitant decreaseofinhibinBlevels.Inparticular, characterized by an abnormal rise inFSH levels and signs ofdeclinedSertolicellfunctionattheendpuberty including onepatientwithaprenataldiagnosis,presented five patientsare reported in for fivepatients( not sobenign? 45,X/46,XY phenotypicboys, N

= 125–330) at the end of puberty. Conversely, Leydig Fig. 4A ). Clinicalcharacteristicsofthese Downloaded fromBioscientifica.com at09/27/202110:51:05PM ±

s Fig. 4B . d . score.(B)Longitudinal . Most of these patients, 179 www.eje-online.org :3 s . d . scoreafter pg/mL 185 via freeaccess European Journal of Endocrinology www.eje-online.org yolk sactumorcomponent, adjacent toadysgenetictissue carcinomaexamination revealedanembryonal witha on anincreaseoftheright testis sizeat6 testicular cancer was diagnosed initiated. At age17 years, 45,X/46,XY mosaicism,growth hormonetherapywas department forshortstature.Upondiagnosisofthe hewasreferredtothepediatricendocrinology 12 years, correction during infancy.penile curvature At the age of for life foringuinalherniaontheleftsideandsurgery ( carcinomaOne patientdevelopedatesticularembryonal Testicular tumor men ( in situ hyperplasia andspermatocyticarrest,withoutcarcinoma a testicularbiopsyperformedthatshowedLeydigcell increased LHlevelsinonepatient.Oneadultpatienthad levels between4.5and7 with testosterone Leydig cell function was preserved boxes representnormalrangevalues. (D) inhibinBlevelsand(E)testosteronelevels.Shadedgray pubertal stages.(A)LHlevels,(B)FSH(C)AMH Reproductive hormonelevelsofthepatientsaccordingto Figure 3 Fig. 4 Clinical Study 9 component,aspreviouslydescribedin45,X/46,XY , patient 4). This boy had surgery at 4 months of at4 months , patient4).Thisboyhadsurgery ). ng/mL, althoughassociatedwith L Dumeigeandothers cm. Pathology 18 years old.(B)Clinicaldescriptionofthesepatients. levels accordingtoageinfivepatientsfollowedupfrom10 throughout puberty. (A)LH,FSH,inhibinBandtestosterone Longitudinal reproductivehormonelevelsoffivepatients Figure 4 of , in mirror to 45,X/46,XY patients have Turner-like syndromefeaturesandacertaindegree (EMS of 45,X/46,XY boys with normal or mild genital anomaly This studydescribestoourknowledge, thelargestcohort Discussion after germcellpreservation. recurrence, itwasdecidedtoperformaleftorchidectomy therapy wasinitiated.Consideringtheriskoftumor azoospermia. Treatment by intra-musculartestosterone levels werelow(2.15 and 30.6( a highincreaseinFSHandLHlevels(42.1( left testis,thepatientdevelopedtesticularfailure,with radiotherapy was necessary. of the Despite preservation systemic metastaticextension,andnochemotherapyor was performed.Thereneitherlocoregionalnor comprising a carcinoma not sobenign? 45,X/46,XY phenotypicboys, > 10). We demonstrate thatthesepatientsmay N UL rsetvl) Testosterone respectively). =1.7–8.6)IU/L, ng/mL) andspermcountshowed in situ Downloaded fromBioscientifica.com at09/27/202110:51:05PM component. Orchidectomy 179 :3 N =1.5–12.5) 186 via freeaccess European Journal of Endocrinology • • • • • • Initial screening atdiagnosis Table 3 pubertal onset.However, patientsfollowedlongitudinally mini-puberty andmostpatientshadspontaneous have testicularfunctionwithinnormallimitsduring However, dysfunctionappearstobetransientaspatients inadequate atacriticaltimeofgenitaldevelopment. this suggests that production may have been masculinization of somethese patients. Nevertheless, EMS scoremaythusunderestimatethedegreeofunder which mayhavehiddenamoreseverehypospadias.The had aglanularhypospadiasand/orpenilecurvature, population ( which appears more frequent than in the general such as unilateral cryptorchidism or glanular hypospadias, patients had minor abnormalities of external genitalia, certain degreeoftesticulardysgenesis.Indeed,55%our patients withnormalmaledifferentiationmaypresenta Interestingly, ourresultssuggestthateven45,X/46,XY cells inpatientswithtestesandamalephenotype( with afemalephenotype,andpredominanceof46,XY predominance of45,Xcellsinstreakgonadspatients ( colonizing the urogenital ridge during embryogenesis differentiation depends on the percentage of 45,X cells ( determining thedistributionof45,Xcellsareunknown ( 45,X cellsonlymphocytickaryotype phenotype isnotcorrelatedwiththepercentage of a broadphenotypicspectrum( within theorganism, differs amongpatients, producing and therefore, the number and distribution of 45,X cells Y chromosomeinacellline.Thetimingofthisloss, causinglossofthe mitotic errorduringembryogenesis, diagnosis and long-term follow-up as proposed in with genitalambiguity, highlightingtheneedofanearly 4 19 Clinical Study , concentrations, bloodpressure, standardlipidevaluation) metabolic evaluationafterpuberty (fastingglucose Auto-immune evaluation(thyroid, coeliacdisease)and ENT evaluation malformations Cardiac andrenalultrasoundfordetectionofpotential ducts Pelvic ultrasoundfordetectionofpotentialMullerian AZF loci abnormality oftheYchromosome,anddeletion Identification onthekaryotypeofpotentialstructural skeletal defectsandpsychomotorevaluation identification of Turner syndromedysmorphicfeaturesor Clinical examinationincludingexternalgenitalia, ). Inthegonads,ithasbeensuggestedthatgonadal 45,X/46,XY mosaicism is due to a post-zygotic 20 ). Indeed,severalcasereportshaveshowna Suggestion offollow-upguidelinesfor45,X/46,XYmalepatients withnoormildgenitalanomaly(EMS 23 ). Itshouldbenotedthatfivepatients 18 L Dumeigeandothers ). Neverthelessclinical 6 , 7 , 8 ). Factors Table 3 21 , 22

). . • • • • • • • • Annual follow-up Proposition offertilitypreservation attheendofpuberty initial evaluation ENT, cardiac,renalororthopedic follow-updependingonthe every twoyears concentrations, bloodpressure, standardlipidevaluation) metabolic evaluationafterpuberty (fastingglucose Auto-immune evaluation(thyroid,coeliacdisease)and puberty, orincaseofultrasoundanomaly combination withorchidopexyifrequired)andattheendof Testicular biopsyshouldbediscussedduringinfancy(in Testicular tumorscreening:palpationandannualultrasound Testicular function,startingfromonsetofpubertyorage12 Growth monitoring progression Clinical examinationincludingassessmentofpubertal mosaicism or AZF microdeletions ( readily beenproposedforpatientswith45,X/46,XY techniques suchastesticularspermextraction,ithas an early concern in orderto propose assisted reproductive ( related totesticulardysgenesisanddefectsoftheAZFloci required for normal spermatogenesis ( of thechromosomeand/orduplicationotherfragments rearrangements induceinstabilityandresultinlossofpart with majorgenitalanomalies( patients, corroborating results from 45,X/46,XY patients structural defectsoftheYchromosomefoundin50%our of the45,Xcelllineingonads. to acceleratedloss of the Y chromosome and emergence alteration oftesticularphenotypetowarddysgenesis,due during pubertyorwhetheritisinrelationtoaprogressive from thefetalperiod,whichisunmasked for mostpatients is linkedtoamoderatelyalteredgonadalfunctionstarting ( ambiguity ( puberty, asdescribedin45,X/46,XYpatientswithgenital withincreaseoftestosteronelevelsduring be preserved increased FSHlevelswhileLeydigcellfunctionseemedto end ofpuberty, characterized by lowinhibinBlevelsand demonstrated signsofdeclinedSertolicellfunctionatthe patients referred for non-obstructive azoospermia ( hasaprevalenceof0.3–1%among 45,X/46,XY karyotype patient withadeletionoftheAZFloci.Inliterature, a structuraldefectoftheYchromosomeincludingone azoospermia. Among thesepatients,four patients had five patientsevaluatedforfertilityinourcohorthad fertility byinducingdeletionoftheAZFregion( were predominantlyisochromosomeY(p),compromising ( not sobenign? 45,X/46,XY phenotypicboys, 29 24 25 ). It remains tobe determined whether this phenotype ). Thus, fertility evaluation in these patients should be , Another determinantofthephenotyperelieson 26 ). Inourcohort,Ychromosomestructuraldefects 7 , 9 ) andpatientswithKlinefeltersyndrome Downloaded fromBioscientifica.com at09/27/202110:51:05PM 7 ). Thesechromosomal 13 179 , www.eje-online.org :3 28 30 > ). Indeed, the ). The ethical 10). 11 187 , 27 13 via freeaccess ), ) European Journal of Endocrinology www.eje-online.org height, andtheproportion of 45,Xcellsinlymphocyte’s correlation betweenpatient’s phenotype,including final ( the 45,Xcellularcontingent, bySHOXhaploinsufficiency some authorsproposethatthis alteredgrowthisrelatedto pattern ( or withoutgenitalanomalycoulddisplaysimilargrowth suggests thatpatientswitha45,X/46,XYmosaicism with genitalambiguityraisedasboys( puberty was158 mean finalstatureforpatientsassessedattheend of relation toapoorpubertalgrowthspurt.Furthermore, from the antenatal period and worsens at puberty in inhalfofthepatients.Growth isalteredstarting observed in ,most predominantlyshortstature, function, fertilityandtumorrisk. normal malephenotype,especiallyregardingtesticular it seemsessentialtofollow45,X/46,XYpatientswith ( and attheendofpubertyorincaseultrasoundanomaly infancy (incombinationwithorchidopexy ifrequired) monitoring. Testicular biopsyshould be discussed during systematic orchidopexy andannualultrasonography approachwith i.e.aconservative undervirilization, from similar management than patients with signs of legitimate toproposethatthesepatientsshouldbenefit are ofteninadequatelymonitored( never beenproperlyevaluatedbecausethesepatients infants ( early-stage gonadoblastomaalreadypresentinfetusesor report intra-scrotal testes,althoughsomeobservations is consideredintermediatefor45,X/46,XYpatientswith the caseofpoorlydifferentiatedgonads( Cools germ cellsintoprecursorlesions( proliferation, promotingtransformationofembryonal as OCT3/4andTSPYgene,regulatorsofapoptosis markerssuch their maturation,whichexpressembryonal risk isrelatedtothepersistenceofgermcellsblockedin prevalence couldbeunderestimatedinourcohort.This fewpatientshavehadtesticularbiopsies;thus,this very only 27.5%ofourpatientshavereachedadultageand third decadeaccordingtoDonahoe estimated prevalence of 15% ( carcinoma.testicular embryonal This is less than the suggest aneedforpre-implantationgeneticscreening. Y chromosome remains to be evaluated ( dilemma raisedbypotentialtransmissionofanunstable 38 3 , Clinical Study ). However, manystudieshavefailed tofinda 33 In addition,70%ofourpatientshadfeaturesseen One patientofourcohort(2.5%)developed , t al et 37 1 4 ). Asaresult,despitereassuringpresentation, , , ., gonadaltumorriskismorepronouncedin 14 6 , ). Regardless of these observations, ithas ). Regardlessoftheseobservations, 7 , ± 9

7.6 ). ByanalogywithTurner syndrome, cm, similarto45,X/46,XYpatients 33 L Dumeigeandothers ) reaching 50% in the 35 et al. 35 , 7 36 ). Thus,ourstudy ). Itistherefore 31 ( ). Accordingto 37 34 , ). Tumor risk 32 ). However, ) and may but couldleadtoearlierdiagnosisofthesepatients. screening remainstobeevaluatedbyaprospectivestudy it isalreadydoneingirlstodetectTurner syndrome.This testicular impairment)inboysreferredforshortstature,as (orguidedbyassociatedsignsof a systematickaryotype among 45,X/46,XY boys, itcould be relevant to perform Therefore, considering the importance of growthfailure defective 46,XYcells,inthetestes,boneandgrowthplate. determined bytherelativeexpressionof45,Xcellsand copies andadultheight.Yet, statureisprobablymainly was found between the number of in twocopiesofthe in ourpatientswasisodicentricY(p),whichmayresult chromosome. Themostfrequentcytogeneticabnormality with Ystructuralabnormalityandthosenormal found nosignificantheightdifferencebetweenpatients chromosome PAR1 regioninthe46,XYcells.However, we to anadditivedeletionoftheSHOXgenefromY ( karyotype diagnosed priorbirthhave a lessseverephenotype( missing data.Severalstudies havesuggestedthatpatients natureofretrospectivedata collectionand observational ignored and45,X/46,XYpatientsshouldbeinvestigated. ( an homogeneous45,Xkaryotype of malformation is much lower than that of patients with clinical presentationofthesepatients( detailed cardiovascularscreening,regardlessoftheinitial by Klàskovà these malformationsinourpatients,asalreadysuggested may leadtoanunderestimationofthefrequency of cohort hadacardiacand/orrenalexploration,which However, itshouldbenotedthatonlyabout50%ofthe already beensporadicallydescribedinsomecasestudies. presented cardiacorkidneymalformations,asithas height inthispopulation.Finally, 22.5%ofthecohort GH treatmentcouldbeofbenefitinimprovingadult prospective studiesarestillrequiredtoassesswhether and thattreatmentresultedinasimilarheight.Thus, that GHtreatmentwasofferedtotheshortestpatients as alreadydescribed( last evaluation between the treated and untreated group, initial GHresponse,therewasnostatisticaldifferenceat terms ofinitialtwo-yearheightgain.However, despitethe ambiguity ( with results similar to 45,X/46,XY patients with genital likely duetothesignificantly longerfollow-upperiod in patientswithapostnatal diagnosis.However, thisis We also found ahigher prevalence ofTurner-like features not sobenign? 45,X/46,XY phenotypicboys, Results mustobviouslybenuancedbecauseofthe In ourcohort,16patientsweretreatedwithGH, 15 14 et al ) and45,X/46,XYTurner patients( ). Growthfailurecouldalsobelinked ., underlyingthecrucialimportanceof SHOX 40 ). Thismayberelatedtothefact Downloaded fromBioscientifica.com at09/27/202110:51:05PM gene.Anyhow, nocorrelation SHOX 39 179 ), itshouldnotbe 41 :3 ). Eveniftherisk gene estimated 39 188 ) in 42 via freeaccess ). European Journal of Endocrinology and agreetobeaccountableforall aspects ofthework. the manuscript.Allauthorsapproved thefinalmanuscriptassubmitted manuscript. RCoutantcoordinated data collectionandcriticallyreviewed B Donadille,J-CCarelcollecteddata and criticallyreviewedrevisedthe Blond, CNaud-Sandreau,Dupuis, JLéger,PSiffroi, SChristin-Maitre, C Hyon,BEsteva,DSamara-Boustani, DZenaty, MNicolino,SBaron,CMetz- initial analyses and reviewed the manuscript. C Bouvattier, M De Kerdanet, and revisedthemanuscript.LChatelais,collecteddata,carriedout drafted theinitialmanuscript,coordinateddatacollectionandreviewed L DumeigeandMartinerieconceptualizeddesignedthestudy, Author contributionstatement the public,commercialornot-for-profit sector. This researchdidnotreceiveanyspecificgrantfromfundingagency in Funding perceived asprejudicingtheimpartialityofthisstudy. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest considered. shouldeventuallybe screening andfertilitypreservation paid togrowth,testicularfunctionandtumor followed throughouttheirlife,withparticularattention features. Finallythesepatients,upondiagnosis,mustbe have associated gonadal malfunction or Turner syndrome referred for growth failure especially among those who inpatients the systematicevaluationofkaryotype seems essential to identify these patients by considering the absenceofprospectivefollow-upstudies.Therefore,it prevalence ofthesefindingsisdifficulttospecifygiven of developingatesticulartumor. However, the current function atpuberty, raisingconcernsforfertilityandrisk mild gonadal dysgenesis with exhaustion of Turner syndromeincludingstuntedgrowthandhave have shownthatthesepatientsmayexhibitsignsof Our resultshaveimportantclinicalimplications.We Conclusion children diagnosedpriorbirth. conduct alongitudinal prospective studyof45,X/46,XY accurately assesstheirphenotype,itwouldbeessentialto or impairedgonadalfunction.Nevertheless,inorderto the 45,Xmonosomysuchasshortstature,malformations patients arenotexemptfromcomplicationsrelatedto should befollowedonthelongterm.Indeed,these that allpatients,includingthosediagnosedprenatally, at puberty( abnormalities mayappearonlyduringlatechildhoodor diagnosis. Indeed,dysmorphicfeaturesororthopedic of thesepatientscomparedtothosewithaprenatal Clinical Study 43 ). Asaresult,ourfindingsalsoemphasize L Dumeigeandothers References

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Accepted 3July2018 Revised versionreceived9June2018 Received 12April2018

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