2 182

L Maione and others Height in CHH/KS 182:2 185–194 Clinical Study

Congenital hypogonadotropic / Kallmann syndrome is associated with statural gain in both men and women: a monocentric study

Luigi Maione1,2,5, Giovanna Pala2,3,4, Claire Bouvattier1,3,5, Séverine Trabado1,5,6, Georgios Papadakis2,7, Philippe Chanson1,2,5, Jérôme Bouligand1,5,6, Nelly Pitteloud7, Andrew A Dwyer8, Mohamad Maghnie4 and Jacques Young1,2,5

1Paris-Saclay University, Paris-Saclay Medical School, Le Kremlin-Bicêtre, France, 2Endocrinology and Reproductive Diseases Department, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France, 3Paediatric , Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France, 4Paediatric Department, Istituto Giannina Gaslini, Istituto Pediatrico di Ricovero e Cura a Carattere Scientifico, Università di Genova, Genova, Italy,5 INSERM U1185, Le Kremlin-Bicêtre, France, 6Molecular Genetics, Pharmacogenomics, and Hormonology, Assistance Publique-Hôpitaux Correspondence de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France, 7Endocrinology, Diabetes, and Metabolism Service, should be addressed University Hospital of Lausanne, Lausanne, Switzerland, and 8Boston College, William F. Connell School of Nursing, to J Young Chestnut Hill, Massachusetts, USA Email [email protected]

Abstract

Context: Congenital hypogonadotropic hypogonadism/Kallmann syndrome (CHH/KS) is a rare condition characterized by deficiency and pubertal failure. Adult height (AH) in patients with CHH/KS has not been well studied. Objective: To assess AH in a large cohort of patients with CHH/KS. Patients: A total of 219 patients (165 males, 54 females). Parents and siblings were included. Methods: AH was assessed in patients and family members. AH was compared to the general French population, mid

European Journal of Endocrinology parental target height (TH) and between patients and same-sex siblings. Delta height (∆H) was considered as the difference between AH and parental TH.∆ H was compared between patients and siblings, normosmic CHH and KS (CHH with /hyposmia), and according to underlying genetic defect. We examined the correlations between ∆H and age at diagnosis and therapeutically induced individual statural gain. Results: Mean AH in men and women with CHH/KS was greater than that in the French general population. Patients of both sexes had AH > TH. Males with CHH/KS were significantly, albeit moderately, taller than their brothers. ∆H was higher in CHH/KS compared to unaffected siblings (+6.2 ± 7.2 cm vs +3.4 ± 5.2 cm, P < 0.0001). ∆H was positively correlated with age at diagnosis. Neither olfactory function (normosmic CHH vs KS) nor specific genetic cause impacted ∆H. Individual growth during replacement therapy inversely correlated with the age at initiation of hormonal treatment (P < 0.0001). Conclusions: CHH/KS is associated with higher AH compared to the general population and mid-parental TH. Greater height in CHH/KS than siblings indicates that those differences are in part independent of an intergenerational effect.

European Journal of Endocrinology (2020) 182, 185–194

https://eje.bioscientifica.com © 2020 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-19-0537 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 01:41:38PM via free access

-19-0537 European Journal of Endocrinology https://eje.bioscientifica.com academic medicalcenter(Department ofEndocrinology This studywasconducted atasinglelargetertiary Patients andmethods of treatment(i.e.sexsteroidreplacement)onstature. underlying CHH/KS.Inaddition,weexaminetheeffects CHH vs KS) andidentified raregenetic variants (mutations) height accordingtoclinicalpresentation(i.e.normosmic same sexsiblings.Secondarily, weaimedto examine adult the generalpopulation,mid-parentaltargetheightand cohort ofpatientswithCHH/KSandcompareheight ( hormonedeficiencyand deficiency/multiple pituitary disorders ofpubertyhasfocusedongrowthhormone much oftheliteratureongrowthandheightinendocrine into accountinthispatientpopulation( changes in successive generations) is yet tobe taken ( steroid treatmentonheightparametersinthispopulation growth ( associated withCHH/KSneitheracceleratesnordelays of 36patientssuggeststhatthesexsteroiddeficiency of menandwomenbornwithCHH/KS( is apaucityofdataonpubertalgrowthandadultheight epiphyseal plates(so-called‘growthplates’)fuse( growth endswhenthehyalinecartilagecomprising skeletal growthandbonematuration.Long both genders( therapy havenegativepsychologicalconsequencesin 4 not diagnoseduntil late adolescence or earlyadulthood ( deficiency ( breast underdevelopmentinthesettingofestradiol and variable typically present with primary whilefemales deficiency isevidencedbyundervirilization incomplete) pubertaldevelopment.Inmales, 3 approximately 1/4000 and 1/10 000 respectively ( hormone (GnRH)( deficient secretion(oraction)ofgonadotropin-releasing rare cause of disrupted and caused by impairment(Kallmannsyndrome,KS)isa with olfactory function(normosmicCHH)or with normalolfactory Congenital hypogonadotropichypogonadism(CHH) Introduction 7 , ). Clinically, CHH/KSischaracterizedbyabsent(or ). Moreover, intergenerational effects (i.e. howheight Clinical Study 5 ). Diagnosticdelayandthusinitiationofreplacement This studyaimstoassessadultheightinasizable Puberty in both sexes is associated with accelerated 9 ). Onlyonestudyhasexaminedtheeffectofsex 1 ). Accordingly, thevastmajorityofcasesare 1 , 2 , 12 4 1 , , , 5 13 ). 2 ). ). Theestimatedprevalenceis L Maioneandothers 10 7 , , 8 11 , 9 ). To date, ). Astudy 6 ). There 1 1 , , mL) inthesettingofloworinappropriatelynormal( IU/L)); ( (LH, IU/L) serumgonadotropinlevels(luteinizinghormone testosterone incomplete puberty;( (CHH/KS) wasbasedonthefollowing( 2018. AdefinitivediagnosisofisolatedGnRHdeficiency recruitment ofthestudypopulationrangedfrom1975to Patients withCHH/KSwereenrolledinthestudy. Periodof Patients Law andtheprinciplesofDeclarationHelsinki. informed consentinaccordancewithFrenchBioethics 2017-A01584-49). All participants provided written the study protocol and provided ethics approval (RCB France). TheNationalAgencyofMedicalSafetyreviewed and ReproductiveDiseases,BicêtreUniversityHospital, patients hadtotalserumtestosterone levelsbelow1.5ng/ replacement therapy. Afterwashout,allmaleCHH/KS puberty, andafter a3-monthwithdrawalofsexsteroid in ordertoexcludeaconstitutional delayofgrowthand and 17years,thedefinitive diagnosis wasmadeat18years patients inwhomCHHorKSwasdiagnosedbetween13 hypoplasia/aplasia) as previouslydescribed ( bulb testing and cranial imaging (olfactory olfactometry syndrome (CHH were considerednormosmicCHHorhavingKallmann of previoussexsteroidreplacementtherapy).Patients FSH associated withestradiol and FSH after age18(totaltestosterone repeat hormoneprofilingfollowingatreatmentwashout 13 and17yearsofage,thediagnosiswasconfirmedwith cases whenpatientswerediagnosedwithCHH/KSbetween disorders, lowBMI,malabsorption,chronicdiseases).In causes ofhypogonadotropichypogonadism(i.e.eating region;and( the hypothalamic–pituitary after 2005 growth factor-1(IGF-1)levels(before1995: ferritin concentrationsandage-adjustedinsulin-like DHEAS (males: after 2005viainsulintolerancetest( growth hormone(GHpeak pmol/L, TSH0.8–4.3mIU/L)andnormalstimulated ng/mL) andnormalthyroidfunction(freeT4:12.0–22 ng/mL) cortisol, normal basal ( evidenced bynormalbasal( Height inCHH/KS < < 8.5 IU/Linfemalesaftera3-monthwithdrawal 5.6 IU/L),follicle-stimulatinghormone(FSH, 3 < ) otherwise normal anterior pituitary function normalanteriorpituitary ) otherwise 7.6 IU/Linmales,andpersistentamenorrhea > 198 ng/mL)( < 1.5 ng/mL,females:estradiol(E2), > 640 ng/mL,females: + anosmia orhyposmia)basedon 2 ) lowserumsexsteroidlevels(males: Downloaded fromBioscientifica.com at09/30/202101:41:38PM < 15 35 pg/mL,LH > > , 80 ng/mL)/stimulated( 10 ng/mL)eitherbeforeor 16 < 1.5 ng/mL,LH , 17 14 ); ( 182 > ); ( 1 5 412 ng/mL),iron/ :2 , ) normalMRIof 4 6 2 ) normalserum ) nofunctional < ): ( > 6.5 IU/Land 8.0 and > 1 18 172 ng/mL ) absentor < , 5.6 IU/L < 19 35 pg/ 186 > ). In < < < 180 7.5 5.5 20 via freeaccess European Journal of Endocrinology adult andtargetheightare equivalent.Apositive height (AH height difference (incm)between adult andmidparentaltarget height +mother’s cm) cm) TH =(father’s height +13 female height +mother’s TH =(father’s was determined(incm)usingTanner’s formulas(male estat_1981_132_3.pdf https://www.epsilon.insee.fr/jspui/bitstream/1/19240/1/ cress-umr1153.fr/index.php/courbes-carnet-de-sante/ other FrenchNationalHealthpublicdatabases( 18–74. Data are consistent with less recent figures from healthy adults from Frenchgeneral population aged published in July 7, 2011. This study included 3115 aviesan.fr birthday method,seealso one individual per household, adult or child, using the (landlines, redlists,mobilephonesandunbundled);( eight majorregions;( municipalities ( a three-stagesampling:( a sample from the French general population by using encompassed Institut deveillesanitaire(InVS)).Thesurvey Health (AgencenationaleSantépubliqueFrance,formerly 2264), fundedbytheFrenchNationalAgencyofPublic Study (ENNS, CNIL no. 905481; Paris Cochin CPP no. We usedtheFrenchNationalNutritionalandHealth Institute ofHealth( of Statistics( French population(1980–2010)-NationalInstitute population, we used publicly available data on the general and siblings’ heights by telephonesurvey. As areference hospital consultation,inasubgroupweaskedforparent using awall-mountedstadiometer. Whennotpresentin Whenever available,parentsandsiblingsweremeasured two measurementsperformedatleast6monthsapart). height measurements( as reachingadultheight (AH) bytwoormorestable hormonal replacementtherapy. Patientsweredefined stadiometer at first visit and before introduction of Height (incm)wasmeasuredusingawall-mounted Anthropometric measures affected parents(i.e.,withnCHHorKS)fromthestudy. measures wereexcludedfromthestudy. We alsoexcluded below 35pg/mLassociatedwithpersistentamenorrhea. mL, andallCHH/KSfemaleshadserumestradiollevels Clinical Study Mid parentaltargetheight(TH)foreachpatient CHH/KS patientswithoutavailableparentalheight × .) ( 0.5) ). We used inour study the latest database 20 − TH = http://www.insee.fr/ ). Deltaheight( n

= ∆ 190) stratifiedbyurbanunitsizeand H) ( http://invs.santepubliquefrance.fr/ ). 2 21 ) householdsfromphonelists < 1 ). A 1.5 cmdifferencebetween ) municipalitiesorgroupsof https://epidemiologie-france. ∆ ∆ H) wascalculatedasthe H equaltozeroindicates L Maioneandothers ) andFrenchNational https:// × − 0.5, ∆ 13 3 H ). ) ; KS: coding regionsofthefollowinggenesunderlyingCHH/ with availablegeneticanalysiswefoundmutationsinthe traditional Sangersequencing.Fromatotalof215patients protocols, anddirectsequencingwasperformedusing from peripheralbloodleukocytesusingstandard Following informedconsent,genomicDNAwasextracted Genetic analyses hormonal therapy(i.e.sexsteroidreplacement). AH andthebasalheightmeasuredpriortoinitiating therapy wascalculatedasthedifferencebetween both genders. The individual growth during replacement to compare in male and female (see Results section) we were able height ( ∆ value indicatesthatAHissuperiortoTH,whilenegative than 0.05wasconsideredstatistically significant. using mean and Software, Inc.).Dataarereported asindividualvaluesor conducted using GraphPad Prism, version 5.0f (GraphPad and ANOVA tests.Graphicsandstatisticalanalyses were according togeneticvariants,weperformedKruskal–Wallis 0.05, power0.8).Forcomparisonofheightmeasures needed todetectastatisticsignificantdifference(alpha previous pertinentliterature,anumberof34pairsare statulator.com/SampleSize/ss2PM.html com/stats/samplesize.aspx calculated withSampleSizeCalculator( growth respectively. Samplesizeforpairedtests was of hormonal substitution and therapeutically induced the relationship between as appropriate.We usedlinearregressiontoexamine employed forcategoricalcomparisonsbetweengroups using Student Patient andsiblingstaturalparameterswerecompared Statistical analyses out of215. did notfindanydeleteriousgeneticmutationin103cases as previouslyreported( and 3.3%), ( ( ( ( Height inCHH/KS n n n n H valuesindicatethatAHisinferiortoTH.Becausedelta /1, 1.9%), =4/215, 5.1%), =11/215, 6.1%), =13/215, 16.8%), =36/215, WDR11 ANOS1 TAC3 ∆ H =AH (formerly ( ∆ ( n t H data of male CHH/KS from siblings of -tests. Chi-squareorFisher’s exacttestswere n

= /1, 0.9%), =2/215, s 0/215, 0%).Thesegenesweresequenced . KISS1 d − . TH)werenotstatisticallydifferent unless otherwise noted. A unless otherwise GNRH1 CHD7 PROK2 ( 22 KAL1 Downloaded fromBioscientifica.com at09/30/202101:41:38PM n /1, 0%), =0/215, , ) andStatulatorBeta( ∆ 23 ( H and age at diagnosis/start ( ( , , n n n 24 /1, 3.7%), =8/215, n https://eje.bioscientifica.com /1, 2.3%), =5/215, /1, 0.9%), =2/215, 025 9.3%), =20/215, TACR3 , 25 182 , 26 ). Byanalyzing ( KISS1R :2 , n https://clincalc. 27 /1, 0.9%) =2/215, , 28 P ( value less n , SEMA3A =7/215, PROKR2 29 GNRHR http:// FGFR1 187 ). We via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com LH, luteinizinghormone; BMI, bodymassindex;DHEAS,dehydroepiandrosterone sulfate;FSH,follicle-stimulatinghormone;FT4,free thyroxine;IGF-1,insulin-likegrowthfactor1; *Normative valuesforcirculatingIGF1 arefrompreviouspublishedwork( Data arereportedasmeans DHEAS (ng/mL) Cortisol (8:00h)(ng/mL) FT4 (pmol/L) TSH (mIU/L) Prolactin (ng/mL) IGF-1 (ng/mL) FSH (IU/L) LH (IU/L) Total estradiol(pg/mL) Total testosterone(ng/mL) Hormonal profile Normosmic CHH/KS( Ovarian volume(mL) Testicular volume(mL) BMI (kg/m Weight (kg) Age attreatmentinitiation Age atdiagnosis(years) Table 1 female patients with CHH/KS surpassed their mid-parental (median: 166cm,IQR:162–170.5 (181.3 patients weresignificantlytallerthantheirbrothers cm, surpassed theirmid-parental TH (179.0 (TH) revealedthatonaverage,malepatientswithCHH/KS cm, cm (median:179cm,interquartilerange(IQR):174–185 end ofthisarticle). 1, seesectionon Fig. population – neither 1980 nor 2010 (Supplementary AH of the patients did not differ from the reference French reference population ( KS patientswasabovethemedianheightreportedin ( normosmic CHH( after age18years. Cases were equally divided between and 17yearsofage–allwhomhadCHH/KSconfirmed males and16femaleswereinitiallydiagnosedbetween13 included inthestudy( A totalof219patients(165males,54females)were Results n

Clinical Study (years) = 110). Atotalof172/219(79%)patientshadsiblings. In female patients mean AH was 166.0 In maleCHH/KSpatients,meanAHwas179.0 Median adultheight(AH)inmaleandfemaleCHH/ Fig. 1A P

± <

0.0001, 7.9 vs179.0 Clinical andbiochemicalcharacteristicsofpatientswithCHH/KSatdiagnosis. 2 ) ). ComparingAHtomid-parentaltargetheight Fig. 1A supplementary materials supplementary n n , numberofpatients;TSH,thyroid-stimulating hormone. ± ) n 6.9, ±

=

s 109) andKallmannsyndrome . d Table 1 ). Interestingly, maleCHH/KS . P .4) ( =0.045) Figs 1A Male CHH/KS ). Ofthesepatients,56 L Maioneandothers 1766 24.8 17.8 17.5 0.48 192 251 2.2 7.2 1.0 0.8 9.1 3.3 76 15 Fig. 1B 76/91 and – ± Fig. 2A ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

8.2 vs175.0 2.4 6 23 6.2 6.0 929 76 3.4 1.7 4.3 105 1.2 1.1 8.9 0.7 ( n givenatthe ). 2A = 165) ). Similarly, ). Parental ± . cm 6.7 ± ± 8.2 5.6 Normal range 15 in males , 643–3731 198–397* 0.8–4.3 2.2–7.4 1.6–5.6 3.4–8.5 16 94–214 12–22 10–38 20–25 > ( 73.8%, compared to their unaffected siblings ( Further, patientsweremorelikelytohavepositive between theageoftreatmentinitiationandindividual As shownin replacement initiationwereavailablefor118patients. who hadgeneticscreening( were identified based on genetic causes in the 214 patients Fig. 4A CHH andthosewithKS(4.4 KS patients161/219(73.5%)hadapositive the (6.2 ( generational staturalgain( was alsopositive(3.4 4.3 values weresimilarinmaleandfemalepatients(4.0 ( sisters ( patients withCHH/KS( TH (166 9–20 Height inCHH/KS , n Fig. 3C Fig. 2B 12 – – – – – 17

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European Journal of Endocrinology recent decades(negativecorrelation: indicating thatageattreatment initiationwasearlierin the yearofbirthand age attreatmentinitiation, recruitment, we found a negative correlation between It shouldbenotedthatwhenanalyzingdataaboutperiod growth potentialwhenthetreatmentwasinitiatedlater. P statural gainduringreplacementtherapy( Individual valuesandmean KS malesandthatoftheirunaffectedbrothers( Comparison betweentheadultheightinasubgroupofCHH/ according toTannerformula( height hasbeencalculatedbymeansoftheparental Health, from thepublicdatabaseofFrenchNationalInstitute line indicatesmedian.GeneralFrenchpopulationdataare min andmaxlimitsoftheFrenchgeneralpopulation.Dotted of theFrenchmalegeneralpopulation.Lightgreyindicates target height.Darkgreyzoneshowsthe2.5to97.5centile mean their brothers.(PanelA)Individualvalues( Adult andmid-parentaltargetheightinCHH/KSmales Figure 1 B A

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< 0.0001). r = − 2.5 median 97.5 0.57, and mean and thatoftheirunaffectedsisters.Individualvalues( between theadultheightinasubgroupofCHH/KSfemales to Tannerformula(20).**** has beencalculatedbymeansoftheparentalheightaccording http://invs.santepubliquefrance.fr/ the publicdatabaseofFrenchNationalInstituteHealth, indicates median.GeneralFrenchpopulationdataarefrom and maxlimitsoftheFrenchgeneralpopulation.Dottedline French malegeneralpopulation.Lightgreyindicatesthemin ( female CHH/KSadultheightversusmid-parentaltarget their sisters.(PanelA)Individualvaluesandmean Adult andmid-parentaltargetheightinCHH/KSfemales Figure 2 age of14(18.1 patients startinghormonal treatment beforeorafterthe whendichotomizing differences werealsoobserved Important and significant individual statural growth later (16.6 compared totheircounterpartswhostartedtreatment significantly greaterindividualstaturalgrowthpotential starting treatment before the age of 16 years exhibited Height inCHH/KS B A n = 54). Darkgreyzoneshowsthe2.5to97.5centileof Adult height (cm) Height (cm) We thatpatients dichotomizedthedataandobserved 140 150 160 170 180 190 140 150 160 170 180 190 ± ±

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s . e n . , inset). of = 16) 189 2.5 median 97.5 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com is availableat confidence intervalisshown. A fullcolourversionofthisfigure cm) andtheageatfirstreplacement therapy.Bestfitand95% (in years),indicatingcorrelation betweenthedeltaheight(in female CHH/KSpatientsaccording totheageatfirsttreatment (Panel C)Individualvaluesofdeltaheight( (no differencebetweenadultandmidparentaltargetheight). parental targetheight,incm).Verticalredlineindicateszero patients. Onx-axisnumbersrepresentthedelta(adult–mid population. Eachverticalbarrepresentsthenumberof (AH effect, seeResultssection).(PanelB)Distributionofpositive Note thatdeltaheightinsiblingsisabovezero(generational between adult and mid-parental target height). **** whiskers (mintomax).Redlineindicateszero(nodifference Methods andResultssection).Dataareshownasbox patients andtheirmalefemalesiblings( Delta heightvaluesbetweenpooledmaleandfemaleCHH/KS (delta) inpooledmaleandfemaleCHH/KSpatients.(PanelA) Difference betweenadultandmid-parentaltargetheight Figure 3 C B A Delta height (cm) Clinical Study

> No. patients Delta height (cm) -20 -10 -20 -10 TH, 10 20 30 10 20 30 10 20 30 40 0 0 0 -14 > CHH/KS patients 0 cm)andnegative(AH -12 -10 10 https://doi.org/10.1530/EJE-19-0537 AHTH < L Maioneandothers TH, 30 10 12 < 0 cm) ∆ 14 H) in male and H) inmaleand n 16 = 172) (see text, = 172) (seetext, r p 0. 0. 18 ∆ 28 0015 H in CHH/KS H inCHH/KS . 20 40 22 P

< 24 0.0001. 0.0001. 26 cm 28 mean height). Dataarereportedasindividual zero (nodifferencebetweenadultandmid-parentaltarget without identifiedgeneticabnormalities.Dottedlineindicates height ( and mid-parentaltargetheight).(PanelB)Individualdelta Dotted lineindicateszero(nodifferencebetweenadultheight Kallmann syndromeversusnormosmicCHHpatients(nCHH). genetic form.(PanelA)Individualdeltaheightvaluesin patients accordingtoolfactorystatus(KSversusnCHH)and mid-parental targetheight)inpooledmaleandfemaleCHH/KS Delta height( Figure 4 and boneage( A positivecorrelationwasfound betweenchronological 16.3 age (females:16.7 agewassignificantly lowerthanchronological patients (15females,44males)beforehormonaltreatment. P cm, P before or after the age of 18 (13.1 Height inCHH/KS =0.0051).

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< ± .01 males: 0.0001; . cm, 6.1 ± Fig. 3A . cm, 3.9 n 190 =33, ± 8.8 via freeaccess ). European Journal of Endocrinology target height (i.e. target height (TH)) as well as to AH in target height(i.e. (TH))aswelltoAHin background bycomparing patient AHtomid-parental with CHH/KSasame-sex referencepopulation. the presentworkisfirst tocompareAHinwomen patients were3cmtalleronaverage.To ourknowledge, reference group of young American males, male CHH/KS 41 maleswithCHH/KSandfoundthatcomparedto a and colleagues( patients isconsistentwiththepreviousstudybyUriarte 12 include patientswithothercausesofpubertaldelay( sizes andareconfoundedbythefactthatsomestudies KS. Thesestudiesarequitedated,limitedbysmallsample Few studieshaveexaminedheightinpatientswithCHH/ mid-parental targetheight(TH)andsiblingadultheight. that meanAHofpatientsexceededthegeneralpopulation, identified usingrigorous,well-definedcriteria. Wefound cohort ofmenandwomenwithCHH/KSwhowere Herein wereportadultheight(AH)inasingle-center Discussion EJE-19-0537 version ofthisfigureisavailableat than olderCHH/KSpatients;**** 16 years solely for indicating more growth potential in younger whom hormonal substitution started before or afterthe age of post-replacement therapygrowthgaininCHH/KSpatients years. Bluelineshowsthenonlinearfit.Inset:individual x-axis, theageatbeginningoftreatmentisexpressedin substitution. Ony-axis,thisgrowthgainisexpressedincm. between theadultheightandbeforehormonal this figure,eachindividualpointindicatesthedifference age atbeginningofhormonaltreatmentinCHH/KSpatients.In Individual post-therapeuticstaturalgrowthaccordingtothe Figure 5 Clinical Study , 30 Distinct from prior studies, we accounted for genetic Distinct frompriorstudies, we accountedforgenetic ). OurfindingsofincreasedheightamongCHH/KS . 8 ). TheseinvestigatorsanalyzedAHin P

< https://doi.org/10.1530/ L Maioneandothers 0.0001. Afullcolour 7 , 8 , sex siblings.We revealedthatmaleCHH/KSpatientswere controlled forthisinthepresentstudybyincludingsame- siblings, consistent with this generational effect. We further apositivedeltaheight( observed sexes exceedsmid-parentaltargetheight( even inhealthypopulations,theAHoffspringofboth are progressivelytallerthanpreviousgenerations.Thus, generationaleffectonAHinwhichoffspring observed with CHH/KS.Thisisparticularlyrelevantduetothe siblings asgeneticcontrolstoexamineAHinpatients The presentstudyisthefirsttousehealthy, sex-matched growth potentialcomparedtotheirunaffectedrelatives. Rather, patientswithCHH/KSarelikelytohavehigher height potential–ashasbeenpreviouslysuggested( CHH/KS doesnothaveadeleteriousgeneticeffecton indicate significantly exceededTH.Theseobservations In thepresentstudy, bothmaleandfemalepatientAH component isknowntohaveamajoreffectonAH( sex-matched siblings. This is relevant, as familial genetic explanation forthisfinding isthat,beforediagnosisand earlier haverelativelylower CHH/KS diagnosisand height ( environmental andnutritionalfactorsplayaroleinadult potential play a part. It is widely acknowledged that AH aremultifactorialandcontributorsotherthangenetic unrelated tothediseaseanditstreatment.Growth inaminorityofpatients thusseems stature observed siblings (CHH/KS) tohave negative brothers/sisters weremorelikelythantheiraffected (TH)). However, this wasnotuniquetopatients.Indeed, had anegative with thiscondition. tolowendogenoussexsteroidslevelsassociated secondary and delayedmaturationweldingofgrowthcartilage a generationaleffect,butcouldbeexplainedbytheslow statural growthpotentialinCHH/KSisnotsolelydueto Thus,theincreased increase inheightwasalsoobserved. when compared to their siblings, a modest but significant could be explained by a secular trend ( patients’ adultheightandtheirmid-parentaltarget findings suggestthatpartofthedifferencebetween patients weresignificantlytallerthantheirsiblings.Our thus bypoolingmalesandfemalestogether, CHH/KS sample size.However, byanalyzing patients andtheirsisters,probablybecauseofaninsufficient to detectasignificantdifferencebetweenfemaleCHH/KS significantly tallerthantheirhealthybrothers. We failed Height inCHH/KS We a positive relationship between age at observed It isworthwhiletonotethataminorityofpatients 33 ). ∆ H (AHbelowmid-parentaltargetheight Downloaded fromBioscientifica.com at09/30/202101:41:38PM ∆ H. Patientswhoarediagnosed ∆ https://eje.bioscientifica.com ∆ H) in CHH/KS unaffected H) inCHH/KSunaffected H values.Apossible ∆ 182 ∆ H. The relative low H differences and H differencesand :2 10 10 ). Indeed, we ). Indeed,we ). However ). However 191 32 31 via freeaccess ). ). ). European Journal of Endocrinology https://eje.bioscientifica.com general population,exceed theirmid-parentaltarget women withCHH/KSare, on average,tallerthanthe (normosmic CHHvsKS)or geneticetiology. Menand stature inadulthoodregardless ofsex,clinicalform We demonstratethat CHH/KSdoesnotnegativelyaffect Conclusions maturation inthesepatients. CHH/KS patients( mostly derivedfromadrenalprecursors,arepresent in steroid deficiency. Lowcirculating sexsteroidslevels, had fused( suggeststhat the growthplates height. Suchobservation changein around theageof30yearshadnoobservable patients whowerestartedonsexsteroidtreatment growth canoccur–albeitmuchless.Inthehandfulof replacement treatmentisstartedafterage18years,further however emphasizethatinCHH/KSpatientsevenwhen more growthpotentialthanolderCHHpatients.We must explanation is that younger CHH/KS patients just have was greatest when treatment was initiated earlier. An show thatindividualstaturalgrowthduringtreatment sex steroiddoses.Inthepresentstudy, asexpectedwe regarding thetimingforinitiatingtreatmentandselected specific toeachdiseaseinfluencesclinicaldecision-making at presentation( looking physicallydifferentfrompeersisamajorconcern consultation amongadolescents( stature areamongthemostcommoncausesforendocrine patients. Abnormal growth, disrupted puberty and short the hyalinecartilagecomprisingepiphysealplates. mutations donotalterthedevelopment/maturationof that includedfiveKSpatients( findings areinagreementwiththosefromapriorstudy phenotypes inCHH/KS( on bonedevelopmentandisassociatedwithskeletal did not have impaired AH. This gene has known effects interesting thatpatientsharboringmutationsin increased sexsteroidstypicalduringpuberty. Itisalso hypogonadotropic hypogonadism–i.e.absenceof the increased AH appears to be intrinsic to congenital effect on AH. Thus, cause had any specific observed steroid replacementisinitiated. continue without cartilage epiphyseal fusion untilsex concentrations ofsexsteroids( low prior toanyhormonaltreatment, because ofthevery Clinical Study Clinically, heightisamajorconsiderationfor Neither form (i.e. normosmicCHHvsKS)norgenetic 6 ) despiteasevere(yetnotcomplete( 1 , 34 2 , 4 ) andmaycontributetoslowerbone , 39 1 , ). Importantly, theAHprognosis 2 , 36 34 38 , 37 L Maioneandothers , ) suggestingthat 35 ). However, thepresent ) lineargrowthcould 4 , 39 ). Moreover, 34 FGFR1 FGFR1 )) sex

EJE-19-0537 at paper the of version online the to linked is This Supplementary materials bone masspeakacquisition. or feminization of CHH/KSadolescents, and suboptimal of adetrimentqualitylife,lackmasculinization with alatetreatmentcouldbeobtainedattheexpense the potentialmodestincreaseinadultstatureassociated answer tothishypothesis.Finally, wecannotexcludethat adult stature,butfurtherstudiesareneededtodefinitively hand, latetreatmentcouldproduceatallerthanpredicted make itclosertomid-parentaltargetheight.Ontheother not seemtonegativelyimpactadultstaturebutsolely unaffected brothers. height andmaleCHH/KShavegreateradultstaturethan References Assistance PubliqueHôpitauxdeParis(toPC). French Ministry of Health Grant P081216/IDRCB 2009-A00892-55 (Variété), Clinique, Recherche de Hospitalier Programme Y); J (to 09-GENO-017-01 ANR- Grant Recherche la de la Nationale Agence Y); J (to pour Recherche) Qualite Fondation Y); (Bonus Paris-Sud University J Y); J (to (to FRM-2009 Grant Médicale agency) Recherche antidoping French contre Lutte (the de de Dopage Française Agence le Hôpitaux Y); J de (to Publique Health Hospitalier of Ministry Assistance Programme and Paris, the ‘Hypo-Proteo,’ by Clinique part in Recherche supported was work This Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisstudy. no is there that declare authors The Declaration ofinterest

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Height inCHH/KS 39 38 37 Dwyer AA, Phan-Hug F, Hauschild M,Elowe-Gruau E&Pitteloud N. Hero M, Laitinen EM,Varimo T, Vaaralahti K, Tommiska J &Raivio T. Villanueva C, Jacobson-Dickman E,Xu C,Manouvrier S, org/10.1530/EJE-14-0947) ofEndocrinology European Journal TRANSITION INENDOCRINOLOGY: Hypogonadisminadolescence. org/10.1111/cen.12504) mutations. Childhood growthoffemaleswithKallmannsyndromeandFGFR1 org/10.1038/gim.2014.166) mutations. malformation: aclinicalentitywithhighfrequencyofFGFR1 Congenital hypogonadotropichypogonadismwithsplithand/foot Dwyer AA, Sykiotis GP, Beenken A,Liu Y, Tommiska J, Hu Y 178 next-generation sequencing. R55–R80. Clinical Endocrinology Genetics inMedicine (https://doi.org/10.1530/EJE-17-0749) Downloaded fromBioscientifica.com at09/30/202101:41:38PM European Journal ofEndocrinology European Journal 2015 2015 2015 17 173 82 651–659. 122–126. R15–R24. 182 :2 (https://doi. (https://doi. (https://doi. et al 2018 194 . via freeaccess