European Journal of Endocrinology 10.1530/EJE-16-0526 precocious puberty(PP)isa hallmarkfeatureingirlsand endocrinopathies ( of bone,café-au-laitmacules andhyperfunctioning in aclinicalspectrumthat includesfibrousdysplasia due tosomaticactivatingmutationsin McCune–Albright syndrome (MAS) is a rare disorder arising Introduction effects onskeletalmaturation,growthvelocityandpredicted adultheight. Conclusions events overthetreatmentperiod. with untreatedhistoricalcontrols( treatment reachedadultheight increased significantlyfrom−2.9 and growthvelocity in changeboneageoverchronological(ΔBA/ΔCA)from1.7(IQR:2.3)to0.50.4)( follow-up. Letrozoletreatmentwashighlyeffective atdecreasingtherateofskeletalmaturation,withadecline (range: 0.5–10.9)andmeanfollow-upwas6.0 Results maturation, growthvelocity, predicted adultheightandheight. on 28letrozole-treatedgirls.Adultheightwasreviewedfor42historicalcontrols.Outcomesincludedrateofskeletal Methods Design letrozole treatmentinlargecohortofgirlswithMAS-associatedPP. (PP) duetorecurrentestrogen-secretingovariancysts.Thisstudyevaluatesthelong-termsafetyandefficacy of Objective Abstract *(A EstradaandAMBoycecontributedequallytothiswork) and SportsMedicine,Children’s NationalHealthSystem,Washington, DistrictofColumbia,USA Maryland, USA, National InstituteofDentalandCraniofacialResearch,InstitutesHealth,Bethesda, 1 Rachel I Gafni Andrea Estrada McCune–Albright syndrome for precocious pubertyingirlswith Long-term outcomesofletrozole treatment Section onSkeletalDisordersandMineralHomestasis,CraniofacialDiseasesBranch, DOI: 10.1530/EJE-16-0526 www.eje-online.orgwww.eje-online.org Clinical Study : Retrospectivecohortanalysis. : Twenty-eight girlsreceivedletrozole treatment.Treatment durationwas4.1 : Clinicaldata,includinghistoryandphysicalexamination,boneage,pelvicultrasounds,werereviewed : McCune–Albrightsyndrome(MAS)isararedisorderwithbroadspectrumincludingprecociouspuberty : Inthisstudywiththelongestfollow-uptodate,letrozoletreatmentresultedinsustainedbeneficial 2 Division ofEndocrinologyandDiabetes,

1

and 1 , 2 , 3 1 , MichaelT Collins *, AlisonM Boyce Z , -scores, whichdeclinedfrom2.2 2 , 3 ). Gonadotropin-independent © 2016EuropeanSociety ofEndocrinology © 2016EuropeanSociety ofEndocrinology Z ± and others A Estrada,MBoyce -scores rangingfrom−1.5to1.7(median:−0.6),whichwereincreasedincomparison

3.2 to−0.8 P

= 0.02). Therewasnochangeinuterinesizeorovarianvolumes,andadverse 1 1 , 2 GNAS , Printed inGreatBritain 3 , *, BethA Brillante ± ±

, resulting 1.5 forsubjectsontreatment(

3.3 years(range:0.5–15.0),foratotalof135.9person-years 3 Bone HealthProgram,DivisionofOrthopaedics

±

2.3 to−0.6 bleeding, resultingingrowth accelerationandskeletal exposure, including breast development and vaginal Girls typicallypresentwith episodicsignsofestrogen ovarian cystsleadingtointermittent estrogenproduction. PP istheresultofrecurrent,autonomouslyfunctioning is frequentlythepresentingsymptom( letrozole inMAS Long-term outcomesof 1 Published byBioscientifica Ltd. , LoriC Guthrie ± . ( 1.6 P

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2.6 years(mean

(2016) Endocrinology European Journal of [email protected] Email to AMBoyce should beaddressed Correspondence 175 175 : 5 175

4 ). MAS-associated :5 ± , 477–483 1 P

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–483 via freeaccess European Journal of Endocrinology www.eje-online.org laboratory data and radiology studies were reviewed.laboratory NIDCR InstitutionalReview Board.Clinicaldocuments, assent/consent, andthestudy wasapprovedbythe All subjectsand/ortheir guardiansgaveinformed study (ClinicalTrialshistory Number NCT00001727). seen attheNIHaspartofalong-standingFD/MASnatural This isasingle-center, retrospectiveanalysisofsubjects Study design Subjects andmethods a well-characterizedcohortofsubjectswithMAS. the long-termsafetyand efficacy ofletrozoletreatment in literature andpotentialsafetyconcerns( been limitedbysmallsubjectnumbersreported in the overall promising,theroutineuseofletrozoleinMAShas is unclear. Althoughfindingsfromthispilotstudywere relationship between letrozole treatment and this event other conditionswithovarianenlargement( However, giventheestablishedriskoftorsioninMASand about apotentialtreatment-relatedadverseevent. ovarian torsionwhileonletrozole,whichraisedconcerns subject withunrecognizedcomorbidcentralPPdeveloped growth velocityandvaginalbleedingepisodes( effects, includingreductionsinskeletalmaturation, third-generation AIletrozoledemonstratedbeneficial efficacy ( generation AIanastrozoledemonstratedasimilarlackof ( beneficial effectsonskeletalgrowthormaturation testolactone andfadrozoledemonstratednosustained Early reportsofthefirst-andsecond-generationAIs studies inmostformulationshavebeendisappointing. and mitigateitseffectsonskeletalmaturation;however, advocated asapotentialtherapytodecreaseserumestradiol been established.Aromataseinhibitors(AIs)have development. Thepreferredmethodoftreatmenthasnot mitigate psychosocialconsequencesofearlysexual prevent disablingshortstatureinadulthoodandto height ( skeletal advancement,centralPPandcompromisedadult more oftenprogressive,andifuntreatedcanleadto experience amildcoursewithfewcysts,thediseaseis these findingsaretypicallyabsent.Althoughsomemay cysts on pelvic ultrasound; however, between episodes, estradiol levels,suppressedgonadotropinsandovarian maturation. Clinicalevaluationmayshowelevated 6 , Clinical Study 7 The purposeofthisstudyistoretrospectivelyevaluate Treatment goalsinMAS-associatedPPareto , 8 ). Findings from a more recent study on the third- 5 9 ). ). Incontrast,asmallpilotstudyofthepotent and others A Estrada,MBoyce 13 ). 11 , 10 12 ). One ), the

Height andskeletalmaturation on thenormalityofdistribution. median (interquartilerange), as appropriatedepending Data arepresentedasmean using GraphPad Prism6 for Windows, version 6.02. analyses wereperformedandfiguresprepared signed-rank testsandMann–Whitneytests.Statistical evaluated usingpaired Pre- andon-treatmentsafetyefficacymeasureswere and heightmeasurementswereobtainedforreview. studiesbone ages, pelvic ultrasounds,laboratory and clinicaldatafromtheseevaluations,including the discretion of the patients’ local endocrinologists, and betweenNIHvisits,clinicalcarewasprovidedat bone ageandtransabdominalpelvicultrasound.Before andphysicalexamination,biochemicaltesting,history serialclinicalevaluationincludingSubjects underwent uterine volumeswerecalculated usingtheformula for thoseremainingon treatment.Ovarianand completed treatment and the most recent ultrasound just beforeletrozolediscontinuation forsubjectswho data. On-treatmentstudies weredefinedbyultrasound before letrozoleinitiationwasusedasthebaseline at eachNIHevaluation.Thepelvicultrasoundjust Transabdominal pelvic ultrasounds were performed Pelvic ultrasound treatment. and themostrecentboneageforthoseremainingon discontinuation forsubjectswhocompletedtreatment as theevaluationofboneageattimeletrozole data ( Z rates andgrowthvelocities.Heightvelocity used todeterminepre-treatmentskeletalmaturation pre-letrozole boneageandheightmeasurementswere initiation wasusedasthebaselinedata.Whenavailable, heights. Theboneageobtainedjustbeforeletrozole height (MPH)wascalculatedusingreportedparental to theBayley–Pinneaumethod( predicted adult height (PAH) was calculated according For subjectswithaskeletalageof7yearsorgreater, determined usingtheGreulichandPylemethod( average ofthreeserialmorningvalues.Boneageswere obtained usingastadiometeranddeterminedasthe Height measurementsattheNIHClinicalCenterwere letrozole inMAS Long-term outcomesof -scores weredeterminedfromnormativereference 16 , 17 , 18 ). On-treatmentstudiesweredefined t Downloaded fromBioscientifica.com at09/25/202101:25:24PM -tests, Wilcoxon matchedpairs ±

15 standard deviation,or ). Mid-parentaltarget 175 :5 478 14 via freeaccess ). ).

European Journal of Endocrinology ‡ HT, hyperthyroidism;PW, phosphatewasting;CS,Cushing’s syndrome. PP, precociouspuberty;CA,chronologicage;BA,boneB,breast; PH,pubichair;FD,fibrousdysplasia;GH,growthhormoneexcess; 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Subject Table 1 by Feuillan This groupincludedtheninechildrenoriginallyreported minimum of6monthsandwereincludedintheanalysis. Twenty-eight girlsreceivedletrozoletreatmentfora Clinical characteristicsatbaseline Results ultrasonography data( for statisticalpurposesbasedonnormativepediatric standard pre-pubertalvolumeof0.7 due to small size,orabsent due tosurgical resection, a and leftovarianvolume.Ifovariescouldnotbevisualized ovarian volumes were calculated as the mean of the right ( volume =length×widththickness0.52 28 27 26 25 24 Treatment discontinuedbeforeletrozole. *Treatment givenconcomitantlywithletrozole. Clinical Study Baseline clinicalandtreatmentcharacteristics. symptoms Age atPP t al et 4.8 2.0 0.5 2.9 2.0 3.7 3.1 1.8 0.9 2 3.1 1.7 4 0.3 0.2 1.3 4.2 2 3.5 2.8 2.5 4.5 2 0.1 1.5 0.8 2.2 2.3 . ( (y) 10 19 ), inadditiontosubsequently Age atletrozole ). start 4.3 2.2 3.4 4.8 6.1 4.6 4.7 2 3.3 4.9 5.8 3.8 6 8.3 2.4 5.9 4 4.8 6 2 4.3 5.4 7.9 3.9 1.5 3.3 6.7 4.8 and others A Estrada,MBoyce (y) mL wasassigned BA/CA 1.2 1.5 2.7 1.9 1.7 1.5 1.7 1.6 1.5 2.1 1.5 1.5 1.8 2.5 2.3 1.4 1.4 2.0 1.2 1.4 1 1.4 2.0 2 1 1.5 1.4 1.2 19 ). Mean Tanner stage

(B/PH) 3/3 2/1 3/1 3/3 3/2 3/1 2/3 4/4 4/1 2/1 2/1 2/1 2/1 4/2 4/3 3/2 2/1 3/1 4/3 2/3 4/1 2/2 4/3 2/2 4/1 2/1 – – published guidelines( for additionalendocrinopathiesaccordingtopreviously development in7subjects.Allsubjectsreceivedtreatment evaluation wasvaginalbleedingin21subjectsandbreast PP at 2.2 Z and acceleratedlineargrowth(meanvelocity advanced skeletalmaturation(meanBA/CA1.6 subjects are summarized in mutations in a doubtaboutthediagnosis,mutationtestingfortypical according topreviouslypublishedcriteria( grounds (twoormoreoftheclassicfeaturesMAS) of patientswerediagnosed with MASbasedonclinical collected follow-updatainthesesubjects.Themajority letrozole inMAS Long-term outcomesof

-score 2.2 Letrozole dose Baseline individualclinicalcharacteristicsofthe28 (mg/day) 2.5 2.5 1 2.5 2.5 2.5 2.5 1.25 2.5 1.25 2.5 1 1 2.5 1.5 2.5 1 1.5 1.9 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 ±

1.3 years (0.1–4.5). The symptom prompting ±

2.3). Subjectsinitiallydevelopedsignsof GNAS FD, GH,HT, PW, FD, HT, CS FD FD FD FD, GH FD FD – – FD FD, HT FD FD, GH,HT, CS FD, PW FD FD, HT FD FD, PW FD FD FD, HT Other endocrine FD, GH,HT, CS FD, HT FD, HT FD, HT FD FD, HT, PW wasperformed. CS 3 ). Downloaded fromBioscientifica.com at09/25/202101:25:24PM Table 1 . Subjects had overall Leuprolide* Testolactone Anastrozole Leuprolide* – – – – – Leuprolide* – – – – Leuprolide* Tamoxifen* Anastrozole Cyproterone – – Anastrozole – – – – Leuprolide* Medroxyprogesterone Other PPtreatment Tamoxifen – Leuprolide Tamoxifen – – 175 www.eje-online.org :5 3

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± 479 0.4) via freeaccess ‡ European Journal of Endocrinology discontinuation. on-treatment observationperiod afterletrozole letrozole treatmentandwhite barsrepresentingthe treatment, blackbarsrepresenting thelengthoftimeon the lengthofobservationbefore initiatingletrozole bars indicateindividualsubjects,withgrayrepresenting Duration ofobservationandtreatmentperiods.Horizontal Figure 1 www.eje-online.org completed letrozoletherapyatthetimeofanalysis, person-years of follow-up ( was 6.0 0.5–10.9), andmeanfollow-upafterletrozoleinitiation The meandurationoftreatmentwas4.1 dosing parametersforeachsubjectareincludedin administering asingle2.5 of letrozoleinchildren,clinicalpracticeshiftedto in thepilotstudydemonstratingincreased metabolism with pubertal progression ( with theoptiontoincrease2 included atargetof1.5 dosed according to the parameters of that study, which subjects. Ninesubjectsfromtheinitialletrozolepilotwere (range 1.5–8.3).Letrozoledosingwasvariablebetween The meanageatletrozole initiation was4.6 Letrozole initiationandtreatment duration acceleration afterinitiatingletrozole. therapy forsubject9duetopersistentlineargrowth letrozole initiation. Tamoxifen was added as adjuvant These therapieswerediscontinuedatorshortlyafter continued toprogressinskeletaladvancement( for PPbeforestartingletrozole,duringwhichtheyhad Clinical Study Subjects 6, 9 and 21 had received previous treatment ±

3.3 years(range0.5–15.0),foratotalof135.9 mg/m 10 mg doseoncedaily. Individual Fig. 1 ). Based in part on the finding 2 /day intwodivideddoses, ). Of the 11 subjects who and others A Estrada,MBoyce mg/m ± 2 /day insubjects

2.6 years(range ± . years 1.7 Table 1 Table 1

). . one standarddeviationinpanel B. median andinterquartilerange inpanelAandthemean course ofthetreatmentperiod. Errorbarsrepresentthe ΔCA) (panelA)andgrowthvelocity of changeinboneageto inchronologicage(ΔBA/ growth velocity. Therewasasignificantdecreaseintheratio Effects ofletrozoleontherateskeletalmaturationand Figure 2 velocity 0.5 (IQR0.4)ontreatment( letrozole, fromapre-treatmentmedianof1.7(IQR2.3)to was asignificantdecreaseinΔBA/ΔCAafterinitiating period was 1.3 pre-treatment observation on-treatment ΔBA/ΔCAfor24subjects.Themean bone ageswereavailabletodeterminepre-and Pre-treatment, baselinestartoftherapyandon-treatment age over change in chronological age (ΔBA/ΔCA). Skeletal advancementwasdefinedaschangeinbone Skeletal advancementandgrowth velocity to allowpubertyprogress. pilot study( developing ovariantorsionasdescribedintheprevious (range 7.0–12.3).Subject14discontinuedletrozoleafter the meanageatdiscontinuationwas10.5 mid-parental height (MPH) baseline to−0.8 increase overthetreatmentperiodfrom−2.9 previously describedmethods( and on-treatmentskeletalages PAH PAH andadult height excluded fromtheanalysis( additional MAS-associatedendocrinopathieswere ( baseline of2.2 letrozole inMAS Long-term outcomesof i. 2B Fig. There wasasignificantdecreaseinmeangrowth Z -scores weredeterminedfor18subjectswithpre- ). This effect was preserved whensubjectswith ). Thiseffectwaspreserved Z -score afterletrozoletreatment,fromameanat 10 ± ), andtheremainderdiscontinuedtherapy

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European Journal of Endocrinology or ovarianvolumesoverthe treatmentperiod( for 26subjects.Therewasno changeinmedianuterine Pre- andon-treatmentpelvic ultrasoundswereavailable Uterine andovarianvolumes statistical significance( (−3.5 from MPH)comparedwiththehistoricalcontrolgroup height ( with that in the historical control group (−3.0 the fourletrozole-treatedsubjects(−0.1 The meanadultheight control groupwithuntreatedorinadequatelytreatedPP. compared withadult heights ofsubjects from thehistorical group (0.3 (−3.5 height PP and4subjectswithoutPP. SubjectswithPPhadadult ( group vs0.5 without PP(adultheight the womenwithPPwere significantly shorter thanthose and/or testolactone.Within thehistorical controlgroup, ineffective, includingprogestin,leuprolidemonotherapy or treatedwiththerapiessubsequentlydeterminedtobe ofPPthatwaseither untreated 42 (70%)hadahistory study. Twenty ofPPand women(30%)hadnohistory group of62womenwithMASinthenaturalhistory respectively). −5.4 cm shorter thanPAH attreatmentcompletion(−1.1,−6.4and and adultheight.Inallthreesubjects,heightwas for comparisonbetweenPAH attreatment completion performed justbeforeletrozolediscontinuation,allowing above MPH). Subjects 1, 6 and 22 had BA examinations adult height of 1.1(0.6 reached anadultheight with MPH MPH). Subject3reachedanadultheight Z reached adult height. Subject 1 reached an adult height treatment ( increased from−3.1 treatment period,thedifferencebetweenPAH andMPH the groupofsubjectswithavailablePAH data.Overthe P P -score of−0.8withMPH Clinical Study

= <

0.04). Subjectstreatedwithletrozolehadadult 0.0001). MPHdatawereavailablefor14subjectswith Adult heights of subjects treated with letrozole were Adult heightdatawereanalyzedinahistoricalcontrol Four subjectswho completed letrozoletherapy ± ± 3.1 3.1 Z Z -scores thatweresignificantlylowerthanMPH -scores thatwereclosertoMPH(−0.7 ± s Z P s . 0.5 . =0.003). d -score of0.9(2.4 d s Z . . ± . fromMPH);however, thisdidnotreach fromMPH)comparedwiththenon-PP d -score 1.7withMPH

1.2 forthenon-PPgrouprespectively) . s belowMPH).Subject22reachedan . d . fromMPH)( ±

3.1 atbaselineto−1.1 P Z =0.1). -score wassignificantly higherin Z Z Z -score 0.5withMPH -score of−0.3(0.5 -scores −3.0 s . d P and others A Estrada,MBoyce . belowMPH).Subject6 =0.001). Z -score of0.7(1 ± ±

Z .) compared 1.4) 2.7 forthePP -score of−1.5 ± s . . after 1.8 ± d 1.4 . i. 3 Fig. Z below -score ±

2.7) s s . . d d ). . .

Pre- and on-treatment uterine volumes were 5.4 (IQR 5.6) and 3.3 during thetreatmentperiod (II–IVandI–IVrespectively, letrozole-treated group 0.2 and 0.5 bleeding episodes per year (median for the no bleedingepisodesand5subjects experiencingbetween significantly onletrozole,with14subjectsexperiencing episodes peryear(IQR4.6)(range0–10).Thisdeclined vaginal bleedingoccurredatamedianfrequencyofthree were availablefor19subjects.Beforeletrozoletreatment, Pre- and on-treatment vaginal bleeding frequency data Clinical characteristicsatfollow-up were unchanged( to 17 treatment levels ranged from undetectable (14 subjects) subjects, drawn concomitantly with estradiol levels. Pre- on-treatment testosteronelevelswereavailablefor19 to 39 were reduced, ranging from undetectable (16 subjects) 1523 were variablerangingfromundetectable(9subjects)to of estradiolproductioninMAS,pre-treatmentvalues for 24subjects.Asexpected,giventheepisodicnature Pre- andon-treatmentestradiollevelswereavailable Hormone levels 1.5 cm on-treatment ovarianvolumeswere2.0 standard deviation.cm treatment period.Errorbarsrepresentthemeanandone change inmeanvolumesforeitherparameterduringthe transabdominal pelvicultrasound.Therewasnosignificant and meanovarianvolumes(panelB)asdeterminedby treatment. Pre-andon-treatmentuterinevolumes(panelA) Uterine andmeanovarianvolumesbeforeafterletrozole Figure 3 letrozole inMAS Long-term outcomesof Pubertal stagesofbreastsand pubichairstabilized pg/mL (median 30.4, IQR 139). On-treatment levels ng/dL (median 0.0, IQR 10), and on-treatment levels pg/mL (median 0.0, IQR 20.2) ( 3 (IQR4.6)( P P =ns). cm .) respectively. =0.8) 3 etmtr cubed. =centimeters 3 (IQR 2.5) ( = Downloaded fromBioscientifica.com at09/25/202101:25:24PM 0.0, IQR0.2)( P

175 = P P 0.2) and pre- and .0) Pe and Pre- =0.006). cm

www.eje-online.org < :5 0.0001). 3 (IQR3.7)and 481 cm via freeaccess 3

European Journal of Endocrinology www.eje-online.org originally developedforthetreatment ofbreastcancer( anti-estrogen treatmentisanother approach,whichwas of thedisease,smallnumbers ofsubjects.SimilartoAIs, pathophysiology, safetyconcerns,and,owingtotherarity challenges, includingevolving understandingofdisease MAS-associated PPhasbeenlimitedbymultiple adult height,furthersupportingtheefficacyofthistherapy. treatment resulted in a statisticallysignificantincreasein rare disorder. Despitethesmallsubjectnumbers, letrozole opportunity to evaluate adult heightoutcomes in this historical controlswithandwithoutPPprovidesaunique growth achievednormaladultheights.Theavailability of treated withletrozoleandsubsequentlycompletedskeletal a significant novel contribution. Four subjectswhowere ingirlswithMAS,representing height foranyintervention disorders suchasMAS.Thisstudyisthefirsttoreportadult follow-up andisonlyrarelyreported,particularlyinrare PP is adultheight, which requiresanextended length of increased riskofovariantorsion. treatment islikelysafe,andunlikelytobeassociatedwith These findingsprovidesupportiveevidencethatletrozole cases oftorsionduringthetreatmentorfollow-upperiod. increase inuterineorovarianvolumes,andnoadditional treatment waswell-toleratedwithnoadverseevents, is aneffectivetreatmentforMAS-associatedPP. Letrozole other AIformulations,thethird-generationletrozole findings demonstrate that unlike previous studies in velocity, andPAH ingirlswithMAS-associatedPP. These had beneficialeffectsonskeletalmaturation,growth In thisretrospectivecohortstudy, letrozoletreatment Discussion no suspectedtreatment-relatedadverseevents. discontinued letrozoletoallowpubertycommence. with theexceptionofsubject7whoatage12.3years with gonadotropin-releasinghormoneanalogtherapy, respectively. Subjectswithcentralpubertyweretreated 8.9 and boneageforentranceintocentralpubertywere puberty whileonletrozole.Themeanchronologicage subjects 1,9,14,20and22subsequentlyenteredcentral peripheral PP. No subjects were in central PP at baseline; development inchildrenwithtreatedanduntreated Subjects weremonitoredforcentralPP, whichisatypical before treatmentversusI–IVandI–Vaftertreatment). Clinical Study ± Determining the preferred treatment for The ultimate outcome of interest in the treatment of There werenoadditionalcasesofovariantorsionand

1.9 years(7.0–12.3)and11.5 and others A Estrada,MBoyce ±

1.1 years(10.0–13.0)

20 )

MAS-associated PPandwaswelltoleratedwithnoadverse was evaluated in a recent prospective trial of girls with Fulvestrant is a pure estrogen receptor antagonist that that tamoxifenshouldbeusedwithcautioninMAS. term therapyingirlswithPP, itistheauthors’opinion potential malignancyrisks,andthelikelyneedforlong- transformation inaffectedtissues( place patients with MAS at higher risk of malignant that activating and cancer( of endometriallesions,includinghyperplasia,polyps treatment has been associated with an increased risk tamoxifen onendometrialstroma.Inadults, volumes, which is consistentwiththeagonistic effect of efficacy, however, ofconcernwasanincreaseinuterine tamoxifen ( MAS involvedtheuseofestrogenreceptormodulator The firstprospectivetrialofanti-estrogentreatmentfor and wassubsequentlyadaptedforthetreatmentofMAS. needed toconfirmtheeffect ofletrozoleonadultheight. completed treatmentandreached skeletalmaturityare Future studieswithadditional patientswhohave additional endocrinopathies wereanalyzedseparately. whensubjectswithout effects ofletrozolewerepreserved carefully assessed and managed medically. The beneficial this study, allpotentialcomorbidendocrinopathies were syndrome, whichmayleadtogrowthdeceleration.In well asFGF23-mediatedhypophosphatemiaandCushing’s growth hormoneexcess,whichmayaccelerategrowth, as other endocrinopathies,specificallyhyperthyroidismand confounders. Theseincludeskeletaldeformitiesand in MASarecomplexandmaybeimpactedbymultiple elements such as bleeding frequency. Growth outcomes periods andinconsistentcollectionofcertaindata letrozole dosing,durationofthepre-andon-treatment prospective study. Asaresult,therewasheterogeneityin extensionofapreviouslypublished3-year observational primarily duetotheretrospectivedesign.Thiswasa9-year for anytreatmentMAS-associatedPP. Limitationsarise follow-up. Thisreportrepresentsthelongestfollow-up detailed clinicalphenotypingandextensivelengthof large number of subjects given the disease rarity, effects ontheuterus. demonstrates long-termefficacywithoutstimulatory the onlyavailabletreatmentforMAS-associatedPPthat efficacy offulvestrantmonotherapy. Letrozoleistherefore on growthvelocityorPAH, callingintoquestionthe was adecreaseinskeletalmaturation,therenoeffect events orchanges in uterinesize( letrozole inMAS Long-term outcomesof Strengths ofthisinvestigationincludetheuniquely 21 22 ). Thisstudyfoundpromisingshort-term GNAS ). Thisisparticularlyconcerninggiven mutationsareoncogenicandmay Downloaded fromBioscientifica.com at09/25/202101:25:24PM 23 24 175 ). Inlightofthese ). Althoughthere :5 482 via freeaccess European Journal of Endocrinology References Medicine, Children’s NationalHealthSystem. DHHS, andtheBoneHealthProgram,DivisionofOrthopaedicsSports of theNIDCR,NICHD,IntramuralResearchProgramNIH, This researchwassupportedinpartbytheDivisionofIntramuralResearch Funding perceived asprejudicingtheimpartialityofresearchreported. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest 9 8 7 6 5 4 3 2 1 Clinical Study jc.2007-2090) Endocrinology andMetabolism puberty ingirlswithMcCune-Albrightsyndrome. inhibitor anastrozoleisineffectiveinthetreatmentofprecocious Metabolism McCune-Albright syndrome. efficacy offadrozoleintreatingprecociouspubertygirlswiththe (doi:10.1210/jc.77.3.647) ofClinicalEndocrinologyandMetabolism Journal for precociouspubertyingirlswiththeMcCune-Albrightsyndrome. 1986 aromatase inhibitortestolactone. of precociouspubertyintheMcCune-Albrightsyndromewith Dwyer A, Malley JD,Barnes K,Loriaux DL&CutlerGBJr. Treatment (doi:10.2165/00024677-200403030-00002) and experiencetodate. 7-S1-S4) of Rare Diseases the extraskeletalmanifestationsoffibrousdysplasia. Seattle, WA, USA:UniversityofWashington, 1993. A Amemiya,LJHBean,TDBird,CRDolan,CTFong,RJHSmith In 325 McCune-Albright syndrome. Gproteininthe Spiegel AM. Activatingmutationsofthestimulatory (doi:10.1056/NEJM193704292161701) report of5cases. and endocrinedysfunction,withprecociouspubertyinfemales: characterized byosteitisfibrosadisseminata,areas,ofpigmentation, Mieszczak J, Lowe ES,Plourde P&Eugster EA.Thearomatase Nunez SB, Calis K,CutlerGBJr, Jones J&Feuillan PP. Lackof Feuillan PP, Jones J&CutlerGBJr. Long-termtestolactonetherapy Feuillan PP, Foster CM,Pescovitz OH,Hench KD,Shawker T, Eugster EA. Aromataseinhibitorsinprecociouspuberty:rationale Collins MT, Singer FR&Eugster E.McCune-Albrightsyndromeand Boyce AM &Collins MT. Weinstein LS, Shenker A,Gejman PV, Merino MJ,Friedman E& Albright F, Butler AM,Hampton AO&Smith P. Syndrome GeneReviews(R). 1688–1695. 315 1115–1119. 2003 2012 (doi:10.1056/nejm199112123252403) 88 New England Journal ofMedicine New EnglandJournal EdsRAPagon,MPAdam,HHArdinger, SEWallace, 5730–5733. 24 (doi:10.1056/NEJM198610303151802) (Supplement1)S4. 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