181

European Journal of Endocrinology -19-0177 5 Sorbonne ParisCité,Paris,France, Histiocytoses, HôpitalSaint-Louis,EquipedeRechercheenBiostatistiquesetEpidémiologieClinique,U1153CRESS,UnivParisDiderot, Foix, SorbonneUniversité,FacultédeMédecine,Paris,France, Ouagadougou, BurkinaFaso, 1 Fleur Cohen Yempabou Sagna Langerhans cellhistiocytosis adulthood andchildhoodonsetpatientswith Endocrine manifestationsinacohortof63 be evaluatedcarefullyatdiagnosisandduringfollow-up. APDwasnotalwaysassociatedwithDI. Conclusion: moreover, occurrenceofnewdeficiencieshasbeendescribed duringfollow-up. systematically associatedwithDIregardlessoftheage onset.Endocrinedysfunctionwasmostoftenpermanent; deficiency in30.4%andthyrotropin16%.APDwasmorecommonCOpatients( (23.7%). Inthesubgroupof25incompletelyevaluatedpatients,wefoundDIin44%,GHD50%,gonadotropin diabetes insipidus(DI)andGHD(55.3%each),followedbygonadotropindeficiency(34.2%)thyrotropin dysfunction (APD)wasfoundin63.2%ofthem.Inthissubgrouppatients,themostprevalentdeficiencieswere Results: underwent follow-upassessments. evaluations performedin63consecutivepatientswithLCH(AOpatients:40,COpatients:23).Fifty-eight Method: University Hospital(Paris,France),atertiarycarehospital. Design: with LCH. describe endocrinemanifestationsinalargecohortofadulthoodonset(AO)andchildhood(CO)patients tissue. Endocrineinvolvementhasmostlybeendescribedincasereportsandsmallretrospectivestudies.Weaimed to Objective: Abstract Paris, France Médecine Interne,HôpitalUniversitairePitiéSalpêtrière–CharlesFoix,SorbonneUniversité,FacultédeMédecine, Universitaires LaPitiéSalpêtrière–CharlesFoix,ServicedeNeurologie2-Mazarin,Paris,France,and Sorbonne Université,Inserm,CNRS,UMRS1127,InstitutduCerveauetdelaMoelleépinière,ICM,AP-HP,Hôpitaux Service deMédecineInterne,CHUYalgadoOuedraogo,UFRScienceslaSanté, UniversitéOuagaIPrJosephKiZerbo, https://doi.org/ https://eje.bioscientifica.com Clinical Study Single-centerobservationalstudyconductedbetweenJanuary2002andDecember2017atPitié-Salpêtrière Completepituitaryevaluationwasperformedin38/63patients(60.3%);atleastoneanterior Clinical,biologicalandmorphologicalevaluationsofpituitary,gonadal,adrenalthyroidfunction Langerhanscellhistiocytosis(LCH)isarareinflammatorymyeloidneoplasmwhichcaninfiltrateanyorganor Thespectrumofendocrinedisordersappearstobelarge inLCH(bothAOandCOpatients)should 10.1530/EJE 6 , Zahir Amoura 1 -19-0177 , 2 , Carine Courtillot 2 Service d’EndocrinologieetMédecinedelaReproduction, HôpitalUniversitaire Pitié Salpêtrière–Charles 3 4 Service d’Hémato-OncologiePédiatrique,Hôpital Trousseau,Paris,France, © 6 , JulienHaroche 2019EuropeanSociety ofEndocrinology Y Sagnaandothers 2 , Joseph Y Drabo Printed inGreatBritain 6 and 3 Service dePneumologie, CentreNationaldeRéférencedes Philippe Touraine 1 , Abdellatif Tazi Endocrine manifestationsinLCH Published byBioscientifica Ltd. 2 3 , Jean Donadieu 6 Service de Downloaded fromBioscientifica.com at09/29/202112:24:44PM 4 , Ahmed Idbaih P (2019) Endocrinology European Journalof [email protected] Email to PTouraine should be addressed Correspondence = 0.003) butwasnot 181 181 :3 , 275–285 ,

275 5 ,

–285 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com followed byadrenocorticotropin (ACTH)deficiency, hormonedeficiency,the mostcommonanterior pituitary associated withDI.Growth hormone(GH)deficiencyis in upto20% of patientswithLCH and isalmostalways dysfunction isfound of AOpatients.Anteriorpituitary symptom of LCH in about 15–25% of CO and 12–30% to diabetesinsipidus(DI)isthemainknownendocrine ( done whentherewasasuspectedendocrineabnormality endocrine manifestation, though evaluations were only had1478patients,ofwhom223 (15%)hadan registry ( in a few case reports and in small retrospective AO series patients withhigh-riskdisease( with vinblastine and prednisone, plus mercaptopurine for oftherapy standard ofcare,basedonLCHIII,is1 year of thediseaseandseverityatonset. The current with orwithoutinvolvementofriskorgans)( (MS-LCH: twoormoreorganssystemsareinvolved, system,lungsinadults)andmultisystemdisease nervous skin, lymphnodes,thehypothalamic–pituitary/central organ orsystemisinvolved,suchasonemorebones, lung LCHorsinglesystem(SS-LCH:onlyone the lungsaremostcommonlyaffected( gland(2–4%).Inadultpatients, excluding thepituitary system each), lymphnodes(5–10%)andcentralnervous liver, spleen,hematopoieticsystemandlungs(15% gland(25%), bones (80%ofcases),skin(33%),pituitary but thosemostcommonlyinvolvedinchildrenare Any organ or system of the human body can be affected, progressive diseasethatrequiressystemicchemotherapy. self-limiting lesionsthatresolvespontaneouslytorapidly is nowincreasinglyrecognizedinAOcases. that ismoreneoplasticthanreactive( have beenidentified,indicatingthatLCHisadisorder component alongwithafrequentBRAFV600Emutation pathogenesis isstillnotpreciselydefined;aclonal that arerequiredfordefinitivediagnosis( Langerin (CD207)-positivecellsonimmunostaining histiocytic disorder, characterizedbyCD1aand/or organ ortissueofthebody( myeloidneoplasmthatcaninfiltrateanyinflammatory Langerhans cellhistiocytosis(LCH)isarare Introduction 11 9 , Clinical Study ). Infiltration of the hypothalamo-pituitary axis leading ). Infiltrationofthehypothalamo-pituitary 10 Endocrine manifestationshavebeendescribedinLCH Treatment dependingontheextent optionsvary The currentclassificationdifferentiatesbetween from clinically The clinical presentations of LCH vary Initially describedinchildhoodonset(CO)disease,it ). In 2016, the French national CO LCH patients 1 ). Itisthemostcommon 8 ). Y Sagnaandothers 3 4 ). , 5 , 6 7 ). ). 2 , 3 ). Its AO andCOLCHinourcohort. single-center studyevaluatingtheendocrinefeaturesof describe theirevolutionduringfollow-up. the prevalenceofendocrinemanifestationsinLCHandto referred toourdepartment.Ouraimsweredetermine LCH with or without known endocrine dysfunction (ED) evaluations onallconsecutivepatientsdiagnosedwith cohort study. We thusdecidedtoperformhormonal endocrine manifestationshasbeenconductedinalarge treatment withglucocorticoidsinparticular. hormonedeficienciesand cytokines, anteriorpituitary are severalpredisposingfactors,suchasinflammatory of bonemetabolismdisordersinAOdisease,butthere hyperprolactinemia ( thyroid-stimulating hormone(TSH)deficiencyand with incompleteendocrineevaluation. endocrine evaluationandthe otheroneincludingpatients in twosubgroups,onewith patientswithcomplete done inthesedepartments. We distinguishedourpatients collected retrospectivelyandweonlyreportedevaluations had endocrinereevaluationsduringfollow-up.Datawere endocrinology andreproductivemedicinedepartments Patients intheinternalmedicineand/orneurology medicine departmentorintheofneurology. anendocrineevaluationin theinternal possible underwent and reproductivemedicine.Thoseinwhomthiswasnot consecutive patientsinthedepartmentofendocrinology cut-off ageof18 years. AO wasmadeusingtheageoffirstsignsLCH,witha already someknownED.ThedistinctionbetweenCOand received as part of transition to adult health care and had include onlyLCH( lesions, weexcludedtheothertypesofhistiocytosisto disorder. Then,basedonhistologicalproofand/ortypical neurology. of endocrinologyorthoseinternalmedicineand Patients could have been managed in the department Salpêtrière-Charles FoixUniversityHospital(Paris,France). patients (COandAO)diagnosedwithLCHatLaPitié- 2002toDecember2017andincludedall from January study conducted This was a single-center observational Patients andmethods Endocrine manifestations in LCH epeet1 yearsofexperience fromthisfirst We present15 To date,nocomprehensiveinvestigationofthe There seemstobenoinformationabouttheprevalence An endocrine evaluation was proposed for all An endocrineevaluationwasproposedforall We firstlistedallpatientsfollowedforhistiocytosis i. 1 Fig. 9 ). Downloaded fromBioscientifica.com at09/29/202112:24:44PM ). MostCOLCHpatientswere 181 :3 276 via freeaccess

European Journal of Endocrinology – – and peripheralglandfunctionasfollows: breast andgenitalexamination. of waterintakeanddiuresis,thyroidexamination assessment. signs, endocrineinvolvementknownbeforethe LCH andageatfirstclinicalsigns,endocrine Data werecollectedfromhospitalpatientmedicalrecords. Data collection insipidus; LCH,Langerhanscellhistiocytosis. in thestudy.APD,anteriorpituitarydeficiency;DI,diabetes Flow charttoindicatehowsubjectswereselectedforinclusion Figure 1

Childhood onsetLCH With comp With comp Clinical Study (E2), in women and total testosterone in men. based onFSHandLHin allpatients,estradiol Gonadotropin and gonadal functions were evaluated test ( desmopressin treatmentfollowingawaterdeprivation had apolyuria–polydipsiasyndromeresponding to already beingtreatedwithdesmopressinorifthey Patients were considered to have DI if they were Hormonal assays were performed to explore pituitary Hormonal assayswereperformedtoexplorepituitary Clinical examinationdataincluded,24-hevaluation The followingdatawererecorded:ageatdiagnosisof Dead 12 le le : Paent ). te te 0 DI APDtesn LCH and te s wi s assessment LCH with : ng 23 th hisocytos LC mixed : g: H: 23 1 8 endocrine 6 0 fo : rm 63 is s: : 109 assessmen Without endocrine 18

Mixed 0 Y Sagnaandothers Adulthood onset With compl With compl fo rm t: s: 1 2 7 Non LC 9 ete DI ete APDtesn

LC H: t es H: 7 n 1 4 g: 0 g: 4 0 2 2

– – – – performed: pituitary magneticresonanceimaging performed: pituitary concentrations. serum phosphorus,PTH1–84 and25-hydroxyvitaminD Bone metabolism was assessed based on the serum calcium, Endocrine manifestations in LCH

(PRL) concentration.Hyperprolactinemiawasdefined Lactotropin functionwasevaluatedbasedonprolactin mildly elevatedTSH( reference rangeinconjunctionwithalow, normalor characterized by an FT4 levelbelow the laboratory antibody concentrations.Centralhypothyroidismwas thyroid peroxidase(ATPO) andantithyroglobulin (ATG) evaluated basedontheTSH,freeT4,T3andanti- Thyrotropin functionandthyroidwere gonadotropin dysfunction( serum FSHandLHwassufficientforadiagnosisof In postmenopausalwomen,theabsenceofhigh addition tolowestrogensandgonadotropinlevels. exclusion of other causesof menstrual irregularity) in by thepresenceofoligomenorrhea/amenorrhea (after the diagnosis of central hypogonadism was defined of increasedgonadotropins.Inpremenopausalfemales presence of lowtestosterone levels withtheabsence Central hypogonadism was defined inmen bythe 4 and 7 period) definedcompleteGHDandapeakbetween peak concentrationbelow4 concentration between3and5 of (severe GHDwasdefinedasapeakGHconcentration peak GHconcentration 18 an ITT, when possible.Accordingtoguidelines( the IGF-IandGHconcentrationsunderstimulationby Somatotropin functionwasevaluatedbasedonlyon with elevatedACTH( the samethresholdsforcortisolasthoseassociated Adrenal glucocorticoid insufficiency was defined by cortisol,associatedwithnormalorlowACTH. salivary < tolerance test(ITT)or0.25 cortisol levelof Corticotropin insufficiencywasdefinedbyaplasma men ( when PRLwas reference concentrations( concentrations wasevaluatedusingnormalage-related confirm diagnosiswhenGHDwasisolated.TheIGF-I A secondGHstimulationtestwasnotperformedto The followingradiological examinationswere 18 , < 19 3 μ g/dL forplasmacortisoland µg/L, andpartialGHDwasdefinedasapeakGH 14 ), GHdeficiency(GHD)wasdefinedinadultsbya ). µg/L indicated partial GHD ( > 25 < 3 µg/L inwomenand μ Downloaded fromBioscientifica.com at09/29/202112:24:44PM 13 15 g/dL, aresponsetoaninsulin < ). , 16 5 24 µg/L afterastimulationtest ). 13 ). µg/L (5 https://eje.bioscientifica.com ). µg/L). Inchildren,aGH mg ofSynacthen 181 µg/L intransition :3 20 < 1.3 , 21 > gL in 20 µg/L μ , g/dL for 22 13 277 , , 23 17 via freeaccess ). ,

European Journal of Endocrinology https://eje.bioscientifica.com Predictive Analytics Software (PASW Statistics) version 18. were consideredstatistically significant. exact test. compared usingthechi-square( sided deviation ( Continuous variablesareexpressedasamean Statistical analysis no IRBadvicewasrequiredtoconductthisstudy. study.This isaretrospectiveobservational ByFrenchlaw, Ethical consideration measured byPhadia250EliA. Beckman Coulter),ATG andATPO antibodieswere DHEA-S wasmeasuredbychemiluminescence(Access, an extractionmethod Vercelli, Italy).D-4androstenedionewas measuredby by achemiluminescencemethod(LiaisonXLDiasorin, aldosterone, renin and 25-OH vitamin D were measured precipitation to detect macroprolactinemia. GH, IGF1, hyperprolactinemia, weusedpolyethyleneglycol method (RocheDiagnostics).Inpatientswith according to the Modular E170 chemiluminescence cortisol, TSH,T4L,T3LandPTH( progesterone, total testosterone, prolactin, ACTH, plasma department of Pitié-Salpêtrière Hospital. FSH, LH, E2, assays wereprocessedinthebiochemicalandhormonal Blood testswereperformedat08:00 Assay methods for age’( and aZ-scoreabove lower wasdefinedas‘belowtheexpectedrangeforage,’ aZ-scoreof in malesyoungerthanage50 years, neck was if theT-score ofthelumbarspine,totalhiporfemoral in menaged50andolder, osteoporosiswasdiagnosed (DEXA).Inpostmenopausalwomenand absorptiometry mineral density (BMD) assessmentbydual-energy X-ray (MRI), pelvicultrasound,thyroidultrasoundandbone Clinical Study All reported Categorical variablesarepresentedaspercentages and The statisticalanalyses were performedusing t -test. 25 − s 2.5 orless.Infemalespriortomenopauseand ). . d . ) andcomparedbyStudent’s unpaired,two- P valuesaretwo-sided. − 2.0 was‘withintheexpectedrange

+

RIA IM0674(BeckmanCoulter), Y Sagnaandothers χ 2 1 ) testortheFisher’s – 84

h, andhormonal ) weremeasured P values

±

standard − 2.0 or < 0.05 Complete anterior pituitary evaluationwasobtainedin Complete anteriorpituitary – – endocrine evaluationformanyreasons: and wereexcludedfromthestudy. department of neurologyhad no endocrineassessment assessments ( were followed at Pitié-Salpêtrière hospital withendocrine AO with15malesand23CO12males)LCH 2002toDecember2017,63patients(40 From January Results dysfunction wasDIin36% ofpatients(925), LCH in12%patients(3of 25);andthefirstendocrine APD ( in 2.6%each(1/38). deficiency, hyperprolactinemiaandthyrotropin deficiency 38), growthdeficiencyin13.2%(5ofgonadotropin 38). Overall,thefirstEDwasDIin47.4%ofpatients(18 of an ED was the first sign of LCH in 36.8% patients (14 of APDs and5others(13.9%)had4APDs.Inthissubgroup, (APD, dysfunction CO forms) had at least one anterior pituitary patients (63.2%,including50%ofAOLCHand81.2% of Considering the38patientswithcompleteevaluation,24 Pituitary andperipheralglandfunction mostly concernedDIin27patients. patients hadknownEDbeforeevaluation( identified in3cases(21.4%). 14 patients (22.2%) and a BRAFV600E mutation was AO patientsand14ofthe23COhadMS-LCH. forCOpatients.Eighteenofthe40 for AOand1.6 years first clinicalsignsandthediagnosisofLCHwas1.7 years are summarizedin 38 patients(60.3%). Endocrine manifestations in LCH

endocrinological tests. of thosepatientsindepartmentswithlowerpractice 2, 4and23patients,mainlybecauseofthemanagement stimulation test,wedidnotobtaindatarespectivelyin concerning gonadotropinfunction,prolactinemia,GH for LCHatthetime, in five patients under treatment with corticosteroids concerning corticotropinfunction,itwasnotevaluated All of the 63 included patients did not have a complete For theother25patients,12(48%)hadatleastone Twelve ofthe40AOpatientsand1823CO The BRAF status was evaluated for LCH lesions in The baselinecharacteristicsofallpatientswithLCH Table 2 al 2 Table ). Amongthem,anEDwas thefirstsignof i. 1 Fig. ): 8(22.2%)had2APDs,5(13.9%)3 ). Seventeenpatientsfollowedinthe Table 1 Downloaded fromBioscientifica.com at09/29/202112:24:44PM . Themeantimebetweenthe 181 :3 P

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European Journal of Endocrinology A GH stimulation test by ITT was performed in 40 patients. Somatotropin function difference wasnotsignificant( and 19ofthe32patients(59.4%)withMS-LCH,butthis was foundin13ofthe31patients(41.9%)withSS-LCH significantly foundinCOthanAOdisease( (55.3%) and in11ofthe25 others (44%).Itwasmore DI wasfoundin21ofthe38completelyevaluatedpatients Diabetes insipidus evaluated patients(15.8%)and3inthe25others(12%). suspected endocrineabnormality:6inthe38completely hyperprolactinemia in4.8%each(1of21). gonadotropin deficiencyin4.3%(1of23)and Age atdiagnosis,years(median/min–max) Table 1 *All genital, Alcohol Tobacco Toxics Progressive disease Regressive disease Stable disease Non-active disease LCH diseaseactivityatthetimeofendocrineevaluation Positive BRAF statusperformed(%) Histological proofofLCH(%) Intestinal Hepatic Lymph node Hematological Central nervoussystem Mucous Cutaneous Pulmonary Multifocal Unifocal Skeletal Type ofinvolvement(%) Multisystemic LCH Single systemicLCH Type ofLCH(%) Time beforediagnosis,years(mean/min–max) Age atfirstclinicalsignsofLCH,years(median/min–max) Afro-American Unknown Caucasian Origin Clinical Study We thusfoundEDinninepatientswhohadno Baseline characteristicsofpatientswithLCHattheirfirstendocrineevaluation. ** other thanhypothalamo–pituitaryinvolvement. ** P =0.26). Y Sagnaandothers P .0) It =0.006). (21%) and 3 in the 20 others (15%), all with a history of (21%) and3inthe20others (15%),allwithahistory was foundin8ofthe38completely evaluatedpatients and wasnormalin 81% of them. Corticotropin deficiency axiswasevaluatedin58patients The pituitary–adrenal Corticotropin function SD and13ofthemhadalevel in whom3(20%)hadalevel < evaluated patientsand13ofthem(34.2%)hadalevel ( frequency wasnotdifferentbetweenCOandAOdisease patients (55.3%) and 1 among the 2 other patients; the Endocrine manifestations in LCH P Adulthood onset − 20/40 (50) 15/24 (62.5) 24/40 (60) 18/40 (45) 22/40 (55) 25/40 (62.5) 20/40 (50) 39/40 (97.5)

= 0/40 0/40 2/40 (5) 3/40 (7.5) 3/40 (7.5) 9/40 (22.5) 9/24 (37.5) 2/40 (5) 6/40 (15) 5/40 (12.5) 9/40 (22.5) 9/40 (22.5) 2/40 (5) 2 SD.Itwasalsoevaluatedin15oftheotherpatients 32.5 (18–87) 1/9 (11.1) 0.1). FouroftheGHDadultpatientswereobese. All the22patientswithGHDhadanIGF-Ilevel The IGF-Ilevelwasevaluatedinallthe38completely It revealedGHDin21ofthe38completelyevaluated 1.7 (0–12) 34 (19,87) 30 1 9 * Downloaded fromBioscientifica.com at09/29/202112:24:44PM Childhood onset 11/23 (47.8) 15/23 (65.2) 14/23 (60.9) 13/23 (56.5) 10/23 (43.5) 23/23 (100) 0/23 0/23 0/23 3/23 (13) 3/23 (13) 9/23 (39.1) 9/23 (39.1) 6/15 (30) 9/15 (60) 9/23 (39.1) 3/23 (13) 2/23 (8.7) 2/23 (8.7) 9/23 (39.1) 5/23 (21.7) 2/5 (40) < 1.6 (0–12) 16 < − 4 (0–17) 4 (0,23) 1 6 https://eje.bioscientifica.com − 2 SD. 2 SD. 181 :3 P 0.345 0.841 0.699 0.013 0.301 0.568 0.529 0.045 0.529 0.045 0.005 0.293 0.046 0.421 0.878 0.878 0.887 0.341 0.341 value – – – – – – – – – 279 < − via freeaccess 1 European Journal of Endocrinology https://eje.bioscientifica.com no anti-ovarianantibodiesand nofragileXabnormality) the 12others(50%). women (30.4%,including1 postmenopausal)andin6of gonadotropin deficiency in 7 of 23 completely evaluated axis wasnormalin61.1%ofthewomen.There a Hormonal evaluation showed that the pituitary–gonadal amenorrhea andthe7otherwomenhadoligomenorrhea. premenopausal women,10hadregularmenses,11 ( (30.4%) withnodifferencebetweentheCOandAOforms evaluated patients(34.2%),andin7ofthe23others We foundgonadotropindeficiencyin13of38 completely Gonadotropin function of adrenalglucocorticoidinsufficiency. corticosteroid treatment.Nopatientshowedthefeatures hormone. APD, anteriorpituitarydysfunction;DI,diabetesinsipidus;GH,growthhormone;NA,non-applicable,nonewasevaluated;TSH,thyroid-stimulating corticotherapy, *Some ofthemhadundertakingendocrineevaluationsinchildhoodbutherewejustconsiderdoneourdepartment, Corticotropin deficiency TSH deficiency Peripheral deficiency Central deficiency Gonadotropin deficiency Hyperprolactinemia GH deficiency At least1APD Diabetes insipidus Endocrine dysfunction Patients withincompleteevaluation Corticotropin deficiency TSH deficiency Central deficiency Gonadotropin deficiency Hyperprolactinemia Severe Partial GH deficiency At least1APD Diabetes insipidus Endocrine dysfunction Patients withcompleteevaluation At least1APDwithoutDI At least1APD DI Known endocrinedysfunctionbeforeevaluation Age atfirstendocrineevaluation,years(median/min–max) Age atfirstendocrinesigns,years(median/min–max) Hormonal dysfunction Table 2 P

Clinical Study = 0.56). We ofdelayed pubertyinfiveCO. foundahistory Eight women were postmenopausal. Among the 28 We foundoneidiopathic ovarianinsufficiency(46XX, Frequency ofendocrinedysfunctionsinpatientswithLCH. *** complete GHD. Y Sagnaandothers evaluated patients(8of38) ( Hyperprolactinemia wasfound in21%ofthecompletely Serum prolactin testicular infiltration). and showednoabnormalities(inparticular, no Testicular ultrasoundswereperformed infivemen deficiency. Therewasnoclinicaltesticularabnormality. 9.1% of the others (1 of 11); we did not find any testicular evaluated men(6of15;2haddecreasedlibido)and in gonadotropin deficiency in 40% of the completely erectile dysfunction.Thehormonalevaluationshowed in 11.5%(3of26,allAOpatients)andtherewasno infiltration asidefromoneovarianendometriosis). and showednoabnormalities(inparticular, noovarian of LCH.Pelvicultrasoundswereperformedin13women andbeforethediagnosis diagnosed attheageof37 years Endocrine manifestations in LCH 10/40 (25) 12/40 (30) In malepatients,decreasedlibidowasmentioned 1/40 (2.5) 7/40 (17.5) 13.6 (3/22) 18.2 (4/22) 31.8 (7/22) 22.7 (5/22) 45.4 (10/22) 36.4 (8/22) 31.5 (18–58) 38.9 (7/18) 38.9 (7/18) 100 (7/7) 7.1 (1/14) 50 (9/18) 60 (6/10) 40 (4/10) 50 (11/22) 50 (11/22) 39 (20–88) 25 (1/4) 75 (3/4) 25 (4/16) 25 (4/16) NA 45 (18/40) 55 (22/40) Adulthood 0 % ofpatients Downloaded fromBioscientifica.com at09/29/202112:24:44PM 13/23 (56.5) 17/23 (73.9) 18/23 (78.3) ( n 1/23 (4.3) 71.4 (5/7) 31.2 (5/16) 31.2 (5/16) 37.5 (6/16) 18.7 (3/16) 72.7 (8/11) 27.3 (3/11) 81.2 (11/16) 81.2 (13/16) 81.2 (13/16) 93.7 (15/16) 33.3 (2/6) 57.1 (4/7) 42.8 (3/7) 71.4 (5/7) 57.1 (4/7) 30.4 (7/23) 69.6 (16/23) / 100 (6/6) 100 (3/3) 20 N 20 (1/5) 50 (1/2) Table 2 Childhood ) 6 (2–23) * 0 (14–62) ** *** ), respectively24%in ** 181 :3 ** all after P value 0.201 0.062 0.625 0.948 0.201 0.656 0.406 0.243 0.449 0.746 0.546 0.659 0.659 0.2 0.08 0.008 0.005 0.730 0.003 0.000 0.000 – – – – – – – – 280 via freeaccess

European Journal of Endocrinology Absence ofthephysiological Non-infiltrated Infiltrated Hypothalamic region Decreased Increased Normal Thickness ofthepituitarystalk Decreased Increased Normal Pituitary glandsize patients withendocrinedysfunction. abnormalities atthemagneticresonanceimaging(MRI)of Table 3 without DI,eighthadatleastoneAPD:sixinthesubgroup DI (75%)hadatleastoneAPD.Amongthe31patients significant ( 63.1% patientswithMS-LCH,butthisdifferencewasnot ED was found in 73.7% of patients with MS-LCH and Considering patientswithcompleteevaluation,an and DI Correlation betweenAPD,LCHdiseaseextension evaluation). goiter (weexcludedthesepatientsfromthethyroid atotalthyroidectomyformultinodular other underwent hypothyroidism beforethediagnosisofLCHandone disease ( ( and 4 of the 25 others (16%) had thyrotropin deficiency Nine ofthe38completelyevaluatedpatients(23.7%) Thyrotropin function examination. and twowomenhadgalactorrheaontheclinical had bilateralgynecomastiawithnormalserumprolactin had galactorrheaontheclinicalexamination.Oneman induce hyperprolactinemiawasreported.Onewoman 32.3 the meanPRLlevelinmenwas31.7 other patients(23.8%). women and18.5%inmen.Itwasfound5ofthe21 Table 2 Clinical Study pituitary bright spotoftheposterior The PRL elevation was very mildinallpatients: The PRLelevationwasvery ±

10.8 ). ItwasmorefrequentintheCOformthanAO P Frequency ofpituitaryandhypothalamic

= ng/mL inwomen.Nouseoftreatmentsthat 0.016). Six patients had primary autoimmune 0.016). Six patients had primary P

= 0.07). Twenty-four ofthe32patientswith

50 (10/20) 95 (19/20) 20 (4/20) 75 (15/20) 10 (2/20) 10 (2/20) 80 (16/20) Adulthood 5 (1/20) 5 (1/20) Y Sagnaandothers % ofpatients

± gm and 12ng/mL

84.2 (16/19) 15.8 (3/19) 15.8 (3/19) 15.8 (3/19) 68.4 (13/19) 15.8 (3/19) 84.2 (16/19) 54.6 (12/19) Childhood ( n 0 / N )

Bone evaluations physiological T1brightspotintheposteriorpituitary. whom hadDI.NinepatientswithDIstillavisible wasfoundin36.1%ofpatients,all posterior pituitary abnormalities. detected forthefirsttimeonscreeninghadMRI with unsuspectedendocrinedeficienciesthatwere infiltrated in9.6%ofpatients(661).Four deficiencies.Thehypothalamicregionwaspituitary region orstalk( MRI showedavisibleinfiltrativelesionofthepituitary Twelve apituitary ofthe61patientswhounderwent Imaging others (8%). of completelyevaluatedpatients(15.8%)andtwointhe of the pituitary deficiencies werepermanentandsome of thepituitary third evaluationswasrespectively 1.3and2.7 years. Most second evaluationsandbetween thesecondand assessments. Themeantime betweenthefirstand atleastthree evaluations, and35patients underwent two endocrinological Forty-eight patientsunderwent and 38AOpatients). endocrine treatments. Thirty-four patients(54%,15AOand19CO)required Evolution after corticotherapy). range forage(onegonadotropindeficiencyandtwoother assessment, 4(14.8%)hadaZ-scorebelowtheexpected aBMD yearswhounderwent younger thanage50 aBMDassessment. who underwent There werenomenaged50andolderamongthepatients ofcorticotherapy). gonadotropin deficiencyandahistory and osteopeniainonecaseeach(thesetwopatientshad postmenopausal women and we found osteoporosis a BMDassessmentbyDEXA.Fourofthemwere vitamin Dlevels. calcium levels and 83.9% of patients (26 of 31) with low except in1of62assessedpatientswithmoderatelylow We foundnoabnormalityincalciummetabolism, Endocrine manifestations in LCH An absenceofthephysiologicalT1brightspotin The meanfollow-uptimewas52.1 Follow-up datawereavailablefor58patients(20CO Among the27nonmenopausalwomenandmen Thirty-one patients(meanage al 3 Table Downloaded fromBioscientifica.com at09/29/202112:24:44PM ). Ten ofthem(83.3%)had https://eje.bioscientifica.com = 36 years) underwent underwent 36 years) 181 :3 ± 35 months. 43.5 281 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com insulin-like growthfactor-1;ITT,insulin tolerancetest;LH,luteinizinghormone;MRI,magneticresonanceimaging; PRL,prolactin. ACTH, adrenocorticotropin;CT,computed tomography;E2,estradiol;FSH,follicle-stimulatinghormone;FT4, freeT4;GH,growthhormone,IGF-1, Follow-up Adrenal glands Thyroid Gonads Pituitary Table 5 young people. and difficultyinperformingdiagnosisofosteoporosis are apossiblepaucityofauxologicalandclinicaldata deficits. Finally, thisstudyhasotherlimitationsthat to thisstudycouldhavehadundiagnosedpituitary that the17patientsseeninneurologyandexcluded included their data from our hospital. It is also possible time. Moreover, fortheCOLCHpatients,weonly evaluation toexamineexactlyhowEDevolvedover sectional design that does not allow for a longitudinal study mayhavecertaindatalimitations,suchasthecross- pituitary, gonadal,adrenalandthyroidfunction.This endocrinologicalevaluationsofLCH whounderwent We report here a cohort of 63 consecutive patients with Discussion progressively ( that were notpresentat the firstevaluationappeared GH, growthhormone;NA,notavailable. Mean timebetweenthefirstandsecondevaluationthirdevaluation:1.32.7 yearsrespectively. Diabetes insipidus Thyrotropin deficiency Corticotropin deficiency GH deficiency Gonadotropin deficiency Hyperprolactinemia Endocrine dysfunctions Table 4 Clinical Study Recommendations forendocrineassessmentandsurveillanceprotocolinpatientswithLCH. Follow-up dataof58patientswithLCHandendocrinedysfunction. Table 4 Every year Search forsignsofadrenal Search foragoiterandnodules 24-h diuresisandwaterintake Search forsignsofanterior Clinical evaluation deficiency pituitary deficits ). Disparition Y Sagnaandothers 3 0 0 1 1 2 2nd evaluation, At anytimeifclinicalorbiological Adrenal CTscan Thyroid sonographyifclinicalanomalies Pituitary MRI Morphological evaluation abnormalities Stable 32 10 14 7 1 5 n New occurrence ( of LCH,andDIisusuallythefirstendocrinemanifestation dysfunction isacommonendocrinologicalmanifestation AO forms.Aspreviouslyreported,posteriorpituitary manifestations inLCHalargecohortstudy. exhaustive investigationofendocrineandmetabolic with MS-LCH or 94% in the presence of other pituitary with MS-LCHor94%inthepresenceofotherpituitary has beendescribedtopossiblyreach40%inpatients subgroup ofincompletelyevaluated.Thisprevalence previous studies( evaluations ( LCH patients with complete endocrine adult pulmonary one found in another recent study in a small population of those withcompleteevaluation,andwassimilartothe systematically ( national LCHregistry, butevaluationswerenotdone manifestation in2.1%ofCOpatientstheFrench Endocrine manifestations in LCH 9 , 10 0 1 2 1 2 0 ED wasmoreprevalentintheCOformsthan Nevertheless, thisstudyprovidesthefirstnear- In ourstudy, DIreachedaprevalenceof55.3%in , 26 , 27 , 10 28 31 ) buthigherthanthe30%describedin , Disparition 29 ). 32 , NA 0 1 0 3 1 30 , Every 3 yearsoratanytimeifclinical Renin, aldosterone ACTH, cortisolunderITTorafter TSH, FT4 FSH, LH,E2(women),total Natremia andurinaryosmolarity ACTH, cortisolunderITTorafter IGF-I, GHunderITT TSH, FT4 PRL FSH, LH,E2(women)/total Biological evaluation 33 ). DIwasthefirstendocrinological Downloaded fromBioscientifica.com at09/29/202112:24:44PM abnormalities Synacthen test testosterone (men) Synacthen test testosterone (men) ), evenwhenconsideringour 3rd evaluation, Stable NA 32 13 9 5 4 181 :3 n New occurrence NA 0 1 1 0 4 282 via freeaccess European Journal of Endocrinology diagnostic criterionofGHD ( against relianceonGHprovocative testresultsasthesole thepediatricguidelinesrecommend previously observed, testingandauxologicaldata.As the lackofaconfirmatory patients inwhomitwasisolated orinchildrendueto probably overdiagnosedespeciallyinthefourobeseadult 29 are similartothoseintheLCHandECDliterature( thyrotropin deficiencyinourtwosubgroups.Ourfindings gonadotropin deficiency, hyperprolactinemia and when DIisalreadydiagnosed( be themainpredictorsofahigherriskdevelopingAPD risk clinicalformsandfewerreactivationepisodesseem to Older ageatthediagnosisofLCHorpresencelow before evaluation. APD is almost never associated with DI. ED but they had no suspected endocrine manifestation of completelyevaluatedand12%inthesecondgrouphad patients, especiallyas15.8%ofourpatientsinthesubgroup evaluationshouldbeperformedinallLCH pituitary recommendations ( to probably underestimated. Our results suggest,contrary which meansthattheprevalenceofsomedeficienciesis have reported patients with a completeevaluation, or ECD( also higher than the 8.7–33% reported previously in LCH gland abnormalities are a known risk factor ( pituitary did notfindany neurodegenerative complicationsbut impairment. scan isnotsufficienttoruleoutpituitary We stalk thickening( common MRIabnormality is infundibular or pituitary brightspot.Thesecondmost as theposteriorpituitary posterior wallofthesellaturcica wasfalselyconsidered the conclusionofneuroradiologist,fatbony had avisiblebrightspot,itislikelythat,dependingon LCH ( toECDor with DIandcouldbeidiopathicorsecondary iscommoninpatients bright spotintheposteriorpituitary incidence ofDI20%( study of70COLCHpatientsfounda10-yearcumulative almost threequartersofthepatientshadDI.Oneprevious prevalence wasalsoattributabletoCOLCHinwhich assessment wasdonesystematically( histiocytic infiltrativedisorder( in ErdheimChesterDisease(ECD),whichisanother was alsomorethantheapproximately30%reported difference between SS-LCHandMS-LCH. Our prevalence deficiencies ( Clinical Study ). Butwecannot discard thatGHdeficiencyhasbeen The mostcommonAPDwasGHD,followedby The prevalenceofAPDinourtwosubgroupswas As shown in this study, the absence of the physiological 34 , 10 35 , , 11 9 38 , , 32 , 29 31 39 , , 1 , 34 ). ForthepatientswithDIwhostill 34 , 38 2 ), butinourstudy, therewasno , ), thatacompletehypothalamo- , 37 35 39 ). , ), but a normal pituitary MRI ), butanormalpituitary 41 44 43 , ). 7 42 Y Sagnaandothers ), evenwhenacomplete ). ), but very fewstudies ), butvery 35 , 36 ). Ourhigh 9 , 40 10 ). , condensing bonelesions). hormonal replacement,andcorticosteroidtherapy, non- cytokines,APDand of osteoporosis(proinflammatory it isknownthatthispopulationhasmultipleriskfactors perform anactiveresearch forvertebralfractures( age ofourpatientsandbecausewedidnotsystematically ascertain onthebasisofBMDalonebecauseyoung is knowntobeinvolvedinLCH( autoimmune hypothyroidism),butthyroidinvolvement treatment ratherthantheLCH. thus consideredthattheyweredeficientbecauseofthe ofcorticosteroidtreatment,andwe reported ahistory stalkinfiltration( attributed topituitary prolactin levelsweremoderatelyelevated,whichcanbe ee fr eern LH ains o s o flo-p n u department, our in follow-up for us to patients LCH referring for Leger Juliane and Polak Michel Delemer, Brigitte thank to like would authors The Acknowledgements the public,commercialornon-profit sector. This research did not receive any specific grant from any funding agency in Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisstudy. no is there that declare authors The Declaration ofinterest presented in and monitoringprotocolinpatientswithLCHare LCH patientandfurtherregularmonitoring. we recommendacompleteendocrineevaluationineach of LCH patients who were evaluated systematically. Thus, manifestations are extremely frequent in a large cohort few patients. probably low because this test was performed only in a ranges from 38 to 60% ( alterations. hormonedeficienciesormetabolic detect furtherpituitary using establishedendocrineinvestigationalprotocolsto important thatallLCHpatientsbemonitoredregularly and generallyaredefinitive( or ECD,EDscanappearprogressivelyduringfollow-up Endocrine manifestations in LCH As describedinotherstudiesofpatientswithLCH The skeletalstatusofourpopulationwasdifficultto We hypothyroidism(otherthan foundnoprimary All ofourpatientswithcorticotropindeficiency Our recommendationsfortheendocrineassessment In summary, wehaveconfirmedthatendocrine The prevalenceoftheBRAFV600EmutationinLCH As foundinotherLCHandECDstudies( Table 5 . Downloaded fromBioscientifica.com at09/29/202112:24:44PM 49 , 50 9 , https://eje.bioscientifica.com , 51 29 35 ). This frequency was , , 181 45 37 , 1 :3 46 , ). 42 , 47 ). Itisthus 10 ). , 48 35 283 ). But ), the via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com

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Accepted 3July2019 Revised versionreceived19June2019 Received 18March2019

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