Pituitary Stalk Interruption Syndrome: Etiology and Clinical Manifestations

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J Vergier and others Pituitary stalk interruption 181:5 R199–R209 Review syndrome

DIAGNOSIS OF ENDOCRINE DISEASE Pituitary stalk interruption syndrome: etiology and clinical manifestations

Julia Vergier1,2,3, Frederic Castinetti1,2,4, Alexandru Saveanu1,2,5, Nadine Girard6,7, Thierry Brue1,2,4 and Rachel Reynaud1,2,3

1Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Marseille, France, 2Assistance Publique-Hôpitaux de Marseille (AP-HM), Centre de Référence des Maladies Rares de l’hypophyse HYPO, Marseille, France, 3Assistance-Publique des Hôpitaux de Marseille (AP-HM), Department of Pediatrics, Hôpital de la Timone Enfants, Marseille, France, 4Assistance-Publique des Hôpitaux de Marseille (AP-HM), Department of Endocrinology, Hôpital de la Conception, Marseille, France, 5Assistance-Publique des Hôpitaux de Marseille (AP-HM), Laboratory of Molecular Correspondence Biology, Hôpital de la Conception, Marseille, France, 6Aix-Marseille Université, UMR CNRS 7339, Marseille, France, should be addressed and 7Assistance-Publique des Hôpitaux de Marseille (AP-HM), Department of Neuroradiology, Hôpital de la Timone to J Vergier Adultes, Marseille, France Email [email protected]

Abstract

Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect. This syndrome is an antenatal developmental defect belonging to the holoprosencephaly phenotype spectrum. It is heterogeneous regarding clinical, biological and radiological presentation and is characterized by the following triad: thin (<1 mm) or interrupted pituitary stalk connecting the hypothalamus to the pituitary gland, no eutopic posterior lobe, and hypoplasia or aplasia of the anterior lobe. This review reports current knowledge about the composite pathogenesis, for which underlying mechanisms remain unclear. Current data suggest genetic origins involving early developmental gene mutations with complex inheritance patterns and environmental influence, placing PSIS at the crossroads between Mendelian and multifactorial diseases. The phenotype associated with PSIS is highly heterogeneous with a high incidence of various

European Journal of Endocrinology combinations of hormonal deficiencies, sometimes associated with extra-pituitary birth defects. The age at onset is variable, but typical presentation is evolutive combined anterior pituitary hormone deficiencies at pediatric age, which progress even during adulthood to panhypopituitarism. Therefore, patients’ follow-up throughout life is essential for adequate management.

European Journal of Endocrinology (2019) 181, R199–R209

Introduction

Pituitary development is a complex embryonic process As the differentiated gland contains specialized involving oral and neural ectoderm to form functionally cell types that produce hormones to regulate basic distinct lobes, anterior and posterior. Many aspects of physiological functions in response to signals from pituitary embryogenesis have become better understood the hypothalamus, failure of physiological embryonic over the past decades. The initial gland formation and development results in congenital hypopituitarism. the following differentiation require cascades of signaling Pituitary stalk interruption syndrome (PSIS, ORPHA pathways with accurate interactions of transcription 95496 (2)) was first reported in 1987 with the presence factors, acting as activators or repressors with a precise of an ectopic posterior pituitary (EPP) being the cardinal spatiotemporal expression (1). feature together with an interrupted stalk (3). The diagnosis

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-19-0168 European Journal of Endocrinology https://eje.bioscientifica.com antenatal origins.Perinatal complications maytherefore association withothercongenital abnormalitiessuggest of familialorconsanguineous casesandthefrequent werepublished. Furthermore,theoccurrence delivery of PSIS in children with normal and many observations section. However, nopathologicalproofhasbeenfound or cesarean in patientswithPSISnormaldelivery the highfrequencyofperinataleventsandbreechdelivery considering rupture orischemiahasbeentheinitialtheory causingmechanicalstalk injury with perinatalpituitary various hypotheseshavebeensuggested.Birthtrauma PSIS pathogenesishasnotbeenfullyunderstoodyet,and Etiology andpathogenesis of thisheterogeneousdisease. for PSIS pathogenesis and the wide phenotype spectrum spectrum. considered asapartoftheholoprosencephaly(HPE)wide diversified clinicalmanifestations. To date,PSISis extra-cerebral midlinedefects,responsibleforextremely abnormalities andPSIScanalsobeassociatedwithvarious deficiencies. increased risk of developing anterior pituitary ( gland stalk connectingthehypothalamustopituitary stalkoralongthepathwayofathinpituitary pituitary the thirdventricle( nodule maybeintheregionofinfundibularrecess hypersignal intheshallowsellaturcica. Thehyperintense stalkornoeutopicposteriorlobe a lackofvisiblepituitary the secondmonthoflife( the posteriorlobe‘brightspot’becomesrecognizableby being describedin10%ofhealthypopulation,andsince stalkcouldnotbeconsideredasPSIS,thisfeature pituitary ( stalk withabsent(asopposedtoectopic)posteriorpituitary feature (suchasEPPorinterruptedstalk) seems tohavewidenedincludepatientswithonesingle anterior lobe.Overthelastdecades,definitionofPSIS gland,EPP,to thepituitary andhypoplasiaoraplasiaofthe stalkconnectingthehypothalamus interrupted pituitary stalk. PSIS was therefore characterized by: thin or pituitary allowed distinctionbetweenthinandinterrupted related endocrinedisease( size, shapeandmicrostructureinpatientswithpituitary- pituitary which isthetechniqueofchoicetoobserve is confirmedthroughmagneticresonanceimaging(MRI), 5 2 ). Bothconditionsareassociatedwithasignificantly withnormal ). Isolatedmissingposteriorpituitary Review The present review will examine the current theories Neuroradiological investigationsmayrevealother 6 ), attheendofashortpedunculated 5 4 ). To sumup,PSISisdefinedas ). ImprovedMRIperformance J Vergierandothers Single pituitary-specificgenes possible digenic( are autosomal (dominant or recessive) or X-linked, with disorders implicated in PSIS ( sequencing madeitpossibletoidentifynewgenetic pathways. Aftercandidategeneapproach,whole-exome such as Wnt, Notch and Sonic Hedgehog (SHH) signaling development pathways criticalforhypothalamic–pituitary found in early development genes ( knowledge concerning CPHD ( There haverecentlybeengreatimprovementsingenetic Genetic diversity defects iswidelyacceptednowadays( developmentcausedbygenetic of anabnormalpituitary abnormalities ratherthanacause( be consideredasaneffectofpreviousdevelopmental harboring variablephenotypes includingaconstellation inheritance ofmutations arereportedinpatients Wnt signaling pathway. Bothrecessiveand dominant 21 hypothalamus andRathke’soptic nerves, pouch( from the placode including the developing forebrain, development ofmultipleanteriorstructuresderived phenotype inthiscase. related geneticvariationsarelikelytounderliethePSIS a consanguineousunion( a PROP1 homozygous mutation in a patient born from familial caseofPSIShasbeenreportedinassociationwith models, asitoftenincludesACTHdeficiency. Only one the hormonalphenotypeismoreseverethaninmurine radiological phenotypedoesnottypicallyincludePSISand morphology ( responsible for variable pituitary gene knowntocauseCPHD( transcription factor and is the most recurrently mutated more complex. factor expression,thephenotypeassociatedwithPSISis inactivation. Accordingtothetimeoftranscription single gene mutations causing complete genefunction ( the mostplausibleexplanationforCPHDandPSIS havebeenconsidered glandembryogenesis the pituitary Molecular disordersoftranscriptionfactorsinvolvedin in malformation never associated with PSIS or extra-pituitary syndrome Pituitary stalkinterruption 17 ). HESX1transcriptionfactor interactswiththe , Ames The homeoboxgene The 18 ). Familial forms of PSIS are usually explained by mice model. In PROP1 gene encodes a late pituitary-specific geneencodesalatepituitary-specific 15 ) andpolygenicinheritance( Downloaded fromBioscientifica.com at09/28/202109:48:10AM 7 PROP1 ), andfurtherconsanguinity- HESX1 12 9 9 ). , ). Mutations have been human mutation, the 13 playsarole in the 7 PROP1 ) andthehypothesis 181 , 10 8 14 ). , :5 , 11 mutationsare 15 ) involved in , 16 19 16 ). Those ) but are R200 ). 20 via freeaccess ,

European Journal of Endocrinology to apparentlynormalphenotype ( development with PSIS severely impaired eye and pituitary spectrum in inhibition ofSHHventralsignals. Thereisawidephenotypic lactotrope, andthyrotropecelltypes,basedonthe controls the established sharp boundaries of somatotrope, gland. Itsexpression marker ofearlyanteriorpituitary have beenpublished,associatedwithPSIS( development, genitalhypoplasia,earanomalies/deafness) heart defect, atresia choanae, retarded growth and gene mutationleadingtoCHARGEsyndrome(coloboma, 7, interactswith gland. stalk,andhypoplasticanteriorpituitary pituitary brightspot,thin presented missingposteriorpituitary along withrenalanomalies( pathway, cerebral post-natal growth causing microcephaly axis,post-retinalvisual affects thehypothalamo–pituitary lead toseveresyndromicphenotype:thelossofARNT2 homozygous mutationsinaconsanguineousfamily mutations arenotclassicallyassociatedwithPSIS,but development. at 8weeksofhumanembryonic gland expressed inthedevelopingbrainandpituitary responsible forPSISalongwithocularanomalies. function correlations ( manifestations butwithoutcleargenotype–phenotype OTX2 of ROBO1 such as OTX2, malformations has also been reported with other genes brain defects. ( of theclassicaltriad( is a rare clinical condition including at least two features homeodomain are first reported with SOD ( ( HESX1 stalk without septo-optic dysplasia (SOD) ( located at median eminence and interrupted pituitary gland,EPP patient withhypoplasticanteriorpituitary up to panhypopituitarism has been described in a deficiencies abnormalities. Evolutiveanteriorpituitary abnormalities,withorwithouteyes of extra-pituitary 2 9 Review ) pituitary hormoneabnormalitiesand( ) pituitary , HESX1 PAX6 isaregulatorofeyedevelopmentanddorsal CHD7, chromodomainhelicaseDNA-bindingprotein ARNT2 is a basic helix-loop-helix transcription factor The transcriptionfactorOTX2isrequiredforactivation This associationofPSISwithophthalmic 23 mutations are associated with variable pituitary mutationsareassociatedwithvariablepituitary ). Noteworthy, missensemutationswithinthe mutations causing PSIS remain very rare mutationscausingPSISremainvery and OTX2 expressioninthedevelopingforebrain( LHX4. PAX6 25 mutationswithinitshomeodomainare ARNT2 ). Heterozygousmissenseorloss-of- heterozygous mutation carriers, from heterozygousmutationcarriers, from SOX2 , 24 CHD7 . Heterozygousloss-of-function ): ( 1 , ) optic nerve hypoplasia, ) opticnerve PAX6 J Vergierandothers 12 26 ). ). Affectedchildren and more recently 11 22 ). ). However, 3 20 ) midline ), which ARNT2 9 ).

and ocularanomaliessuchasstrabismusorptosis( found tocausePSISwithvarioushormonedeficiencies Heterozygous nonsenseormissensemutationswere ROBO1 and brainmalformations( developed sellaturcica, hypoplasia inconstantpituitary haploinsufficiency areresponsibleforPSISwithpoorly ( hormone deficiencies and MRI abnormalities pituitary most ofthemwithincompletepenetranceandvariable found tobeassociatedwithvariableexpressivity, and for phenotypical variability: primordium ontogenesis (Rathke’s pouch), is responsible but nofunctionalstudyhasbeenperformed. it is a key receptor in both development of the olfactory it isakeyreceptorinbothdevelopmentoftheolfactory in endocrineangiogenesisandneuronalmigration, milder formofthephenotype isalsodescribed. mutation ofitsgeneisassociated withPSIS( promotes SHHsignalingactivity; aheterozygousnonsense recommendation asstrongpathogenicvariant( once andkeeponbeingconfirmedaccordingtonew HPE andPSIS( Heterozygous mutationshavebeendescribedlinked to is expressedinthedevelopingmidlinestructures. It isacomponentoftheWntsignalingpathwayand transforming growthfactor(TGFB)andretinoidresponse. of hormonedeficiencies( incomplete penetranceandawidephenotypicspectrum been reportedinPSISatarelativelyhighfrequencywith development ( the pituitary SHH signalingwhichactsintheWntpathway, earlyin pathway. in previousstudies( Mutations in HPE-related genes have been reported Single HPE-relatedgenes patients ( mutations have recently been identified inPSIS hypogonadotropic hypogonadism,andheterozygous PROKR2 alterationinducesKallmannsyndromeand bulb andgonadotropin-releasinghormonesecretion. syndrome Pituitary stalkinterruption 17 , Genetic alterationof Haploinsufficiency oftheaxonguidancereceptor PROKR2 isaG-protein–coupledreceptorinvolved Other genetic defects have been reported only TGIF GLI2 isazinc-fingertranscriptionfactordownstream CDON isacell-surfaceSHH-binding proteinthat 27 genehasbeenidentifiedasanewcauseofPSIS. , encodesahomeodomainproteinthatrepresses 29 28 ). ). Heterozygousmutationscausing 30 ). 30 ) suchasgenesinvolvedinSHH Downloaded fromBioscientifica.com at09/28/202109:48:10AM 31 27 LHX4 ). 16 ). ). Some https://eje.bioscientifica.com LHX4 , involved in pituitary , involvedinpituitary 181 mutations were GLI2 :5 variants have 13 32 ), buta ). R201 LHX4 14 via freeaccess ),

European Journal of Endocrinology https://eje.bioscientifica.com other factors( that penetranceofagenetic defectmaybemodifiedby relatives. affected orunaffectedmutation-carrying withinthesamefamilies( vary clinical presentation,endocrineprofilesandMRIfindings with majorvariations( etiology thusremainsnon-documentedformostpatients. molecular defectandMendelianinheritance( Very fewPSISpatientshavebeendetectedwithonesingle Toward amorecomplexetiology X-linked hypopituitarism( involving Varying lengthsduplicationsordeletionatXq26-q27 infundibular hypoplasiaandhypopituitarism( alterations areassociatedwithsimilarphenotypes over- and under-dosage caused by X-linked genetic development:bothSOX3 hypothalamo–pituitary related toSRY. Itsdosageseemscriticalfornormal SOX3 isamemberoftheHMGtranscriptionfactors identified witharraycomparative genomic hybridization. in patientshavingmicrodeletionorduplications( In additiontomonogenicmutations,PSISwasdiagnosed Micro rearrangements the samepathway( established, even though those two proteins are not in and inheritance withboth bulbmorphogenesis.Digenic forolfactory necessary which contains a homeodomain transcription factor oligogenic mechanism( rare The associationbetweena Digenic inheritance been performed. ( Karaca One homozygousmissensemutationhasbeenreportedby forms. ItalsoregulatesWNTandretinoicacidsignaling. proteolytic conversionofGLI2andGLI3intorepressor 33 Review ). Forthelasttwogenes,nofunctionalstudieshave Genotype–phenotype discordances are very common Genotype–phenotype discordancesarevery WDR11 isamemberoftheWDrepeatproteinfamily GPR 161downregulatesSHHpathway, asitleadsto These complexinheritancepatterns highlightthefact HESX1 PROKR2 et al. SOX3 polymorphisminaPSISpatientsuggestsan , associatedwithPSISanddiabetesinsipidus (c.253C.T;p.R85C) mutationshasbeen 9 ). havebeendescribedinfamilieswith 15 ). 29 11 ). , WDR11 37 13 ). PROKR2 , 8 14 ), frequentlywithmildly J Vergierandothers , (c.1306A.G;p.I436V) 15 mutationanda , 26 , 27 , 38 30 34 ): PSIS , 31 , 36 35 ) : ). ). ) ROBO2 gland in mice. is expressed in the developing pituitary CCDC88C genes wereidentifiedforisolatedPSIS( with othermidlinebrainmalformations.Candidate formationorassociated from genesrelatedtopituitary pathogenic variants inherited from unaffected parents, patients hadacombinationofvariouspotentially to support the hypothesis of a polygenic etiology. Most exome sequencing(WES)in20unrelatedPSISpatients functionally relatedgenes. background withsynergyofcompoundmutations spectrum ofphenotypesmaybecausedbyamultigenic extra-endocrine features,itispossiblethatthiswide As PSISpatientspresentheterogeneousendocrineand Polygenic hypothesis be significantinthemultifactorial etiologyofHPE( considered. Gene–environment interactionislikelyto patients, non-geneticriskfactors mustobviouslyalsobe Since genemutationsarereported inlessthan5%ofPSIS Suspected environmentalinfluences signaling. of SHHsignalingandinhibitsWnt/b-cateninprotein morphogenesis, influencesthetranscriptionaloutcome and hematopoiesis. and homoeostaticprocesses,itisassociatedwithtumor catenin signaling. development. they playmoreimportantrolesinthenormalpituitary pathway) and mutated were involved inthosecriticalpathways.Themostfrequently functionaldomainsofgenes localized inconserved patients hadmultiple(uptofive)mutations,mostly with theNotch,SHHandWntsignalingpathways.Most variants ingenesthatareeithermembersoforassociated genetic interactions.Theyidentified41heterozygous sporadic PSISChinesepatientstosearch forsynergistic neurodevelopmental disorder. disorganization. bulb causes ciliopathiesandmutantmicehaveolfactory a negativeregulatoroftheWntsignalingpathway. system. of themammaliancentralnervous genes. when associatedwithothervariantsindevelopmental syndrome Pituitary stalkinterruption Zwaveling-Soonawala Similarly, Guo playsaroleinaxonguidanceacrossthemidline DCHS1 , and KIF14 isimplicatedinneuronalmigrationand NCOR2 NKD2 ZIC2 KAT6A NCOR2 t al. et (ofSHHpathway),suggestingthat ZIC2 isanegativeregulatorofWnt/b- (ofNotchpathway), ) and syndromic PSIS ( Downloaded fromBioscientifica.com at09/28/202109:48:10AM mutationsareresponsiblefor ( isessentialforpatterningand isinvolvedindevelopmental t al. et 39 ) performedaWESon24 ( 16 ) performed a whole 181 :5 DCHS1 NKD2 CCDC88C , ROBO2 (ofWnt KAT6A R202 KIF14 40 is via freeaccess ). ) ,

European Journal of Endocrinology marker of pituitary function( marker ofpituitary cells; itsinterruptionhasbeen establishedasanimportant hormone transportationfrom hypothalamustopituitary stalk enables reproduction, and homeostasis. The pituitary that regulatephysiological functions, includinggrowth, glandproducesseveral hormones The maturepituitary Hormonal presentation defects. depending onhormoneprofile,ageatonset,andlinked hormone deficiencies, associated with anterior pituitary described firstinthisreview. PSIS diagnosisisconfirmedbyMRI,clinicalfeatures are defect later revealed through a failure to thrive. Although midlinemalformationsoranisolatedpituitary pituitary can be either a congenital association with various extra- be suspectedonclinicalfindings:theinitialpresentation PSIS phenotypeishighlyheterogeneousanddiagnosismay a complexphenotype Clinical consequencesofPSIS: repartition andageatdiagnosis( characteristics variabilitybetweencohortsintermsofsex male predominance( sporadic and only occasionally familial ( showed PSISin4–8%ofthecohorts.Mostcasesare than 8000and13,000patientsstudied,respectively, analyses by C. Deal ( with hypopituitarism( radiological modality inpatients use ofMRIasaprimary rare disease.Incidenceisincreasingbecauseofroutine Exact prevalenceofPSISisunknownbutitremainsa Epidemiology of phenotypes Clinical manifestations:widespectrum abnormalities suchassepto-opticdysplasia( associated withvariousHPEpresentationandpituitary Moreover, vasoactivedrugssuchascocainehavebeen hypothesis’ ( alcoholism or diabetes as suggested by the‘multiple hit contingent factors ( could be a multigenic disease interacting with multiple As PSISmaybeconsideredasamildformofHPE,it Review The commonclinicalpresentationincludessymptoms 42 ) involvingepigeneticmechanisms( 41 44 39 ), such as low cholesterol, maternal 44 ) and M. Maghnie ( , ): thepost-marketingdatabase 46 , 49 47 ). ) andanethnicclinical 48 J Vergierandothers

). 22 43 ). There is a 45 ). ) in more 16 ). linear growthdespiteabnormalGHsecretion( treatment ( patients whodidnotreceiveanyGHsupplementation considerable variationinheighthasbeenpointedoutfor have beendescribedaftertransition( 53 lowpeakGHlevelsonprovocativetesting)( by very and severe(asdefinedbyThePediatricEndocrineSociety reaches 100%ofallpatients( axes leadingtoCPHD( progressive partialortotaldeficiencyinotherpituitary one deficiency, theendocrineoutcomeseemstobea adulthood to panhypopituitarism. After diagnosis of age, whichappeargraduallyandgenerallyprogressin hypoglycemia and jaundice; (2) during the pediatric at birthwithaseverehormonalphenotypeincluding hormone deficiencies: (1) permanent anterior pituitary ( amenorrhea ( gonadotrophin deficiencytonormogonadotrophic with highlyvariableseverity, rangingfromcomplete associated with other deficiencies butcanalso beisolated first yearofGHinitiation( occurred before 3 years of treatment, especially during the abnormality ( defect thanforisolatedidiopathicGHDwithoutanyMRI to GH substitution was better in the context of a pituitary recent study( lesions,7.8%casesofPSISwereidentifiedina pituitary nearly 600 GHD patients with short stature caused by observed, from 17%( observed, ( dopaminergic pathwaydisconnection. Itcanbedeficient hormoneshasalsobeendescribed ( pituitary secretion withdeficiencyoftheremaininganterior central hypothyroidism( may be within the normal limits in most patients with gland,and measurement height oftheanteriorpituitary stalkstatus or withthe is notassociatedwithpituitary stalk( with visiblepituitary lower inpatientswithPSISascomparedtoCPHD and cortisol level after stimulation test are significantly and recurrenthyponatremia( syndrome Pituitary stalkinterruption 41 22 ), but not always since non-persistent cases of GHD , ), or on the opposite hyperprolactinemia can be GHD isthemostfrequentlyexistingdeficiencyand Two typicalPSISclinicalmanifestationincludes Very fewpatientshavecentral diabetesinsipidus Prolactin (PRL)variesdependingonthedegreeof TSH deficiencymayalsobefound.Serumlevel ACTH deficiencycancauseneonatalcholestasis( Gonadotrophin deficiency(LH,FSH)isfrequently 47 ) comparedtootherhormonal deficiencies,as 51 59 57 58 ), andsomechildrenmaintainnormal ). ). Intermsoftreatment,growthresponse ); themostsignificantcatch-upgrowth 22 50 ) toone-thirdofpatients( Downloaded fromBioscientifica.com at09/28/202109:48:10AM ). 62 50 51 ). IsolatedsparingofTSH ). 51 ). 61 https://eje.bioscientifica.com ). Itismostlypermanent ). ACTHmeasurement 54 181 , 55 :5 ). Interestingly, 63 56 ). ). Among 48 R203 ). 60 52 via freeaccess ) , European Journal of Endocrinology https://eje.bioscientifica.com presentation, hypoglycemia, andmicropenis( patients fromthosewith isolatedGHDarebreech CPHD. The clinical factors that best discriminate CPHD previously proposed( dysfunction causingosmoreceptordisturbanceshasbeen brain abnormalities:thehypothesisofhypothalamic incaseofEPPwithmore complex midline be observed insipidus. However, defectiveosmoregulatedAVP can function sinceisolatedEPPisnotresponsiblefordiabetes and EPPseemtohavenormalposteriorpituitary origins. Patientsharboringcongenitalhypopituitarism anterior and posterior lobes have different embryonic third ventriclefloor. and ectopicposteriorlobeofhighsignalatthelevel (anterior lobeheight1.8 mm),absenceofthepituitarystalk years and7monthsofageshowsanteriorpituitaryhypoplasia endocrine profile.SagittalT1-weightedimageobtainedat5 intellectual delayordysmorphicfeaturesassociatedwiththe deficiencies. HerePSISwasisolated,notablytherewereno Hormonal testsshowedbothsomatotropinandthyrotropin pituitary stalk(***),withnootherbrainabnormality. pituitary hypoplasia(*),ectopicposteriorlobe(**),absenceof length 32 cmat25weeks).NeonatalMRIrevealedanterior retardation inacontextofprematurebirth(birthweight670 g, post-neonatal periodinacontextofseverefetalgrowth Early diagnosiswithisolatedPSIS.PSISwasdiagnosedinthe Figure 1 Review Every series reportahighbutvariablefrequencyof Every 64 ). J Vergierandothers 65 ). mechanisms. Imagingrevealsnumerousanatomical radiological presentationduetothemultipleetiological hormone deficiency( the diagnosis and endocrine prognosis of patients with investigations, and ithelpsin MRI iskeyforpituitary PSIS neuro-radiologicalpresentation:theMRIcontribution hypopituitarism ( the prognosisandqualityoflifepatientswith hormones andtreatmentinitiationinfluenceboth life-threatening events( deficiency leads toexcess of long-term morbidities and long polyhormonalreplacementtherapy. Sincepituitary features. as thefirstsignsappear, regardlessofinitialendocrine biological endocrine monitoring remains essentialas soon need forsystematicscreening. 65 case ofCPHD(almost60%) thanfacingisolatedGHD( series ( its associationwithendocrine functionvariesbetween ( of midlineabnormalitiesandconstitutesmildformHPE Recent findingssuggestthatPSISbelongstothespectrum Extra-pituitary malformationsassociatedwithPSIS stalk. pituitary 27 times greater than for GHD patients with identified visualized byGd-DTPA, theriskofdevelopingCPHDis stalkisnot status isthereforepossible:ifthepituitary ( portal vesselspreservation improves information about hypothalamo-hypophyseal stalk and identifying the vascular component of pituitary more sensitivethantheunenhancedMRItechniquein recess ofthethirdventricle( stalk ( visible pituitary MRI characteristics:non-visibleanteriorlobe( functionand been reportedbetweenendocrinepituitary stalk (interrupted,thin,normal)( hypothalamus base,normalinthesellaturcica) and/orthe lobe (absence,ectopicalongthestalk,at (absence, hypoplasia,normal),theposteriorpituitary variations incaseofPSIS,concerningtheanteriorlobe syndrome Pituitary stalkinterruption 73 ). Thehighrateofrelatedmalformations highlightsthe ). The occurrence of extra-pituitary malformations and ). The occurrence of extra-pituitary Treatment isbasedonsubstitutinghormoneswithlife- Therefore, patients’long-termfollow-upwithregular A relationshipbetweenanatomicalandfunctional MRI withgadopentetatedimeglumine(Gd-DTPA) is 6 , 8 ), butbirthdefectsseemtobe morefrequentin 67 , 68 69 70 ). ). PSIStriadhasaheterogeneous Downloaded fromBioscientifica.com at09/28/202109:48:10AM 66 ), and EPP inthe infundibular ), earlydetectionofmissing 72 71 ). ). 65 181 ). Correlationshave :5 38 ), non- R204 via freeaccess 6 , European Journal of Endocrinology deficiencies inadditiontoGHD. further testsrevealedonsetof thyroidandgonadotropic brain abnormalityonthesagittal T1weightedimage(B).Later, pituitary stalk(**),ectopicposterior lobe(***)withnoother MRI showedanteriorpituitary hypoplasia (*),interruptionof compatible withseveregrowthhormonedeficiency(GHD). Dynamic functiontestsrevealedverylowpeakGHlevels progressive growthretardation,from+1SDSto was madeattheageof8yearsbecauseisolated (A andB)LatediagnosiswithisolatedPSIS.DiagnosisofPSIS Figure 2 Review J Vergierandothers − 2 SDS(A). neonatal distressarehigh in thePSISpopulation,with The incidenceofbreechdelivery, cesareansection,and deficiency isprecocious andsevere( uterine growthretardation suggestingthathormonal as cryptorchidism ormicropenis,and sometimesintra- severe formofPSIS( repeated episodes ofhypoglycemialinkedtoparticularly with hypotensionandprolongedcholestaticicterus, patients ( of hypopituitarismarefoundinaboutone-thirdPSIS presentation haspreviouslybeendescribed( at baselineandduringfollow-upaccordingtotheinitial deficiencies. Clinical,hormonalandMRIcharacteristics hormone secretionortheoccurrenceofreversible evolve overtime,withtheonsetofnewaffectedpituitary life, butdiagnosisisoftendelayed( since clinicalsignsoftenappearinthefirstdecadeof PSIS isprimarilyencounteredininfancyandchildhood There isavariabletimingintheonsetofmanifestations. Variable ageatonset but thisassociationhasnotbeenrecentlyconfirmed( associated withmoreseverehormonalimpairment( Stilling–Duane syndromecanbeassociated( Moreover, Fanconi anemia, Pallister–Hall, Currarino, and of GHDpatients. lip, shortchin( bridge, bulbousnasaltip,deepphiltrumwithathinupper bossing, hypotelorism,antevertedhelix,highnasal such assparsefinehair, broadforeheadwithfrontal incisor ( or palate( Craniofacial structures may also be altered with cleft lip failure. canal,centralrespiratory craniopharyngeal hypoplasia,colobomaoftheretina, stenosis, opticnerve Arnold–Chiari malformations,septalagenesis,aqueductal optic dysplasia, partial agenesis of the corpus callosum, cerebellar vermisatrophy, cerebellardysgenesis,septo- heterotopia, bilateralperisylvianpolymicrogyria, microcephaly, hydrocephalus, periventricular nodular with mainly brain and eyes defects ( hypoplasia includedornotinCHARGEsyndrome( tractsuchasunilateralrenalagenesisor tract, urinary skin, heart,extremities,axialskeleton,gastrointestinal syndrome Pituitary stalkinterruption Extra-cerebral abnormalities Distinct butinconstantfacialfeatures In theneonatalperiod,combinedfeaturessuggestive malformationswasfirst The presenceofextra-pituitary Midline defects 30 38 8 ). ), anddentalanomaliessuchassinglecentral , 48 ): hypotonia, secondary adrenal deficiency ): hypotonia, secondary 33 , involve the central nervous system involvethecentralnervous 34 ). Manyofthesefeaturesarethose 38 Downloaded fromBioscientifica.com at09/28/202109:48:10AM ), genitaliaabnormalitiessuch arealsodescribed,affecting https://eje.bioscientifica.com 181 42 :5 ). Deficits might ). Deficitsmight werereported, 47 38 74 8 ). ) ( ). ), such as Fig. 1 R205 38 22 8 via freeaccess ). ). ). ), ),

European Journal of Endocrinology https://eje.bioscientifica.com have previouslybeendescribed inadultpatientswiththin but reversiblesomatotropinand gonadotropindeficiencies seemed tobemorefrequent, about60%incaseofEPP( throughout lifeisthuscrucial ( follow-up: along-termclinicalandbiologicalmonitoring than reportedinchildrenprobablyduetothelonger sometimes revealPSIS( about 4years( missing growspurt( delayed boneage( to medicalattentionbecauseofgrowthretardationwith development andqualityoflife.Mostpatientsarebrought challenging atbirth. but interpretationofhormonalassaysisparticularly with PSISrevealedintheneonatalperiod,oftencomplete, hypoplasia ( ( hypoplasia children havinglesssevereanteriorpituitary hasbeencorrelatedto the absenceofneonatalhistory development ( severely altered pituitary and severeradiologicalphenotype,relatedtomore have acriticalformwithgreaterhormonalimpairment isolated GHD( admitted toneonatalintensivecarethanthosewith Besides, PSISpatientswithCPHDseemmorefrequently a birthlengthusuallyinthelowernormalrange( > Review 2 mm) comparedwiththosemoresevere In theadultpopulation,CPHDseemsmorecommon In childhood, PSIS criticallyaffects growth, PSIS patients diagnosed in the neonatal period often < m ( 2 mm) 75 38 ). ). Exploringintellectualdisabilitymay Fig. 2 48 47 Fig. 3 ). Themedianageatdiagnosisis ), orbecauseofpubertaldelayand ). CPHDisfoundinallpatients ). 51 ). Permanentdeficiencies J Vergierandothers 38 ). Accordingly, 54 38 ), ). though genotype–phenotype discordancesoftenoccur. for genetic counseling, even regions. This will be necessary additional variants,especially locatedinnon-coding factors. High speed gene sequencing will help to detect transcription find newdevelopmentalgenesandpituitary development ofendocrinedeficiencies. for diagnosis and prognosis since there is aprogressive as possible.Patients’follow-upthroughlifeisessential clinicians to substitute the missing hormones as soon Neonatal andchildhoodmanifestationsmustalert mostly affectingbrain,eyesandcraniofacialstructures. birthdefects, of hormonaldeficiencies andextra-pituitary environmental factors,leadingtovariablebuthighrates including unconventionalgeneticmechanismsand can bediagnosedwithMRI. belonging tothespectrumofHPEphenotype,which This syndromeisanantenataldevelopmentaldefect multigenic conditionwithhighphenotypicvariability. stalkinterruptionsyndromeisaheterogeneous Pituitary Conclusions andperspectives in adulthood( achieved inordertovalidatecontinuationofGHtherapy of GHsecretionmustbeconsidered when final heightis stalk( pituitary syndrome Pituitary stalkinterruption Regarding PSISetiology, workstillneedsto be doneto Clinical featuresdependonmultifactorialinteractions 54 55 ). , thyrotropin andsomatotropin level. Hormonalmeasurementsrevealed seen ontheT2imageatrightatrial associated toanependymalheterotopia ectopia inthepharynx.Itisalso of thecraniopharyngealcanal(*)without image. It is associated with the persistence ventricle onthepostcontrastT1-weighted ectopic lobeatthefloorofthird of thepituitarystalkandaposterior anterior lobe(height2.7 mm),theabsence years and5monthsofageshowsasmall sagittal T1-weightedimagesobtainedat2 was performed.AxialT2andpostcontrast delay withlearningdisordersandanMRI neuropediatrician becauseofintellectual year-old childwasreferredtoa ‘Accidental’ diagnosis.Atwo-and-a-half- Figure 3 deficiencies. 76 ). Therefore, additional investigation Downloaded fromBioscientifica.com at09/28/202109:48:10AM 181 :5 R206 via freeaccess European Journal of Endocrinology References the public,commercialornot-for-profitsector. This research did not receive any specific grant from any funding agency in Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisreview. no is there that declare authors The Declaration ofInterest between Mendelianandmultifactorialdiseases. pathological phenotype,placingPSISatthecrossroads predisposed individuals mayberesponsible for the influence ofenvironmentalfactorsongenetically interactions isaplausibleexplanation.Indeed,the patterns ofpolygenicinheritanceandgene–environment incomplete penetrance,thecombinationofcomplex might alsohelpidentifyingnovelgeneticcauses. High throughputwhole-genomesequencinganalyses 9 8 7 6 5 4 3 2 Brauner R. Review 1 Davis SW, Ellsworth BS,PerézMillan MI,Gergics P, Schade V, Fang Q, George AS,Brinkmeier ML, Mortensen AH, Gergics P, Simon D, Hadjiathanasiou C,Garel C,Czernichow P&Léger J. Fernandez-Rodriguez E, Quinteiro C,Barreiro J,Marazuela M, Pinto G, Netchine I,Sobrier ML,Brunelle F, Souberbielle JC& Di Iorgi N,Allegri AEM,Napoli F, Bertelli E,Olivieri I,Rossi A& Argyropoulou MI &Kiortsis DN.MRIofthehypothalamic-pituitary Fujisawa I, Kikuchi K,Nishimura K,Togashi K, Itoh K,Noma S, Genetics of combined pituitary hormone deficiency:roadmapinto Genetics ofcombinedpituitary Cheung LYM, Daly AZ,Ajmal A,PérezMillán MI,Ozel AB 2265.2006.02484.x) Endocrinology ectopia. deficiency associatedwithposterior pituitary Phenotypic variabilityinchildrenwithgrowthhormone org/10.1159/000324087) genetic analysis. adult patients:prevalence,evolutionofhormonedysfunctionand stalkdysgenesis-inducedhypopituitarismin & Bernabeu I.Pituitary Pereiro I, Peinó R,Cabezas-Agrícola JM,Dominguez F, Casanueva FF org/10.1210/jcem.82.10.4295 Endocrinology andMetabolism biological-genetic assessmentofitspathogenesis. stalkinterruptionsyndrome:aclinical- Brauner R. Pituitary ( development. pituitary Maghnie M. Theuseofneuroimagingforassessingdisorders org/10.1007/s00247-005-1512-9) axis inchildren. org/10.1148/radiology.165.2.3659371) with MRimaging. stalk:developmentofanectopicposteriorlobeassessed pituitary Minami S, Sagoh T, Hiraoka T&Momoi T. Transection ofthe php?Lng=EN&Expert=95496 Accessible at 2013 gland developmentanddisease. Foyouzi N, Brinkmeier ML,Mortensen AH&Camper SA.Pituitary https://doi.org/10.1111/j.1365-2265.2011.04238.x To elucidate PSIS wide phenotypic expressivity and 106 1–47. Orphanet: Pituitary stalk interruption syndrome stalkinterruption Orphanet: Pituitary 2006 https://www.orpha.net/consor/cgi-bin/OC_Exp. (https://doi.org/10.1016/B978-0-12-416021-7.00001-8) Pediatric Radiology Neuroendocrinology Radiology 64

416–422. Clinical Endocrinology

1987 1997 ) Current Topics inDevelopmentalBiology (https://doi.org/10.1111/j.1365-

165 2005 82 2011 3450–3454. J Vergierandothers 487–489.

35 93 1045–1055. 181–188. 2012 (https://doi. Journal ofClinical Journal ( 76 ) https://doi. 161–176. Clinical (https://doi. . 2010. (https://doi. et al .

syndrome Pituitary stalkinterruption 14 13 21 18 17 16 15 12 20 11 10 19 22 Bashamboo A, Bignon-Topalovic J, Moussi N,McElreavey K& Bashamboo A, Bignon-Topalovic J, Rouba H,McElreavey K& Reynaud R, Albarel F, Saveanu A,Kaffel N, Castinetti F, Lecomte P, Sobrier M-L, Maghnie M,Vié-Luton M-P, Secco A,DiIorgi N, Davis SW, Castinetti F, Ellsworth BS,Potok MA, Carvalho LR, Reynaud R, Gueydan M,Saveanu A,Vallette-Kasic S, Enjalbert A, Zwaveling-Soonawala N, Alders M,Jongejan A,Kova McCormack SE, Li D,Kim YJ,Lee JY, Kim S-H,Rapaport R& Voutetakis A, Argyropoulou M, Sertedaki A,Livadas S,Xekouki P, Webb EA, AlMutair A,Kelberman D,Bacchelli C,Chanudet E, Dattani MT, Martinez-Barbera JP, Thomas PQ,Brickman JM,Gupta R, Castinetti F, Reynaud R,Saveanu A,Jullien N,Quentien MH, Castinetti F, Reynaud R,Saveanu A,Barlier A&Brue T. Genetic 1095) Metabolism stalk interruptionsyndrome. Brauner R. MutationsinthehumanROBO1genepituitary org/10.1210/jc.2015-2995) Clinical EndocrinologyandMetabolism associated With stalkinterruptionsyndrome. pituitary Brauner R. AnonsensemutationinthehedgehogreceptorCDON org/10.1093/brain/awt218) visual andrenalanomalies. ARNT2 mutationcauseshypopituitarism,post-natalmicrocephaly, Brauner R, Simonin G,Gaudart J,Carmona E doi.org/10.1210/jc.2006-0426) of ClinicalEndocrinologyandMetabolism abnormalities. andnooptic nerve located posteriorpituitary aplasia,butnormally life-threatening neonatalphenotype, pituitary Lorini R &Amselem S.NovelHESX1mutationsassociatedwitha 125–133. septo-optic dysplasiainhumanandmouse. Mutations inthehomeoboxgeneHESX1/Hesx1associatedwith genes. novel regulatory et al Lyons RH, Brinkmeier ML,Raetzman LT, Carninci P, Mortensen AH org/10.1210/jc.2005-2173) Endocrinology andMetabolism hormone deficiency:experiencein195patients. Brue T &Barlier A.Geneticscreeningofcombinedpituitary (https://doi.org/10.1210/jc.2017-01660) ofClinicalEndocrinologyandMetabolism Journal interruption syndromeFromexomesequencingin20patients. stalk Hennekam RC. Cluesforpolygenicinheritanceofpituitary Duijkers FA, Maas SM,Fliers E,Van Trotsenburg ASP & org/10.1210/jc.2017-00332) Endocrinology andMetabolism stalkinterruptionsyndrome. in pituitary Levine MA. DigenicinheritanceofPROKR2andWDR11mutations Lescai F, Andoniadou CL,Banyan A,Alsawaid A,Alrifai MT 174 Mårtensson IL, Toresson H, Fox M,Wales JKH, Hindmarsh PC 2004 the intermediatelobe. enlargementmayoriginate from with Prop1genemutations:pituitary Voutetakis C. magneticresonanceimagingin15patients Pituitary Maniati-Christidi M, Bossis I,Thalassinos N,Patronas N&Dacou- 4–19. pituitary hormonedeficiency.pituitary endocrinology: anupdateinthegeneticaetiologiesofcombined Rochette C, Barlier A,Enjalbert A&Brue T. Mechanismsin ando.2012.03.025) Annales d’Endocrinologie hormonedeficienciesinhumans. causes ofcombinedpituitary org/10.1210/er.2016-1101) the genomeera. . Molecular mechanisms of pituitary organogenesis: insearch. Molecularmechanismsofpituitary of R239–R247. 89

(https://doi.org/10.1016/j.mce.2009.12.012) 2200–2206. (https://doi.org/10.1038/477) 2017 Endocrine Reviews 102 (https://doi.org/10.1530/EJE-15-1095)

(https://doi.org/10.1210/jc.2003-031765) 2401–2406. Journal ofClinicalEndocrinologyandMetabolism Journal 2012 Molecular andCellularEndocrinology

Downloaded fromBioscientifica.com at09/28/202109:48:10AM

Brain 2006 2017 Journal ofClinicalEndocrinologyand Journal 73 European Journal ofEndocrinology European Journal

53–55. 2013 2016 (https://doi.org/10.1210/jc.2016- 91 102 https://eje.bioscientifica.com 2016 3329–3336. 2501–2507. 2006

136 37

(https://doi.org/10.1016/j. Journal ofClinical Journal 636–675. 101 181 3096–3105. Nature Genetics et al 91 2018 12–15. :5 4528–4536. . Pituitary stalk stalk . Pituitary Journal ofClinical Journal

(https://doi. (https://doi. č 103 (https://doi. i č (https://doi.

L, Journal of Journal (https://doi. 415–428. 2010 1998 et al (https:// R207

Journal Journal et al 2016 . 323 19 . via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com

29 28 25 24 23 36 35 34 33 32 31 30 27 26 Review Reynaud R, Jayakody SA,Monnier C,Saveanu A,Bouligand J, Cohen E, Maghnie M,Collot N,Leger J,Dastot F, Polak M,Rose S, Castinetti F, Saveanu A, Reynaud R, Quentien MH, Buffin A, Brauner R, Takagi M, Nagasaki K,Fujiwara I,Ishii T, Amano N,Asakura Y, Dateki S, Kosaka K,Hasegawa K,Tanaka H, Azuma N,Yokoya S, Webb EA &Dattani MT. Septo-opticdysplasia. Kelberman D &Dattani MT. Roleoftranscriptionfactorsinmidline Woods KS, Cundall M, Turton J, Rizotti K,Mehta A, Palmer R, Vetro A, Pagani S,Silengo M, Severino M,Bozzola E,Meazza C, El Chehadeh-Djebbar S,Callier P, Masurel-Paulet A,Bensignor C, Karaca E, Buyukkaya R,Pehlivan D,Charng W-L, Yaykasli KO, Ellard S, Baple EL,Owens M,Cannon S,Eccles DM,Abbs S,Scott R, Costalonga EF,França MM, Jorge AAL,Carvalho LRS, Vasques GA, Tatsi C, Sertedaki A,Voutetakis A, Valavani E, Magiakou MA,Kanaka- interruption. stalk PROKR2 variantsinmultiplehypopituitarismwithpituitary Guedj AM, Simonin G,Lecomte P, Barlier A,Rondard P (https://doi.org/10.1210/jc.2016-3158) ofClinicalEndocrinologyandMetabolism Journal deficitsinacohortof417unrelatedpatients. mutations topituitary Touraine P, Duquesnoy P, Tauber M 93 hypopituitarism. LHX4 mutationwithhighphenotypicalvariabilityinpatients Kaffel N, Albarel F, Guedj AM,ElKholy M Endocrinology in PAX6 geneandcongenitalhypopituitarism. Muroya K, Hasegawa Y, Adachi M&Hasegawa T. Heterozygousdefects 2010 phenotype. pituitary orthodenticle homeobox2mutationsareassociatedwithvariable Muroya K, Adachi M,Tajima T, Motomura K ejhg.2009.125) of HumanGenetics 2009 defects. systemandpituitary central nervous Endocrinology severe hormonalprognosisinmalformativeforms. interruption syndromein83patients:novelHESX1mutationand Wong J, Chong WK, Al-Zyoud M,El-Ali M (https://doi.org/10.1186/1755-8166-7-41) duplication and2q37deletion. malformation inapatientwithchromosome2p25 pituitary Zuffardi O &Bozzola M.Severegrowth hormonedeficiencyand 369–373. interruption syndrome. et al Méjean N, Payet M,Ragon C,Durand C,Marle N,Mosca-Boidron A org/10.1210/jc.2014-1984) Endocrinology andMetabolism stalkinterruption syndrome. family withpituitary exome sequencingidentifieshomozygousGPR161mutationina Bayram Y, Gambin T, Withers M, Atik MM,Arslanoglu I Variant Classification2017 Deans ZC, Lester T, Campbell J doi.org/10.1210/jc.2010-1050) Clinical EndocrinologyandMetabolism lobewithoutholoprosencephaly.posterior pituitary GLI2 mutationsinpatientswithhypopituitarismandectopic Leite CC, Mendonca BB&Arnhold IJP. Novelheterozygousnonsense doi.org/10.1210/jc.2012-3982) Clinical EndocrinologyandMetabolism caused bymutationsinholoprosencephaly-relatedgenes. hypoplasia maybe interruption syndromeandisolatedpituitary Gantenbein C, Chrousos GP&Dacou-Voutetakis C. stalk Pituitary E1068–E1073. 2790–2799. . 17q21.31 microdeletion in a patient with pituitary stalk . 17q21.31microdeletioninapatientwithpituitary 95 14 756–764. 67–82. (https://doi.org/10.1016/j.ejmg.2011.03.001) 2011 2014 Journal ofClinicalEndocrinologyandMetabolism Journal (https://doi.org/10.1210/jc.2011-3056)

(https://doi.org/10.1210/jc.2007-2389) Journal ofClinicalEndocrinologyandMetabolism Journal 2010 164 (https://doi.org/10.1210/jc.2009-1334) 172 Journal ofClinicalEndocrinologyand Metabolism Journal 457–465. 37–45. 18 European Journal ofMedicalGenetics European Journal .

393–397. 2015 (https://doi.org/10.1530/EJE-14-0255)

et al Molecular Cytogenetics (https://doi.org/10.1530/EJE-10-0892) 100 . et al ACGS BestPracticeGuidelinesfor 2010 2013 (https://doi.org/10.1038/ J Vergierandothers

E140–E147. . ContributionofLHX4 et al

et al 95 98 et al . A novel dysfunctional . Anoveldysfunctional Endocrine Development E384–E391. E779–E784. European Journal of of European Journal 2017 European Journal European Journal . Over-and . Heterozygous European Journal of of European Journal Journal ofClinical Journal (https://doi. Journal of Journal 102 2014

et al et al 290–301.

Journal of Journal (https:// (https:// 2011 7 . 2012 . Whole- 41. 2008 2008 54 97

syndrome Pituitary stalkinterruption 41 40 38 37 49 48 47 46 45 44 43 42 39 Wang C-Z, Guo L-L,Han B-Y, Su X,Guo Q-H&Mu Y-M. Pituitary Hong M &Krauss RS.Cdonmutationandfetalethanol Guo Q-H, Wang C-Z, Wu Z-Q, Qin Y, Han B-Y, Wang A-P, Wang B, Bar C, Zadro C,Diene G,Oliver I,Pienkowski C,Jouret B,Cartault A, Bauters M, Frints SG,Van Esch H,Spruijt L,Baldewijns MM,Die- Wang Q, Hu Y, stalkinterruptionsyndrome Li G&Sun X.Pituitary Guo Q, Yang Y, Mu Y, Lu J,Pan C,Dou J,Lv Z,Ba J,Wang B, Zou X Tauber M, Chevrel J,Diene G, Moulin P, Jouret B, Oliver I, Han B-Y, Zhang Q,Li L-L,Guo Q-H,Wang C-Z, Cang L,Jin N, Maghnie M, Lindberg A,Koltowska-Häggström M&Ranke MB. Deal C, Hasselmann C,Pfäffle RW, Zimmermann AG,Quigley CA, Dominguez R, AguirreVila-Coro A, Slopis JM&Bohan TP. Brain Ming JE &Muenke M.Multiplehitsduringearlyembryonic Journal ofNeuroendocrinology Journal stalk interruptionsyndrome:fromclinicalfindingstopathogenesis. e1002999. holoprosencephaly spectrumdisordersinmice. exposure synergizetoproducemidlinesignalingdefectsand Medicine stalkinterruptionsyndrome. pituitary hypopituitarism: awhole-exomesequencingstudyofHanChinesewith Dou J, Wu X &Mu Y. Multi-genicpatternfoundinraretypeof pone.0142354) PLoS ONE radiological assessmentaccordingtotheinitialpresentation. syndrome frominfancytoadulthood:clinical,hormonal,and Ajaltouni Z, Salles JP, Sevely A 2014 and neuraltubedefects. increased Smulders CEMd de,Fryns JP, &Froyen G.Evidencefor Marynen P 833–849. and hypopituitarism. underdosage ofSOX3isassociatedwithinfundibularhypoplasia org/10.1007/s00431-013-2214-1) ofPediatrics European Journal functions. in 59children:thevalueofMRIassessment ofpituitary (https://doi.org/10.1371/journal.pone.0053579) clinical characteristicanalysisof55 cases. et al 266–273. interruption syndrome. stalk disorders andeffectofGHtherapyin35patientswithpituitary Pienkowski C &Sevely A.Long-termevolutionofendocrine 503X.2016.05.007 Xue Bao interruption syndromein114cases. Chen F, Zhao L,Cui J EJE-12-0801) ofEndocrinology Journal deficiency inKIGS(PfizerInternationalGrowthDatabase). Magnetic resonanceimagingofCNSin15,043childrenwithGH org/10.1159/000350829) study. hormone deficiency:datafromaninternationalobservational biochemical phenotypesinchildrenwithcongenitalgrowth imagingabnormalitiesandclinical between pituitary Child CJ, Shavrikova EP, Cutler GBJr&Blum WF. Associations archpedi.1991.02160060106030) Adolescent Medicine to cocaineandotherstreetdrugs. and ocularabnormalitiesininfantswithuteroexposure org/10.1086/344412) ofHumanGenetics Journal development: digenicdiseasesandholoprosencephaly. jne.12451) . Pituitary stalkinterruptionsyndrome inChinesepeople: . Pituitary 164 Hormone ResearchHormone inPaediatrics 2016 2017 1947–1952. 2015 (https://doi.org/10.1086/430134) (https://doi.org/10.1159/000089425) SOX3

(https://doi.org/10.1371/journal.pgen.1002999)

21 38

dosageasariskfactorforX-linkedhypopituitarism 10 3626–3632. 534–538. ) e0142354. 1991

American Journal ofHumanGenetics American Journal et al (https://doi.org/10.1002/ajmg.a.36580) 2013 Hormone ResearchHormone inPaediatrics American Journal of Medical Genetics Part A ofMedicalGeneticsPart American Journal

145 2002 . Clinical features of pituitary stalk . Clinicalfeaturesofpituitary Downloaded fromBioscientifica.com at09/28/202109:48:10AM ( https://doi.org/10.3881/j.issn.1000- 2014 2017 (https://doi.org/10.1111/jcmm.13272) 168 688–695. (https://doi.org/10.1371/journal. et al 71

211–217. Archives ofPediatricsand 1017–1032. 173 29 . Pituitary stalkinterruption . Pituitary Zhongguo Yi XueKeYuan . 2013 Journal of Cellular and Molecular ofCellularandMolecular Journal (https://doi.org/10.1111/ 589–595. (https://doi.org/10.1001/ PLoS ONE

79 181 (https://doi.org/10.1530/ 283–292.

(https://doi. :5

PLOS Genetics (https://doi. 2013 2005 American (https://doi. 2005 8

European e53579. 64 R208 2012

via freeaccess 8

European Journal of Endocrinology

63 62 61 60 59 58 57 56 54 53 52 51 50 55 Review Nawaz A, Azeemuddin M & Shahid J. Pituitary stalkinterruption Nawaz A, Azeemuddin M&Shahid J. Pituitary Zhang Q, Zang L,Li Y-J, Han B-Y, Gu W-J, Yan W-H, Jin N, Chen K, Jang KM &Ko CW. stalkinterruption Delayeddiagnosisofpituitary Mauvais F-X, Gonzales E,Davit-Spraul A,Jacquemin E&Brauner R. Rottembourg D, Linglart A,Adamsbaum C,Lahlou N,Teinturier C, Zenaty D, Garel C,Limoni C,Czernichow P&Léger J.Presenceof Xu C, Zhang X,Dong L,Zhu B&Xin T. MRIfeaturesofgrowth Lee SS, Han A-L,Ahn MB,Kim SH,Cho WK,Cho KS,Park SH, Loche S, DiIorgi N,Patti G,Noli S,Giaccardi M,Olivieri I,Ibba A& Léger J, Danner S,Simon D,Garel C&Czernichow P. Doallpatients Grimberg A &Allen DB.Growthhormonetreatmentforgrowth Grimberg A, DiVall SA, Polychronakos C,Allen DB,Cohen LE, Wang W, Wang S, Jiang Y, Yan F, Su T, Zhou W, Jiang L,Zhang Y& El Chehadeh S,Bensignor C,deMonléon J-V, Méjean N&Huet F. syndrome presentinginaeuthyroid adultwithshortstature. org/10.1097/MD.0000000000009084) stalk interruptionsyndrome. Du J, Wang XL 22 insufficiency. syndrome withsevererecurrenthyponatremiacausedbyadrenal doi.org/10.1371/journal.pone.0147750) stalk interruptionsyndrome. Cholestasis revealsseverecortisoldeficiencyinneonatalpituitary 105–111. stalkinterruptionsyndrome. pituitary Bougnères P &Carel JC.Gonadotrophicstatusinadolescentswith 2265.2003.01768.x Endocrinology children withnonacquiredgrowthhormonedeficiency. response tohumangrowthhormonetreatmentinprepubertal axisisasignificantdeterminantofthefirst3yearsgrowth pituitary magnetic resonanceimagingabnormalitiesofthehypothalamic- 3474–3478. lesions. pituitary hormone deficiencyinchildrenwithshortstaturecausedby 55. syndrome. stalkinterruption hormonedeficiencycausedbypituitary pituitary Jung MH &Suh BK.Growthwithoutgrowthhormoneincombined Development Maghnie M. Growthhormonedeficiencyinthetransitionage. org/10.1210/jc.2004-1274) Clinical EndocrinologyandMetabolism neurohypophysis havepersistentGHDinadulthood? with childhood-onsetgrowthhormonedeficiency(GHD)andectopic MOP.0000000000000505) Opinion inPediatrics hormone deficiencyandidiopathicshortstature. org/10.1159/000452150) ResearchHormone inPaediatrics insulin-likegrowthfactor-Ideficiency.short stature,andprimary children andadolescents:growthhormonedeficiency, idiopathic growth hormoneandinsulin-likefactor-Itreatmentin Quintos JB, Rossi WC,Feudtner C&Murad MH.Guidelinesfor cen.12788) Clinical Endocrinology severity ofhormonedeficiencies:PSinterruptionsyndromerevisited. stalk(PS)visibilityandthe Ning G. Relationshipbetweenpituitary 71 benefits ofgrowthhormonetherapy. stalkinterruptionsyndrome:endocrinefeaturesand The pituitary 102–110. 208–212. (https://doi.org/10.6065/apem.2017.22.1.55) (https://doi.org/10.1111/j.1365-2265.2007.03155.x)

Annals ofPediatricEndocrinologyandMetabolism 2018 (https://doi.org/10.3892/etm.2017.4377) 2003 (https://doi.org/10.1016/j.ando.2009.11.007) (https://doi.org/10.6065/apem.2017.22.3.208) Annals ofPediatricEndocrinologyandMetabolism et al Experimental andTherapeuticMedicine 33 ) 58 . Thyrotrophic status in patients with pituitary . Thyrotrophicstatusinpatientswithpituitary 2017 46–56. 2015 647–652.

83 (https://doi.org/10.1159/000487525) 466–471. Medicine PLoS ONE 369–376. 2016 ( https://doi.org/10.1046/j.1365- 86 2005 Annales d’Endocrinologie 2018

J Vergierandothers Clinical Endocrinology (https://doi.org/10.1097/ 2016 361–397.

(https://doi.org/10.1111/ 90 97 11 650–656. e9084. e0147750.

(https://doi. Current Journal of Journal 2017 (https://doi. (https://doi. Clinical

2017 (https:// 2008 13 Endocrine Endocrine 2017 2010

22 69

Accepted 2September2019 Revised versionreceived5August2019 Received 6March2019

syndrome Pituitary stalkinterruption 67 66 65 64 76 75 73 72 71 74 70 69 68 Maghnie M, Triulzi F, Larizza D,Preti P, Priora C,Scotti G&Severi F. Kao K-T, Stargatt R&Zacharin M.Adultqualityoflifeandpsychosocial Mo D, Blum WF, Rosilio M,Webb SM, Qi R&Strasburger CJ. Mills JL, Schonberger LB,Wysowski DK, Brown P, Durako SJ,Cox C, Pham L-L, Lemaire P, Harroche A,Souberbielle J-C&Brauner R. Secco A, Allegri AEM,DiIorgi N,Napoli F, Calcagno A,Bertelli E, Sarfati J, Saveanu A&Young J. stalkinterruptionand Pituitary Murray PG, Hague C,Fafoula O,Patel L,Raabe AL,Cusick C, Voutetakis A, Sertedaki A&Dacou-Voutetakis C. stalk Pituitary Maghnie M, Genovese E,Villa A, Spagnolo L,Campan R&Severi F. Chen S, Léger J,Garel C,Hassan M&Czernichow P. Growth Kulkarni C, Moorthy S,Pullara SK,Rajeshkannan R& Arnhold IJP,Melo ME, Marui S,Carvalho LR, Leite CC,Mendonça BB Hypothalamic-pituitary dysfunction in growth hormone-deficient dysfunctioningrowthhormone-deficient Hypothalamic-pituitary Paediatrics outcomes ofchildhoodonsethypopituitarism. org/10.1210/jc.2014-2892) Endocrinology andMetabolism controlandcomplicationsstudy.hypopituitary replacement forgrowthhormonedeficiency:ananalysisofthe Ten-year changeinqualityoflifeadultsongrowthhormone 2004 growthhormonerecipients. of pituitary-derived Kong F & Fradkin JE. Long-term mortality in the United States cohort 2013 factors influencingtheheterogeneityofitspresentation. stalkinterruptionsyndromein53postpubertalpatients: Pituitary 2011 ectopic PPandsepto-opticdysplasia. defectassociatedwith evaluation inpatientswithanteriorpituitary Olivieri I, Pala G,Parodi S,Gastaldi R radcr.2017.12.002) Radiology CaseReports 0475-8) Endocrine syndrome andreversiblegonadotropesomatotropedeficiencies. bulbsaplasia/hypoplasia inamanwithKallmann olfactory (https://doi.org/10.1111/j.1365-2265.2008.03236.x) gland. posterior pituitary hormonedeficiency inpatientswithanectopic multiple pituitary Hall CM, Wright NB, Amin R&Clayton PE.Associationswith (https://doi.org/10.4103/0971-3026.107179) 545–550. interruption syndrome. 281–290. function. residual anteriorpituitary stalkinpredicting stalk syndrome:theroleofvascularpituitary Dynamic MRIinthecongenitalagenesisofneuralpituitary 2408–2413. function. stalk assertedbymagneticresonanceimagingandanteriorpituitary variations andrelationshipbetweenthevisibilityofpituitary hormone deficiencywithectopicneurohypophysis:anatomical 95–102. and Metabolism abnormalities. patients withpituitary literature. of clinico-radiologicalfeaturesinadultsandchildrenwithreview stalktransectionsyndrome:comparison Unnikrishnan AG. Pituitary lobe. and ectopicposteriorpituitary LHX4 andHESX1evaluationinpatientswithhypopituitarism magnetic resonance, & Knoepfelmacher M.Hormonal,pituitary 8 165 144 e53189. ( 2015 https://doi.org/10.1111/j.1365-2265.2006.02692.x 411–420. 430–436. (https://doi.org/10.1097/MOP.0000000000000378) (https://doi.org/10.1046/j.1365-2265.1996.00789.x) 2015 Journal ofClinicalEndocrinologyandMetabolism Journal Indian Journal ofRadiologyandImaging Indian Journal (https://doi.org/10.1210/jcem.84.7.5849) 1991 49 84 (https://doi.org/10.1371/journal.pone.0053189) 865–866. 94–101.

(https://doi.org/10.1016/j.jpeds.2003.12.036) (https://doi.org/10.1530/EJE-11-0437) 73 2018 79–83. Current OpinioninPediatrics Clinical Endocrinology Downloaded fromBioscientifica.com at09/28/202109:48:10AM (https://doi.org/10.1159/000430863) 13 (https://doi.org/10.1007/s12020-014- 2014 503–506. (https://doi.org/10.1210/jcem-73-1-79) 99 Clinical Endocrinology https://eje.bioscientifica.com Clinical Endocrinology Journal of Clinical Endocrinology ofClinicalEndocrinology Journal European Journal ofEndocrinology European Journal 4581–4588. et al (https://doi.org/10.1016/j. . Posterior pituitary (PP) . Posteriorpituitary 181

Hormone Research Hormone in 2008 :5 Journal ofClinical Journal 2012 Journal ofPediatrics Journal (https://doi. 2016 69

22 597–602. 1999 PLoS ONE 182–185. 1996 2007 28 )

R209

45 66

via freeaccess