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European Journal of Endocrinology -18-0383 biosynthetic function and is traditionally sub-classified as to defectivethyroidglanddevelopmentorhormone congenitalhypothyroidism (CH) occursdue Primary Introduction and clinicaldiagnosticchallenges,focussingonprimaryCHisolatedCCH. programmes. ThisreviewwilldiscussrecentgeneticaetiologicaladvancesinCHandsummarizeepidemiological data despite subnormalthyroidhormonelevelsandwillthereforeevadediagnosisinprimary, TSH-basedCH-screening pituitary hormonedeficits.CCHismostcommonlydefinedbiochemicallybyfailureofappropriateTSHelevation hypothyroidism (CCH)isararerentitywhichmayoccurinisolation,or(morefrequently)associationwithadditional delay; therefore,CHisscreenedforindevelopedcountriestofacilitatepromptdiagnosis.Centralcongenital structurally intactgland.Delayedtreatmentofneonatalhypothyroidismmayresultinprofoundneurodevelopmental where adefectivemolecularpathwayforthyroidhormonogenesisresultsinfailureofhormoneproductionby a thyroid dysgenesis(TD),referringtoaspectrumofdevelopmentalabnormalities,anddyshormonogenesis, or pituitarypathology. Primary CH isthemostcommonneonatalendocrinedisorder, traditionallysubdividedinto impaired thyroid-stimulatinghormone(TSH)-mediatedstimulationofthethyroidglandasaresulthypothalamic Congenital hypothyroidism(CH)maybeprimary, duetoadefectaffecting thethyroidglanditself,orcentral,dueto Abstract Science, Addenbrooke’s Hospital,Cambridge,UK of CambridgeMetabolicResearchLaboratories,Wellcome Trust-Medical ResearchCouncilInstituteofMetabolic Amsterdam UMC,UniversityofAmsterdam,PediatricEndcorinology, Amsterdam,theNetherlands,and 1 C Peters perspectives Congenital hypothyroidism: updateand DIAGNOSIS OFENDOCRINEDISEASE Department ofEndocrinology, GreatOrmondStreetHospitalforChildren,London,UK, https://doi.org/ https://eje.bioscientifica.com Review into geneticdiagnosticand clinical practice. functionally characterising genes causingthesedisorders;andthentotranslate discoveries and centralhypothyroidism. Sheaimstogainnewinsightsintothyroidbiologyby identifying and generation sequencing approaches to identify known and novel genetic causes ofcongenital primary group investigatesthegeneticbasisofcongenitalhypothyroidism, usingcandidategeneandnext Consultant Endocrinologist at Addenbrooke’sas anHonorary Hospital,Cambridge. Her research at theWellcome Trust-MRC InstituteofMetabolicScience,UniversityCambridge(UK),aswell Nadia Schoenmakers Invited author’s profile 1 , A S P van Trotsenburg 10.1530/EJE -18-0383 isaWellcome Trust Intermediate Clinical FellowandPrincipal Investigator 6 © 2018EuropeanSociety ofEndocrinology C Petersandothers 2 and N Schoenmakers Printed inGreatBritain 3 most commonlyinvolvingthyroidectopy, an abnormally to aspectrumofaberrantthyroidglanddevelopment, thyroid dysgenesis(TD)ordyshormonogenesis.TDrefers update Congenital hypothyroidism: Published byBioscientifica Ltd. 2 Emma Children’s, 3 University Downloaded fromBioscientifica.com at10/05/202110:01:11AM (2018) Endocrinology European Journal of [email protected] Email to NSchoenmakers should beaddressed Correspondence 179 179 :6 , R297–R317

R297 –R317 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com Although mostindustrialized countriesoperateneonatal treatment of CH is an important public health concern. neurodevelopment, therefore, prompt detection and are aprerequisitefornormal childhoodgrowthand biosynthetic pathway( as aresultofdefectsingenescontrollingtheTSH oftenwith anestimatedincidenceofaround1:65 000, hormone deficits,butisolatedTSHdeficiencyoccurs Most individuals with CCH exhibit additional pituitary of upto1:16 400 to1:21 000 intheNetherlands( common thanpreviouslyappreciatedwithanincidence Although assumedtoberare,CCHmaymore hypothyroidism ( as subclinicalormildprimary in onestudy),withthepotentialformisdiagnosis predominantly hypothalamic(maximum12.9 impaired bioactivitymaybedetectedifthedefectis elevated serumlevelsofimmunoreactiveTSHwith subnormal thyroidhormoneconcentrations,mildly manifests withnormalorsubnormalTSHlevelsdespite unresolved ( majority of cases, the molecular basis has remained deficit inTSHsynthesisorsecretion,andthe pathologycausesaqualitativeorquantitativepituitary thyroid hormone biosynthesis. Hypothalamic or stimulating hormone(TSH) results ininadequate stimulation ofanormalthyroidglandbythyroid- ( hormone biosynthesismachinery in genes encoding known components of the thyroid individuals withdyshormonogenesisharbourmutations known TD-associatedgene.Incontrast,themajorityof less than5%TDcasesareattributabletoamutationin thyroid differentiation, migration and growth; however, usually not clear. Genetic causes involve genes mediating be asporadicdiseaseforwhichtheunderlyingaetiologyis with gland incidence ofCHlargelyduetoincreaseddiagnosiscases diagnostic cut-offshavereportedadoublinginthe undertaken morerecentlyusinglowerscreeningTSH occurring due to dyshormonogenesis. However, studies cases havebeenattributedtoTDwiththeremainder biosynthesis is disrupted ( in whichthemolecularpathwayforthyroidhormone normally located, sometimes goitrous thyroid gland refers tofailureofthyroidhormoneproductionbya located buthypoplasticthyroid( of TDcasesandasmallminorityexhibitnormally absence ofthethyroidgland(athyreosis)affects20–30% situated andmostlysmallthyroidgland.Complete Review Adequate circulating thyroidhormonelevels Central CH(CCH)occurswhendefective in situ 5 ). AlthoughCCHmostcommonly (GIS)( 5 3 , ). TDisgenerallyconsideredto 2 9 ). Historically, 75–85% of CH ). C Petersandothers 1 ). Dyshormonogenesis 2 , 4 ). mIU/L 7 , 8 6 ). ). ). to increaseddiagnosisofcaseswithgland- detected incidenceofCHhasdoubledagain,largelydue at 1:3000–4000 ( was found to be almost double these original estimates once screeningwasintroduced,theactualincidence CH was estimated at 1:7000 ( of primary Prior tothedevelopmentofCHscreening,incidence Epidemiology Primary CH for theseconditions. epidemiological data and clinical diagnostic challenges aetiological advancesaswellsummarizingrecent and isolatedCCH,incorporatingdiscussionofgenetic CH but notCCH.Thisreviewwillfocusonprimary CH TSH-based methodologywhichwilldetectprimary screening programmesforCH,mostemployaprimary such patients. for levothyroxinehasnot yet beenfullyevaluatedin when thereisafurtherincreased physiologicaldemand later lifeandpotentialforhypothyroidism inpregnancy years. Theriskofsubclinical oroverthypothyroidismin but sufficienthormonebiosynthesisforlaterchildhood meet theincreasedrequirementsinfirstmonthsoflife, with failureofadequatethyroxine(T4)production to of age. Transient CH may reflect mild dyshormonogenesis longer require levothyroxine when retested around 3 years biochemical criteriaforCHtreatmentininfancybutno with transienthypothyroidism.Thesechildrenmeetthe there isalsoanincreaseintheproportionofchildren provoke CHremainsunclear. in thegenesmediatingthyroidaliodinemetabolismto extent towhichiodinedeficiencyinteractswithvariants with astructurallyabnormalgland with alessercontributionfromthyroidectopyorcases children withslightlyhigherTSHconcentrations( insufficiency mayalsobecontributingtothenumberof of thepopulationsscreened( influences include changes in ethnicity and demographics the cutpointshavenotbeenaltered( prevalence ofCHhasalsoincreasedinprogrammeswhere changes andreportsofmissedcasesCH.However, the of newbornscreeningcutpointsthathasarisenwithassay the increaseinCHcasesisduetoageneralizedlowering incidence arecomplex( children withathyreosisseemsunchanged( update Congenital hypothyroidism: In addition to the overall increased incidence of CH, The contributingfactorsunderlyingthisaltered 12 ). Overthelasttwodecades, 3 Downloaded fromBioscientifica.com at10/05/202110:01:11AM , 13 , 14 14 , 16 , 15 , in situ 17 , 16 179 ) and dietary iodine ) anddietary 14 ). Somearguethat 10 :6 , . Thenumberof 15 , 11 3 ). Additional in-situ ). ); however, 18 R298 (GIS), ). The via freeaccess

European Journal of Endocrinology

Table 1 A summary of the genetic defects implicated in congenital hypothyroidism with thyroid dsygenesis and typical clinical features. Review

Gene Family M/B Additional clinical features CH Radiological features NKX2-1 Homeodomain-containing M† Neurological (BHC, developmental delay, hypotonia), Subclinical-overt, may be euthyroid GIS,athyreosis and ectopy also transcription factor respiratory (IRDS, recurrent infections) reported PAX8 Paired homeodomain transcription M Urogenital tract malformations (rare) Moderate-severe, subclinical Hypoplasia/GIS, athyreosis factor euthyroidism or later onset and ectopy also reported hypothyroidism reported FOXE1 Forkhead/winged-helix transcription B Cleft palate, spiky hair (universal), choanal atresia Severe Athyreosis factor GLIS3 GLI-similar zinc finger protein B Neonatal diabetes, dysmorphic facies, renal cystic Severe, TSH resistance GIS, athyreosis dysplasia, hepatic fibrosis, congenital glaucoma, learning difficulties and skeletal abnormalities NKX2-5 NKX2 homeodomain-containing M Congenital heart disease Euthyroid to severe CH GIS, ectopy, athyreosis

transcription factor C Petersandothers CDCA8 Major component of the M/B Congenital heart disease* Euthyroid to severe CH Athyreosis, ectopy, chromosomal passenger complex hemiagenesis, nodules JAG1 Notch ligand M Alagille syndrome/congenital heart disease/isolated Spectrum from subclinical GIS/hypoplasia/ectopy CH hypothyroidism to severe CH NTN1** Laminin superfamily member M Congenital heart disease Severe CH Ectopy TSHR G-protein coupled receptor M/B Nil Spectrum from compensated Spectrum from GIS to severe hyperthyrotropinaemia to severe CH hypoplasia TSH resistance

*n = 1 case; **n = 1 case, additional variants: 47, XYY karyotype; and atypical 22q11 deletion. Italics denote less common features.† often de novo B, bilallelic; BHC, benign hereditary chorea; GIS, thyroid gland in situ; IRDS, infant respiratory distress syndrome; M, monoallelic. G-protein-coupled receptorforTSH( roles inextrathyroidaltissues( follicular cells, they also have individual developmental to mediateorganogenesisonlyinepithelialthyroid mice. Althoughthesetranscriptionfactorsactinconcert define earlythyroiddevelopmentinbothhumansand an indispensablequartetoftranscriptionfactorswhich HHEX zinc finger3). known as (Paired box 8), 1 of-function mutationsin has establishedfivekeymonogeniccausesofTD:loss- identified; however, geneticascertainmentinCHcases In more than 95% cases, theaetiology for TD cannot be Monogenic causesofTD Genetic advancesinprimaryCH result in cerebral and pulmonary phenotypes in addition result in cerebraland pulmonary hypothalamic neurons.Consequently, contributing todevelopment oftheventralforebrainand surfactantproductionand being requiredforpulmonary differentiated thyroid( maintenance ofthenormalarchitecture andfunctionof ( cell survival suggesting that thyroidbudwhichdisappears aroundE10.5-11, embryonic and involved inthyroiddifferentiation(including NKX2-1 playsamajorroleintheregulationofkeygenes the mostfrequenttranscriptionfactormutationinCH. Heterozygous loss-of-function NKX2-1 family ( penetrance maybehighlyvariable,evenwithinthesame patterns ( reflecting theiradditional,extrathyroidalexpression deficiencies inthesegenesunderliedistinctsyndromes and Monogenic loss-of-functionmutationsin Key transcriptionfactormutationsinTD ( multiple organsfromearlyoninembryogenesis a roleinbothtranscriptionalrepressionandactivation update Congenital hypothyroidism: (NK2homeobox1,previouslyknownas FOXE1 TPO (haematopoeticallyexpressedhomeobox)encode 1 , ), and Table 1 22 TTF2 are rare but well-established causes of TD, and ). 23 PAX8 Nkx2-1 , ) andmostrecently, Nkx2-1 ), however, expressivityandphenotypic 24 FOXE1 ). Additionally, , NKX2-1 mayplayaroleinthyroidprecursor -null mice also exhibit a visible 25 Downloaded fromBioscientifica.com at10/05/202110:01:11AM (Forkhead box E1, previously ) andhasextrathyroidalroles, TSHR and 19 (TSHreceptor), NKX2-1 ). TSHRisthethyroidal FOXE1 Nkx2-1 20 179 GLIS3 https://eje.bioscientifica.com NKX2-1 ), andGLIS3plays :6 mutationsare , togetherwith isrequiredfor NKX2-1 (GLISfamily TTF1 mutations TSHR 21 ), R299 , NKX2- ). PAX8 PAX8 , TG via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com been associatedwithurogenital tractabnormalities( the nephrogenicmesenchyme andrarely, mutationshave childhood oradulthood( may alsobetransientorsubclinical andmanifestinlater Despite CHinmostaffected patients,thyroiddysfunction GIS, ectopyandathyreosismayalsooccur( predominantly exhibitthyroidhypoplasia;however, may mediatediseasephenotype( both dominant negative effects and haploinsufficiency dominant withvariableexpressivityandpenetrance the DNA-bindingdomain.Inheritanceisautosomal 2018.1), themajoritycomprisingsubstitutionsaffecting (Human GeneMutationDatabase(HGMD)Professional mutations defined as‘diseasecausing’arereportedinHGMD adult thyroidfollicularcelldifferentiation( inadultsandisinvolvedthemaintenanceof cell survival ( precursor cell survival at aroundE11–11.5atteststoalikelyroleforPAX8 inthyroid disappearance ofthethyroidcellprecursorsin TG thyroid differentiationandhormonebiosynthesisincluding PAX8 isalsocrucialforexpressionofthegenesinvolvedin PAX8 enhancer inthisregion( implicated, suggestingthepresenceofanupstream moreover, deletionsproximalto be specificallyexcludedinbrain–lung–thyroidsyndrome; 28 dominant negativeeffectshavealsobeendescribed( due tohaploinsufficiency, butaminorityofvariantswith ( reassure parents that the risk to future offspring is minimal but frequentlyoccur inheritance withvariableexpressivityandpenetrance, associated mortalityofupto16%( hypersensitivityandcarriesan infections andairways distresssyndrome(IRDS),recurrent infant respiratory are alsodescribed( although glandhypoplasia,haemiagenesisorathyreosis mild or subclinical with normal thyroid morphology ataxia anddevelopmentaldelay. Hypothyroidismisusually choreabutmaycomprisehypotonia, a benignhereditary mutations. Neurologicalmanifestationstypicallyinclude the distributionofphenotypesincaseswith ‘brain-lung-thyroid’ syndrome. to thyroiddysfunction,withacompletetriadconstituting 22 Review ). Deletionsinvolving , ). Mostmutationsarethoughttoresultinaphenotype Twenty-nine heterozygousloss-of-function NKX2-1 TPO and mutationsmayexhibitautosomaldominant SLC5A5 26 31 ). Pulmonary compromiseincludes ). Pulmonary de novo ( ). Indeed, Pax8 also controls thyroid ). Indeed, Pax8 also controls thyroid NKX2-1 27 19 36 ). , ). PAX8 isalsoexpressedin , which,ifconfirmed,may 29 arecommonandshould 33 , C Petersandothers NKX2-1 iue 1A Figure 22 30 , 34 , ). Additionally, the 27 ). Affectedpatients 32 ). havealsobeen ). Pax8 summarizes Fig. 1B -null mice -null mice NKX2-1 ) ( PAX8 36 35 22 ). ). ,

refer topercentagesofthecohort. three phenotypes(includingthe absenceofphenotype).Numbers were onlyincludedifinformation wasavailableregardingall NKX2-1 180 individualsharbouringmissense orsmallindelmutationsin summarizing neurological,pulmonaryandthyroidphenotypesin cases ineachmorphologicalcategory. (A)Venn diagram ‘disease-causing’ byHGMD.Numbersrefertothepercentageof missense orsmallindelmutationsin (B) Reportedthyroidmorphologiesinthe84individualswith Figure 1 update Congenital hypothyroidism: categorized as ‘disease-causing’ by HGMD. Individuals categorizedas‘disease-causing’ byHGMD.Individuals Downloaded fromBioscientifica.com at10/05/202110:01:11AM PAX8 categorized as categorizedas 179 :6 R300 via freeaccess European Journal of Endocrinology paucity ofcolloidandextensive fibrosis.SignificantTSH gland demonstratedabnormal architecture with a however, histology from an ultrasonographically normal apparently normaltohypoplasia orglandathyreosis; is autosomalrecessive.Thyroid morphologyrangesfrom permanent neonataldiabetes( penetrant multisystemphenotypeconsistentlyincluding associated with CH in all but one case as part of a variably in childrenfrom14differentfamiliesandarerobustly of-function mutationsin maintenance ofnormalkidneyfunction.Biallelicloss- thyroid hormonebiosynthesis,spermatogenesisandthe cell generation and maturation, insulin gene expression, is particularlyimportantintheregulationofpancreatic GLIS3 may act as a transcriptional activator or repressor and roleinembryogenesis. factors, whichplayakeyregulatory subfamily of Krüppel-like zinc finger protein transcription GLIS3 isamemberoftheGLI-similar1–3(GLIS1–3) GLIS3 loss-of-function mutations( phenotype isindistinguishablefromthatassociatedwith of mutation in the same region results in enhanced activity resulting in loss of function. A single gain-of-function both DNAbindingandtranscriptionalactivityofFOXE1 the forkheadDNA-bindingdomain.Allexceptoneimpair autosomal recessive and all described mutations cluster in hair follicles( epiglottis, palate, oesophagus, definitive choanae and may alsooccur, reflecting theexpressionof Lazarus syndrome).Choanalatresiaandbifidepiglottis in associationwithcleftpalateandspikyhair(Bamforth- typically exhibitathyreosisorseverethyroidhypoplasia, mutations havenowbeenreportedandaffectedpatients biosynthesis ( expression ofgenesinvolvedinthyroidhormone the mature,differentiatedthyroid,forexampleenabling gland. Additionally, FOXE1hasaroleinmaintenanceof ofthedevelopingthyroid as differentiationandsurvival supporting aroleforFOXE1inthyroidmigrationaswell in an ectopic site at the base of the tongue, or disappears, thyroidbud,whicheitherremains develop arudimentary oesophagus, choanae and hair follicles. family, whichisexpressedinthedevelopingoropharynx, FOXE1 isatranscriptionfactorintheforkheaddomain FOXE1 Review TG At least seven biallelic CH-associated and TPO 37 39 , promoters,buttheassociatedclinical 38 ). Inheritanceof ). GLIS3 40 ). al 1 Table havenowbeendescribed C Petersandothers FOXE1 ) ( 21 Foxe1 mutationsis ). Inheritance FOXE1 -null mice FOXE1 point in β

hypoplasia, however, atthemilderendofspectrum, manifests asseverebiochemicalCHwithorthotopicgland dominant or recessive ( mutated deleteriousness ofthemutation,andnumber the associatedphenotypeisdependentonboth TSHR TSHR therapy despitenormalizationoffreeT4( treatment withconventionaldosesoflevothyroxine TSH andthyroglobulinlevelsappeartoberesistant hormone ( of thyroidfollicularcellsandbiosynthesis is indispensableforTSH/TSHR-mediatedproliferation actions downstreamofTSHandtheTSHR,sinceGLIS3 harbouring resistance frequentlycompoundsmanagementofchildren point mutationsresultindecreased signaltransduction levels ofTSHRexpressedat the plasmamembrane.Most nonsense and frameshift mutations generally decreasing in individualsfromEastAsia ( ( genetic causeofnon-goitrousCH,affecting5%families Turkish cohort, morphologies, butinaconsanguineousPakistaniand studies involvingsuchcasesincludeadditionalthyroid hypoplasia ismoredifficulttoestimate,sincemost contribution of of non-autoimmunehyperthyrotropinaemia( described, withincidencesof11–29%inItalianstudies causing partial TSH resistance, are most frequently population screened.Heterozygous on theclinicalcharacteristicsandethnicityofCH have beenreported,theincidenceofwhichdepends synthesis andrelease. trimester andsubsequentlystimulatesthyroidhormone ( confirming thepresenceofsomeresidualthyroidtissue associated withameasurableserumthyroglobulin(TG) thyroid hypoplasiawhichisundetectableonimagingbut mutations causeonlyapparentathyreosis,i.e.marked is TSHindependent.Therefore,evensevere thyroglobulin (TG)synthesisattheonsetoffolliculogenesis sized thyroidgland.Earlydevelopment,and thyroidhormonebiosynthesisfromanormal- preserved isolated hyperthyrotropinaemiamaybeassociatedwith update Congenital hypothyroidism: 43 20 ). Founder mutations also operate, e.g. ). TSHplaysaroleinthyroidgrowthfromthethird TSHR Around 100likelyinactivating mutationsresultinTSHresistance,forwhich mutationsoccurthroughout theprotein,with TSHR 21 GLIS3 , alleles, since inheritance may be either 41 TSHR TSHR ). Additionally, insomecases,elevated mutations,perhapsexplainedbyits mutationswerethemostcommon mutationstoorthotopic thyroid Downloaded fromBioscientifica.com at10/05/202110:01:11AM 1 ). Complete TSH resistance 1 ). 179 https://eje.bioscientifica.com TSHR TSHR :6 21 TSHR ). mutations mutations p.R450H 42 R301 ). The TSHR via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com resulting in deteriorating thyroid hormone levels and a elevated TSHlevelsmaybe incompleteandprogress, compensation ofthyroid hormone biosynthesisby factors forthyroiddysfunction, orbiallelicmutations, with eitherheterozygousmutations andadditionalrisk thyroid hormonereplacement.However, inpatients representing acompensatedstatewhichmaynotrequire thyroid hormoneconcentration)weregenerallystable, TSHR that biochemicalfeaturesassociatedwithheterozygous hormone actionwasalsoassessed.Bothstudiesconcluded on developmental parameters and biomarkers of thyroid Italian cohort,theeffectofthyroidhormonereplacement this questioninpatientswith Two recentstudiesfromIsraelandItalyhaveaddressed ( levothyroxine treatment may be unnecessary despite chronicallyraisedTSHsupporttheargumentthat size in untreated cases growth, development and pituitary thyrotoxic symptoms,andanecdotalreportsofnormal normalize TSHinpartialresistancemayprovoke thedosesoflevothyroxinerequiredto is preserved, thyroid hormonemetabolism( axisorgenesmediating hypothalamic–pituitary–thyroid involved insetpointregulationatdifferentpointsthe elucidated andmayincludealteredexpressionofgenes supporting analteredTSHsetpointhavenotyetbeen the normalrange( concentrations arerequiredtoachieveaTSHlevelin thyroid hormones.Accordingly, supraphysiologicalFT4 of thethresholdforTSHsuppressionbycirculating but thisbiochemicalsignaturemayrepresentaresetting of TSH with T4 levels within the normal range are unclear, mechanisms permittingcontinuedsecretionofhighlevels and peripheraltissuestothyroidhormone( thyrotrophs signifying normalsensitivityofpituitary TSH andperipheralbiomarkersofthyroidhormoneaction, administration elicitsnormalfractionalchangesinserum hormone concentrations( are sufficienttomaintainnormalcirculating thyroid controversial since,inthiscontext,elevatedTSHlevels the needfortreatment in partialTSHresistanceremains levothyroxine replacementisunequivocallyrequiredbut ( entraps WTreceptorintracellularlybyformingoligomers some cases, e.g. in association with TSHR p.C41S, which mechanism maycontributetophenotypicseverityin depending ontheirlocation.Adominant-negative by thereceptor, butmayalsoaffectligandbinding, 42 Review ). Since peripheralsensitivitytothyroidhormone In complete TSH resistance with subnormal FT4 levels, mutations(elevatedTSH,normalcirculating 44 , 45 42 ). Themolecularmechanisms ). Additionally, exogenousT3 20 TSHR C Petersandothers ). mutations;inthe 44 , 45 44 ). The , 45 ). attractive candidategeneforTD,havingbeenshownto containing transcriptionfactorsandwasinitiallyan NKX2–5 belongstotheNK-2familyofhomeodomain- NKX2–5 Additional genesassociatedwithTD justify intervention. hypothyroidism ordecliningthyroidhormonelevelsmay some affectedindividuals, signs andsymptomsof for thetreatmentofelevatedTSHalonealthoughin considered onacasebybasisandisnotindicated replacement therapyinpartialTSHresistanceshouldbe management definitively. Meanwhile,levothyroxine broader spectrumofTSHlevels,arestillrequiredtoguide including monoallelic need forlevothyroxinetreatment( patients withheterozygousloss-of-function hypoplasia. However, despiteaninitialreportoffour and murine expressed duringearlymurinethyroidmorphogenesis play aroleinmurinethyroiddevelopment.Nkx2–5is hypothyroidism insixindividuals. Additionally, 4%cases Alagille syndromerevealed mild,non-autoimmune facies. Evaluationofthyroid functionin21caseswith eye andskeletaldefects together withdysmorphic heart disease(CHD)associates withvariablehepatic, associated withAlagillesyndromeinwhichcongenital human heterozygousloss-of-function zebrafish thyroiddevelopmentandvariablypenetrant, of thyroidprecursorcells( zebrafish, aswellindifferentiationandmaintenance thyroid, whichmayplayaroleinthyroidspecification in Jagged1 (JAG1)isaNotchreceptorligandexpressed in JAG1 penetrance andexpressivity. genes arelikelytoplayasignificantrolemodulating NKX2–5 isolated congenitalheartdisease( populations (p.R25C,MAF pathogenic mutationsmayalsooccureitherinhealthy and had normalthyroidmorphologyandbiochemistry) penetrance washighlyvariable(carrierparentsfrequently these familieswasautosomaldominantbutmutation of NKX2–5inTDremainsambiguous.Inheritance mutations and thyroid ectopy or athyreosis, the role update Congenital hypothyroidism: variantsmaycontribute to TDrisk, other factors/ Nkx2–5 -null embryos exhibitthyroidbud -null embryos TSHR Downloaded fromBioscientifica.com at10/05/202110:01:11AM > mutationsassociatedwitha 50 1%) orinassociationwith ). JAG1playsarolein 46 179 , 48 JAG1 47 , :6 ). Largerstudies, 49 mutationsare ). Although NKX2–5 R302 via freeaccess

European Journal of Endocrinology population remainsunclear ( to sharedthyroidandcardiac congenitaldefectsinthe However, theextenttowhich and an atypical 22q11 deletion. to a 47, XYY karyotype deletion involvingpartof and thyroidectopywasreportedinwhomaheterozygous from dysplasticvasculature.AsinglepatientwithVSD the thyroid fails to develop due to lack of guidance cues mesenchyme butnotinthyroidtissue,itislikelythat archparalog ofhumanNTN1,isexpressedinpharyngeal thyroid morphogenesis.Since aortic arch formationinadditiontoabnormal artery demonstrate defective 1-deficient zebrafishembryos tool ininvestigatingthemechanismsinvolvedandNetrin in thyroiddevelopment.Zebrafishhaveprovedauseful autonomous mesenchyme-derived factors mayplayarole with TD, has led to the suggestion that non-cell frequency ofcardiovascularmalformationsinpatients cardiac mesenchymeandvasculature,theincreased The closeproximityofthedevelopingthyroidto Netrin 1( adhesion ( by decreasingtheexpressionofgenesimplicatedinfocal line resultedinalteredcellularmigrationandadhesion cancer. ExpressionofmutantCDCA8inathyroidcell (asymmetry, thyroid nodules)andonedevelopedpapillary exhibited variablethyroidstructuralabnormalities ectopy or athyreosis. Euthyroid heterozygous parents mutations wereassociatedwithCHandeitherthyroid hemiagenesis. In two more families, heterozygous CH and thyroid ectopy or euthyroidism with thyroid (p.S148F) in two siblings was associated either with unrelated families.Ahomozygous and biallelic loss-of-function mutations reported in three most recentlyidentifiedgeneticcauseofTDwithmono- developmentandisthe thyroid tissueduringembryonic segregation andcytokinesis.Itisexpressedinhuman complex withrolesintheprocessesofchromosome CDCA8 is a member of the chromosomal passenger CDCA8 CH ( notion thatJAG1maycontributetothepathogenesisof detected inanunrelatedCHcohortsubstantiatingthe CHD in two patients). Rare harboured heterozygous in a CH cohort without associatedAlagille syndrome Review 51 , (BOREALIN) 52 NTN1 53 ). ). ) JAG1 NTN1 JAG1 54 NTN1 mutations(withassociated ). wasdetectedinaddition C Petersandothers variants have also been ntn1a mutationscontribute CDCA8 , thezebrafish mutation CDCA8

for thyroiddevelopment( factor likelyderivedfromcardiacmesenchyme,required expression inthyroid.TBX1isanon-cellautonomous usually demonstrateubiquitousexpression,including conditions isgenerallyunclear, andthegenesinvolved syndrome) ( syndrome) and Beuren syndrome), Blizzard syndrome), syndrome), Candidate genesinvolvedinclude predominantly extrathyroidal-associated abnormalities. syndromes withanunderlyinggeneticbasisand Risk ofCHmaybeincreasedinthecontextseveral with CH Syndromes whichmaybeassociated (PIOD) inanItalianseries( for 37%CHduetopartial iodideorganificationdefect inKoreancases( up to1:13 501 East Asianindividuals,with amonoallelicfrequencyof mutations are now frequently reported, especially in frequently in East Asian individuals ( in EuropeanandPakistanicases( (TIOD, commonest causeoftotaliodideorganificationdefect of atleast1:100 000 births( cause ofdyshormonogenesiswithanestimatedfrequency for thestudypopulation. the presenceoffoundermutations,andselectioncriteria mutations areheavilyinfluencedbyethnicity, including of thesynthesisdefectandsummarizedin patterns andassociatedfeaturesaredependentonthesite SLC5A5 Mutations mayinvolve goitre. hormone synthesis with or without compensatory resultingininadequatethyroid biosynthetic machinery in genesencodingcomponentsofthethyroidhormone dyshormonogenesis compriseloss-of-functionmutations and adequate iodide substrate ( transporter molecules,enzymes,thyroglobulin(TG) cells requiresanintactsynthesispathwaycomprising at theapicalsurfaceofpolarizedthyroidfollicular identifiable geneticbasis.Thyroidhormonebiosynthesis Unlike TD,themajorityofdyshormonogenesishasan Genetic causesofdyshormonogenesis update Congenital hypothyroidism: The frequenciesofdyshormonogenesis-associated ( 56 NIS ), andfrequentlyunderliedyshormonogenesis TBX1 4 ). The underlying mechanism for CH in these ), DUOX2 KAT6B (diGeorgesyndrome), DYRK1A KMT2D/MLL2 (Ohdosyndrome,Genitopatelar , Downloaded fromBioscientifica.com at10/05/202110:01:11AM DUOXA2 38 TG TG 60 55 ). (Trisomy 21), , ). Somepathogenic mutationsareacommon ). TPO Fig. 2 TPO 58 57 or SALL1 , , SLC26A4 defectsrepresentthe 59 ) butmayoccurless , 179 ). Genetic causes of https://eje.bioscientifica.com ) andalsoaccount KDM6A IYD. :6 58 URB1 (Townes-Brocks ELN , Table 2 Inheritance 59 (Johanson- (Williams- ( ). (Kabuki Pendrin DUOX2 DUOX2 ( R303 1 , 2 ). via freeaccess ),

European Journal of Endocrinology https://eje.bioscientifica.com molecules involved.Mutations inanyoftheseproteinsmayresultdyshormonogenesis. Schematic illustratingthyroidhormone biosynthesisinthethyroidfollicularcell,highlighting thepositionandfunctionofthe Figure 2 with mutationsin This isparticularlywelldocumentedforCHassociated dyshormonogenesis subtypesthaninitiallyappreciated. supports abroaderphenotypicrangeinmost summarized in genetically ascertaineddyshormonogenesesare Biochemical andradiologicalhallmarksofspecific, Clinical phenotypesindyshormonogenesis CH ( such that 000),CHisarareassociation incidence 7.5–10per100 more frequentlyinthegeneralpopulation(estimated East Asiancases( uncommon althoughprobablyoccurmostfrequentlyin in fivefamilies( and than previouslyrecognized( they maybeanevenmorefrequentcontributortoCH populations (e.g.p.Q570LinSouthAsians)suggestingthat mutations have a minor allele frequency of ≥1% in certain Review 2 IYD , 61 seemrare,with , Pendrin 62 ). al 2 Table 59 mutationsaccountforlessthan5%of 55 ). AlthoughPendredsyndromeoccurs ) and DUOX2 ; however, evidenceincreasingly IYD DUOXA2 , whichwerefirstreported 60 mutationsonlyidentified ). Mutationsin C Petersandothers mutationsarealso SLC5A5 , DUOXA oxidase) onthelongarmofchromosome15,with It iscontiguouswith thyroglobulin andcouplingofmonodiiodotyrosine. the finalelectronacceptorduringbothiodinationof which generatesthethyroidalH only in2002.DUOX2isathyroidalNADPHoxidase, about thenumberofthesewhicharetrulypathogenic. functionally characterized,leadingtosomeambiguity However, onlyaround50%missensemutationshavebeen codon, splice-siteandin-framedeletionmutations. mutations havebeenreported,includingmissense,stop do notexhibithypothyroidism( monogenic causeofCH.Additionally, DUOX1-nullmice this, higher levelsinthyroidthanDUOX1andconsistentwith isoenzyme inthyroidhormonogenesis,beingexpressedat intergenic region.DUOX2isthoughttobethedominant DUOX2 mutationswasinitiallyhamperedbyfailure as diseasecausing( likely benignpolymorphismshavebeenmisclassified Indeed, functionalevaluationhasconfirmedthatsome update Congenital hypothyroidism: To date,approximately100different DUOX2 maturationfactorgenesoccupyingthe butnot 60 DUOX1 ). Functionalcharacterizationof DUOX1 Downloaded fromBioscientifica.com at10/05/202110:01:11AM mutationsarearecognized , (anadditionalNADPH 63 2 O ). 2 requiredbyTPOas 179 :6 DUOX2 R304 DUOX via freeaccess

European Journal of Endocrinology thought toresultinpermanent CH,andmonoallelic lacking ( since evidencefordominant negativeactivityiscurrently thought toconferaphenotype duetohaploinsufficiency have beendescribed,and heterozygous mutationsare absent intrinsicH plasma membraneexpression( endoplasmic reticulum to the cell surface and decreased exhibited completeorpartialtraffickingdefectsfromthe which significantlyimpairDUOX2function. All expression wasevaluatedforsixmissensemutations, C-terminal NADPH oxidase domain. Cell membrane in impairedenzymeactivityduetodisruptionofthe Truncating mutationsare usuallypredictedtoresult both complete and partial deficits in H exhibit impairedH mechanisms anddegreetowhichpathogenicmutations the ERandhaspermittedsuchevaluation( DUOX2 enablescorrecttranslocationoffrom coexpression oftheDUOXA2maturationfactorfor heterologous cell systems, however, identification and to achieveplasmamembraneexpressionofDUOX2in organification defect. NIS Pendrin DUOXA2 DUOX2 TPO TG Gene Table 2 B, bilallelic;EVA, enlargedvestibularaqueduct;GIS,thyroidgland *Occasional monoalleliccasesreported. IYD Review Both monoallelicandbiallelicDUOX2mutations A summaryofthegeneticdefectsimplicatedinCHwithdyshormonogenesisandtypicalclinicalfeatures. 66 Basolateral iodide Apical iodideefflux Membrane expression H Organification of Glycoprotein upon Function Recycling ofunused ). Initially, biallelic uptake DUOX2 and functionof organification required foriodide synthesis) (final stepinTH coupling reactions iodide, catalysisof synthesized andstored hormones are which thyroid and DIT) iodide moieties(MIT 2 O 2 production, 2 O 2 O 2 -generating activity( 2 generationarevariable,including 65 DUOX2 C Petersandothers , 66 M/B M/B M/B M/B B* M M ), with preserved or ), withpreserved B mutationswere 2 66 O May presentlaterinchildhood Sensorineural hearinglosswith Transient orpermanent Borderline bloodspotTSHbut Fetal goitre(rare) Inappropriately lowTGwhenTSH Fetal goiter(rare) Additional clinicalfeatures May presentlaterinchildhood Raised urinaryMITandDIT delay resulting inneurodevelopmental EVA confirmatory testing significantly elevatedTSHat subnormal venousT4and is elevated. delay resulting inneurodevelopmental 2 , generation. 67 ). 64 ). The in situ ; M,monoallelic;PIOD,partialiodideorganificationdefect;TIOD,total alone, exhibitseverehypothyroidism, suggestingthat contrast, micehomozygous for aDUOX2pointmutation role for DUOX1 ( consistent with a compensatory not performed,thesecasesexhibited unusuallysevereCH detailed genotype–phenotype segregationstudieswere isoenzyme deficiencywererecentlyreported;although severity ( DUOX2 deficiency, e.g.DUOX1,may modulate CH synthesizing enzymescapableofcompensatingfor putative H thyroid development,forwhichthemechanismand ectopy, raisingthepossibilityofarolefor DUOX2in DUOX2 next-generation sequencingrecentlyidentifiedfrequent a resistance to thyrotropin phenotype ( dyshormonogenesis, CH ( associated withbothmildtransientandseverepermanent variable andbiallelictruncatingmutationsmaybe additionally,with thisobservation; penetranceishighly subsequent studieshaveshownalmost40%discordancy mutations to cause transient CH ( update Congenital hypothyroidism: It hasbeensuggested that variantsin other H 69 NH ). Althoughsometimesassociatedwithgoitrous 2 ) andthefirstcaseswithlikelycompleteDUOX 2 O 2 -terminal mutationsincaseswiththyroid 2 dependencyremainunclear( Spectrum from Euthyroid/mild Mild/transient CH Usually mild-moderateor Sometimes mildCHwith Severe CH Spectrum from CH Spectrum from CH euthyroidism tosevere hypothyroidism transient CH monoallelic variants CH euthyroidism tosevere reported hypothyroidism CH; lateronset euthyroidism tosevere DUOX2 Downloaded fromBioscientifica.com at10/05/202110:01:11AM mutations may also cause 179 https://eje.bioscientifica.com Severely impaired GIS/Goitre PIOD GIS/Goitre PIOD GIS/Goitre PIOD GIS/Goitre TIOD, GIS/Goitre Normal orimpaired GIS/Goitre Radiological features Normal Goitre thyroid iodide organification of uptake iodide organification of 70 :6 68 ). Additionally, 71 rarely PIOD ). However, ). 123 I/Tc R305 72 ). In 2 O via freeaccess 2 - European Journal of Endocrinology https://eje.bioscientifica.com CH casesthanincontrols ( more commonlyineuthyroid first-degreerelativesof Moreover, thyroiddevelopmentalabnormalities occur which is15-foldgreaterthan predictedbychancealone. ofCHhaveanaffectedrelative, French NationalSurvey than currently diagnosed. Two percent of TD cases in a significant aetiologicalroleforgermlinemutationsin TD epigenetic eventsmaybeimplicated. that somatic mutations restricted to the thyroid or simple Mendelianinheritance,ithasbeenhypothesized ectopy ( a strongfemalepreponderanceofTD,especiallythyroid discordance between monozygotic twins with CH ( disease. This notion is supported by a higher than 90% cases, leadingtotheassumptionthatTDisasporadic Causative mutationsareidentifiedinlessthan5%ofTD component inTD Evidence foranundiagnosedgenetic infantile hypothyroidismisdelayed( resulting inneurodevelopmentaldelayifdiagnosisof late, followingnormalneonatalscreeningTSHresults, ( has alsobeendescribedwithhypothyroidismandgoitre childhood-onset hypothyroidism,andoneheterozygote mutation carriersgenerallyexhibitgoitrouscongenitalor are rarelyassociatedwithfoetalgoitre.Homozygous monoallelic defects( cases withPIODhavebeendescribed,sometimesdueto mutations usuallycausesevereCHalthoughmilder iodinecontentishigh. goitre, especiallyifdietary mutations canrangefromsevereCHtoeuthyroid unstable DUOXA2( protein expressionordecreasedlevelsof loss offunctionmaybeassociatedwitheithernormal but mostcasesappeartohavemildortransientCHand in ( DUOX2 screening TSH,raisingthepossibilitythatcaseswith venous FT4measurementsdespiteborderlineneonatal TSHandsubnormal significantly elevatedconfirmatory including characteristics associated biochemistry Italian casesharbouring DUOX2 defectinthemurinemodel( DUOX1 expressionisunabletocompensateforthe 60 55 Review DUOXA2 , ). Clinicalandfunctionaldataforcaseswithmutations However, other linesofinvestigationsupportamore Thyroid dysfunctionassociatedwith 76 ). mutationscouldbemissedonneonatalscreening 79 IYD ). Sincethesefeaturesareincompatiblewith , the accessory proteinforDUOX2,issparse, , theaccessory , NIS and 74 55 , DUOX2 ) andboth 75 DUOX2 ). 80 mutationsmayallpresent mutationsdemonstrated , C Petersandothers 81 TG ) andtheincidence 2 and , 73 60 ). Evaluationof , TPO 76 NIS , mutations 77 or ). 78 ) and TPO IYD TG

this, thegeneexpressionpatternwasdifferentinectopic structures ( alteration withinthethyroidtissueorsurrounding in associationwithanadditionalgeneticorepigenetic two hits,whereagermlinepredisposingmutationoccurs include mechanisms consistentwiththeseobservations supporting anaetiologicalroleforgeneticfactors.Potential the apparentsporadicoccurrenceofTDwithdata for CH,someofwhichhaveattempted to reconcile Recent studieshavesoughtalternativegeneticaetiologies dyshormonogenetic CH geneticaetiologiesinTDand Alternative diverse populations( more frequentlyinconsanguineousorlessgenetically increased inpatientswithCH.Additionally, CHoccurs of extrathyroidaldevelopmentalmalformationsisalso a discordant forTD( identified in lymphocyte DNA from monozygotic twins ( somatic methylationgeneexpressionprofiledifferences thyroid, butthiswasnotattributabletosignificant Mutations ingenescharacteristically associatedwithTD genetic aetiologiesinthetwo morphologicalsubgroups. in mixedCHpopulations, demonstratingoverlapof genes classically associated with TD or dyshormonogenesis likely pathogenicvariantinmorethanonegene( subsequent analysis demonstrating that 23% harboured a than 150ItalianpatientswithdifferentCHsubtypes, study, 11CH-associatedgeneswerescreened inmore with eutopicGISandTD.Inaparticularlycomprehensive now confirmedaroleforoligogenicinheritanceinboth CH deficiencies of TTF1 and PAX8 ( strain-specific TDoccursinmicewithcombinedpartial heterozygous thatmicewith was initiallysupportedbyobservations sporadic occurrence.Anaetiologicalroleforoligogenicity in CH,whichmayalsocontributetoitsapparently have enabledinterrogationoftheroleoligogenicity been identifiedinCH( CH ( reported for monoallelic expressionofamutantallelehasonlybeen genes inbothectopicand eutopic thyroid( monoallelic expression has been reported for some update Congenital hypothyroidism: 85 PAX8 ). Additionally, frequentsomaticmutationswerenot NGS approacheshavealso enabled thescreeningof Next-generation sequencing(NGS)technologies 89 ). Recurrentcopynumbervariantshavealsonot mutation has been reported ( 84 TPO ). However, intheonlystudytoinvestigate TTF1 inassociationwithdyshormonogeneic or 86 82 PAX8 ) althoughsomaticmosaicismfor 90 , Downloaded fromBioscientifica.com at10/05/202110:01:11AM 83 ). ). mutations are euthyroid, but 91 ). Human studies have 179 :6 87 88 ). Autosomal ); however, 52 R306 , 92 via freeaccess ). European Journal of Endocrinology presents an exciting system in which to validate the roles of presents anexcitingsystemin whichtovalidatetherolesof exposed tothyrotropin( structures capableofproducing thyroidhormoneswhen to besufficientfordifferentiation intothyroidfollicular response toexogenousFGF2andBMP4 precursors, expression of and humanpluripotentstemcell-derivedendodermal for thyroiddevelopment( identified byexploringmouseandzebrafishmodels postulated tooccurdueincreasedoxidativestress( atrophyofthethyroid was in TD,wheresecondary ( association withisolatedCHandanormalthyroidgland (e.g. biallelic as themutantprotein. implicated inisolatedTSHdeficiencyareshown.Consequencesofmutationsthesegenesdepictedthesamecolour text hormone receptorisoforms2and1.Theinsetrepresentsapituitarythyrotroph,inwhichtheputativesitesofactiongenes mediated bythyrotropin-releasinghormone(TRH)andnegative(grey)feedbackinfluences,predominantly thyroid Diagrammatic representationofthehypothalamic-pituitary-thyroidaxiswithpositiveregulation(black)predominantly Figure 3 52 Review ). Conversely, Pendrinmutationshavebeen reported Novel candidate genes for CH have also been Novel candidategenesforCHhavealsobeen FOXE1 mutations),havebeenreportedin 95 , NKX2-1 96 94 ). This stem cell technology ). Thisstemcelltechnology ). Recently, inmurine C Petersandothers and in vitro PAX8 was found wasfound alone, in alone, in 93 ). following maturation,reaches thethyrotrophsof paraventricular nucleus (PVN) of the hypothalamus and from theanteriorpituitary. TRHissynthesizedinthe hormone (TRH),which stimulates TSHproduction by the actions of hypothalamic thyrotropin-releasing Thyroid hormonebiosynthesisispositivelyregulated regulation ofthyroid hormonesynthesis The hypothalamic–pituitary–thyroid axis:positive hypothyroidism (CCH) Isolated centralcongenital the futurepossibilityofregenerativetherapyforCH. novel candidategenesforTDinthefutureaswellraising update Congenital hypothyroidism: Downloaded fromBioscientifica.com at10/05/202110:01:11AM 179 https://eje.bioscientifica.com :6 R307 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com is TSHspecific(TSHB).Key structural featuresarerequired (LH, FSH,CG)familymembers andabetasubunitwhich subunit ( sibling ( and treatedfrombirthfollowinggeneticdiagnosisin a often improvedincaseswhoareascertained,diagnosed treatment delay. Incontrast,developmental outcomeis the extentofwhichcorrelateswithdegree of frequently resultsinneurodevelopmentalimpairment, present clinically, theseverityofhypothyroidism CCH. Therefore,ifdiagnosisisdelayeduntilchildren Biallelic loss-of-function, TSHB mutations congenital hypothyroidism Genetic causesofisolatedcentral ( and thetransducinbeta-like1X-linkedgene, immunoglobulin superfamilymember1gene( hormone receptor( now implicatedinitspathogenesis;thyrotropin-releasing total offourgenes,allwitharoleinTSHbiosynthesis,are deficiency hasadvancedoverthelastthreedecades,anda confer normalbioactivity( its post-translational glycosylation, which is required to and promotingbothsecretionofheterodimericTSH facilitating conjugationofTSHalphaandbetasubunits TSHB of the TSH alpha ( activating proteinkinaseC.TRHupregulatestranscription subsequently mobilizing intracellular calcium and receptor, whichactivatesaGq/11-dependentpathway It thenbindstheTRHreceptor(TRHR),aG-protein-coupled glandviathehypothalamicportalvein. anterior pituitary AR, autosomalrecessive;E,enlarged;GH,growthhormone;N,normal;PRL,prolactin;TSH,thyroid-stimulatingXL,X-linked. *Females mayalsobeaffected. Isolated TSHdeficiencyorcombinedpituitaryhormone TBL1X TRHR TSHB Gene Table 3 5

IGSF1 , Review 97 Genetic ascertainmentinCCHduetoisolatedTSH Mature TSHcomprisesaheterodimer ofthealpha ) butalsoexertsimportantpost-translationaleffects, , Table 3

98 Endocrine, neuroradiologicalandextrapituitarymanifestationsofmutationsingenesimplicatedCCHhumans. α Inheritance GSU) commontootherglycoprotein hormone ). XL* XL* AR AR ).

α GSU) and beta subunit genes ( Delayed pubertal TSH TSH TSH TSH Hormone deficits TRHR testosterone rise ± TSHB

PRL, GH(transient) ), TSHbetasubunit( 5 , Fig. 3 mutationsresultinsevere C Petersandothers ). Low normal/normalTSHresponse TSH responsenormal TSH andPRLpeakabsent/preserved Absent TSHresponse,preservedPRLresponse TRH testresponses

CGA TBL1X TSHB IGSF1 and ), )

occur around a conserved CAGYCsequencemotif. occur aroundaconserved heterodimer. Additionalalpha–betasubunitinteractions forms anintra-moleculardisulfide‘buckle’tostabilizethe wraps aroundthelongloopofalphasubunitand a ‘seatbelt’formedfromtheTSHbetasubunit,which to maintaintheintegrityofheterodimerincluding TRHR p.R17*,andanin-frame deletionofthreeamino abolished TRHR activity (compound heterozygosity for In thefirsttwokindreds,truncating mutationscompletely TRHR Cases harbouringbiallelicloss-of-function mutationsin TRHR mutations ( antibody arepreserved if epitopesrecognizedbytheanti-TSHmonoclonal be detectedinanimmunoassay-dependentmanner TSH (egp.Q69*,c.373delT),immunoreactivewill resulting insynthesisofnon-bioactiveheterodimeric beta polypeptides,whereasincaseswithmutations disrupt heterodimerformation between TSH-alpha and undetectable withmutations(p.G49R,p.Q32*),which rise ( serumprolactin administration, despiteapreserved subunit, andseverelyimpairedTSHresponsetoTRH glycoproteinalpha profound CHwithelevatedpituitary been reported( c.162+5 G More recently, twoTSHBsplice-sitemutations(c162G which exhibitsafoundereffectinsomecommunities( premature stop codon at position 134 (p.C125Vfs*10) ( valine change(p.C125V)andsubsequentframeshift nucleotide deletion(c373delT)leadingtoacysteine125 region ( integrity, truncatetheproteinordisruptCAGYC disrupt keydisulphidebridgesrequiredforheterodimeric update Congenital hypothyroidism: All reportedmissenseorindelmutationseither CCH dueto 103 haveonlybeenreportedin fourkindreds( Fig. 4A , > i. 5A Fig. A) (

). Themostcommonmutationisasingle 98 100 , TSHB and 102 , 101 ). mutationsischaracterizedby 103 Downloaded fromBioscientifica.com at10/05/202110:01:11AM ) andtwo B ). SerumTSHlevelsmaybe E, N MRI , N N N 104

). Ovarian cysts(females) Macroorchidism (males) Sensorineural hearingloss Additional features TSHB 179 :6 deletionshave – – Fig. 4B R308 98 99 > via freeaccess A, ). ). ), European Journal of Endocrinology pregnancy andlactationinhumans( for diagnosis, suggesting that TRH action is not obligatory pregnancies with subsequent lactation prior to her the homozygous,p.R17*mutationachievedtwonormal the milderp.I131Tmutation( with patients withabsentTRHRfunctionbutpreserved and prolactin peaks. Boththeseresponseswereabsent in therefore, intravenousTRHusuallystimulatesbothTSH half-life ( with immaturecarbohydratechainsanddecreased increased amountsofbioinactiveTSHmaybesecreted central hypothyroidismduetoTRHdeficiency, where by thyroidhormones.Thishaspreviouslybeennotedin bioactive TSHinresponsetodecreasednegativefeedback enhancedproductionofnon- represents acompensatory it ispossiblethatthehighTSHinhomozygotes of TSH,whichisrequiredtoconfernormalbioactivity, TRH playsakeyrolepost-translational glycosylation mechanism isunclear( exhibited isolatedhyperthyrotropinaemia,forwhichthe or isolatedhyperthyrotropinaemiaandheterozygotes exhibited eithermoderateCCHonthebasisofFT4levels absent signaltransductionwasreported.Two homozygotes mutation (p.I131T)whichresultedinimpairedratherthan therapy ( exhibited improvedqualityoflifewithlevothyroxine mental retardation.However, evenasymptomaticcases thyroid hormoneproductionininfancytopreventovert significant neurologicaldeficitssuggestingsufficient CCH in late childhood or adulthood, but did not exhibit bone age.Someaffectedpatientswerefirstdiagnosedwith manifestations comprisedgrowthretardationanddelayed were euthyroid( lower limitofthenormalrangeandheterozygouscarriers families exhibitedT4concentrationsof40–88%the reported ( equally deleteriousbiallelicp.P81Rmissensevariantwas (p.A118T) orhomozygosityforp.R17*).Morerecently, an acids (S115,I116andT117)withonesubstitution kindreds, morethan30pathogenic description ofIGSF1deficiency inelevenEuropean abnormality underlyingCCH ( are nowthoughttobe the mostcommongenetic immunoglobulin superfamily member1( Loss-of-function mutationsintheX-chromosomal IGSF1 mutations Review TRHR isexpressedinboththyrotrophsandlactotrophs; Last year, thefirstkindred,harbouringaTRHR 105 109 105 ). ). , 106 Figs 5A , 107 ). Homozygousindividualsinthese ). Wherepresent,themainclinical 108 ) ( 110 Fig. 5B is 5A Figs C Petersandothers , IGSF1 111 105 ). Onefemalewith ). However, since ). Sincetheinitial , mutationshave 106 IGSF1 , 107 ) gene , 108 ).

been described ( adulthood. Basal prolactin levels are subnormal in more testicular growth and subsequent macroorchidism in growth spurt and testosterone rise, but normal onset of development inthemajorityofcaseswithdelayedpubertal endocrine abnormalitiesincludedisharmoniouspubertal childhood onward ( TSH response to TRH but a low normal response from mild to moderate and associated with a blunted neonatal Affected malesinvariablyexhibitCCH,whichisusually females, who may have no overt endocrinopathy. exhibit amoreseverephenotypethanheterozygous this carboxyterminaldomain( usually impairtraffickingandmembranelocalizationof plasma membrane.Disease-associated immunoglobulin loopsareexpressedextracellularlyatthe co-translational proteolysis,itssevencarboxyterminal immunoglobulin superfamilyglycoproteinandfollowing (Pit1) lineage in murine and rat pituitary ( (Pit1) lineageinmurineandrat pituitary localizing IGSF1 protein either to all cells of the Pou1f1 two differentantibodieshave yieldeddivergentresults, expression studiesinhumans. Inrodents,studiesusing a paucityofreliableantibodies hashamperedprotein Rathke’s gland( pouchandinadultpituitary syndrome remainunclear. underlying themanifestationsofIGSF1deficiency remain tobedetermined( this context,thebenefitsoflevothyroxinetreatment normal growthanddevelopmentdespiteCCH, in However, some individualsareapparentlyhealthy, with endocrinopathy andbenefitfromhormonereplacement. family screeningexhibitclinicalfeaturesofuntreated is clearthatsomechildren and adultsdiagnosedduring following identification of ayoung affected proband. It hypothyroidism inindividualsacrossthreegenerations, harbouring ovarian cysts( for benign females reported to have required surgery Up to20%demonstratehypoprolactinaemia and four 20% fulfilling the criteria for central hypothyroidism. the lowertertileofnormalrangewithapproximately mutations generally exhibit thyroid hormone levels in may develop.Heterozygousfemalesharbouring range or mildly elevated and acromegaloid features levels areparadoxicallyintheupperhalfofreference necessitating GHreplacement.Inadulthood,IGF-1 transient growthhormone(GH)deficiencyinchildhood, than 60%malesandinfrequently, individualsmayexhibit update Congenital hypothyroidism: Hemizygous malesharbouring The precise molecular role of IGSF1 and mechanisms The precisemolecularroleofIGSF1andmechanisms IGSF1 110 Fig. 5C mutations is the new diagnosis of central , 111 is 5Aand B Figs , ). 112 Downloaded fromBioscientifica.com at10/05/202110:01:11AM IGSF1 110 IGSF1 ). Atypicalfeatureofkindreds , 110 encodes a transmembrane 111 mRNA is expressed in mRNAisexpressedin , , 111 112 179 ) ( https://eje.bioscientifica.com , IGSF1 110 ). IGSF1 :6 112 112 111 , ). Additional ). 111 mutations mutations ); however, ) or (using ) or(using R309 IGSF1 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com (Ser115-Thr117) areshowninred;missensechanges(p.A118T, p.P81R,p.I131T)areshowninblue. truncating mutation(p.R17*theproteininextracaellulardomain)andin-framedeletionof3aminoacids and PYMOLshowingthepositionsoffourpreviouslydescribedmutationsassociatedwithcentralhypothyroidism.The nomenclature Nomenclature canbeconvertedtothatpreviouslypublishedformissensemutationsbysubtracting20e.g.Q69*new HGNC guidelinestoincludethe20aminoacidsignalpeptideofTSHB,thusmaydiffer fromthatcitedintheoriginalarticles. blue) aretruncatingandmissensemutationsatthesameposition.Thenomenclatureofthesefollowsmost recent located intheconservedCAGYCregion;Q69*;F77Sfs*6(orange)truncateproteinprematurelyandE32*E32K(light formation. Spheres:reportedTSHBmutations:C105R;C108Y; C125Vfs*10(yellow)disruptdisulphidebridges,G49R(purple)is alpha subunit(TSH structure andwasmodelledontoFSH-FSHR(1xwd)theTSHR-K1-70FAB (2xwt)structureusingPYMOL.Green:TSHR,Red: TSH reported (A) Modelforheterodimericthyroid-stimulatinghormone(TSH)boundtotheTSHreceptor(TSHR)illustratingposition of Figure 4 most recentlyreportedgenetic causeofisolatedCCH. Loss-of-function missense mutations in TBL1X (transducin macroorchidism remainunresolved. However, the basisforhypoprolactinaemiaand IGSF1 mutations and blunted neonatal TRH testresponse. inmosthumans withhemizygous moderate CCHobserved IGSF1 deficiency, whichwouldbeconsistent withthemild- signalling mayunderliethecentralhypothyroidismseen in synthesis ( expressionofTrhr1pituitary mRNAdespitenormalTRH signalling associatedwithIGSF1deficiencyanddecreased deficient mouse lines have demonstrated impaired TRH or lactotropes( thyrotropes andgonadotropesinrats,butnotsomatotropes a different,commercially availableanti-IGSF1antibody)to Review TSHB 110 = mutationsassociatedwithCCH.ThemodelwasgeneratedusingPHYREforpredictingTSHbetasubunit(TSH Q49* oldnomenclature.(B)TRHRstructuralmodelgeneratedbyhomologymodellingusingthePHYREserver , 113 111 α ). MurinestudiesintwodifferentIGSF1- , α β ). This suggests that impaired TRH ). ThissuggeststhatimpairedTRH GSU), Blue:TSH -like protein 1) C Petersandothers β . Cyan‘seatbelt’region,Yellow: conservedcysteinesinvolvedindisulphidebridge TBL1X are the

well as ligand-induced transcriptional repression. TSHB for negativelyregulated genes suchas in T3-regulatedgeneexpression, itishypothesizedthat, receptor–corepressor complex (NCoR/SMRT)involved Since TBL1Xisanessentialcomponentofthemainnuclear TRH testresponses( CCH wasisolated,andmild-to-moderate,withnormal were significantlylowerthanincontrols.Wherepresent, the referencerangealthoughFT4levelsinaffectedadults exhibiting FT4 concentrations below the lower limit of forms ofCCH,withonlysixmalesandthreefemales was morevariablethanthatinothergeneticallymediated were identifiedinsixunrelatedkindreds( to elevenfemalesharbouringheterozygousmutations eight malesharbouringhemizygousmutations,inaddition Like hearing loss also occurred frequently in affected cases ( update Congenital hypothyroidism: IGSF1 , TBL1Xmayplayarole in basalactivation,as , TBL1X is also located on the X chromosome and isalsolocatedontheXchromosomeand is 5AandB Figs Downloaded fromBioscientifica.com at10/05/202110:01:11AM ). Mildsensorineural 179 :6 97 ). Penetrance TRH R310 β and ) 97 via freeaccess ). ).

European Journal of Endocrinology performed ininfantswith a raisedTSH.Aminorityof sample, andsubsequentFT4 orT4measurementisonly TSH ismeasuredfirst,usually onafilterpaperbloodspot worldwide operateaTSH-based screeningstrategywhere diagnosed followingneonatal screening.Mostcountries CHcasesnow health successwiththemajorityofprimary treated CHandinthisrespecthavebeenahugepublic of eliminatingtheneurodevelopmentalsequelaelate Screening programmeswerefirstintroducedwiththeaim Screening forprimary andcentralCH in impairedbasalactivationofthesegenes. Therefore, TBL1Xloss-of-functionmutationsmayresult characteristic phenotypebutdonotaffect IGSF1trafficking mutations) areknownorlikelytoaffect membranetraffickinga orexpression,whereasmutationsingreyareassociatedwith hypothyroidism aredenoted;alllocatedwithinthecarboxyterminaldomain.Mutationsinblack(missense)andred(truncatin g carboxy-terminal domaindenotedbyablueline.Positionsofnaturally-occurringmutationsassociatedwithcongenitalcentral function. (C)SchematicillustratingtheproteindomainstructureofIGSF1withinternalsignalpeptidedirectingcleavage ofthe < test excluding1IGSF1deficientcaseforwhomresultswerediscrepantattwodifferent ages( (A) Total orFT4measurementsexpressedaspercentagelowerlimitofthenormalrange.(B)PeakTSHresponsetoastandardTRH or Comparisonofendocrinologyinindividualswithbiallelic Figure 5 1 monthold.Referencerangesaredemarcatedaccordingto( Review TBL1X mutations (IGSF1, TBL1X), including all reported mutation carriers for whom numerical biochemical data was available. mutations(IGSF1,TBL1X),includingallreportedmutationcarriersforwhomnumericalbiochemicaldatawasavailable. C Petersandothers TSHB in vitro 87 or ). TRHR . Fourwholegenedeletionshavealsobeenreported. TRHR only bedetectedbyprogrammes measuringT4orFT4 CH.However,subclinical andovertprimary CCHwill CH,and,bydefinition,detectboth sensitive forprimary and disadvantages.TSH-based programmesarethemost direct comparisonofscreeningprogrammes( the determinedcutpoints,allofwhichmayconfound second postnatalweek),thebiochemicalassaysusedand the samples(fromcordbloodtoheelprickin screening programme methodology include the timing of T4 measuredfirst.AdditionaldifferencesinTSH-based measured simultaneouslyorinastepwisemannerwith a methodinwhichtotalorFT4andTSHareeither and Italy, Japan, the Netherlands and Israel) employ countries (somestateprogrammesintheUnitedStates update Congenital hypothyroidism: mutations(TSHB,TRHR),andhetero-orhemizygous Each CHscreeningprogramme hasitsownadvantages mutations abolish (black) or partially impair (red) TRHR mutationsabolish(black)orpartiallyimpair(red)TRHR 125 Downloaded fromBioscientifica.com at10/05/202110:01:11AM ). IGSF1 data excludes neonates dataexcludesneonates 179 https://eje.bioscientifica.com :6 114 , 115 R311 IGSF1 ). via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com screening TSHconcentrations ( and psychomotoroutcomes ofpreschoolchildrenand Belgian study found no relationship between cognitive T4 (FT4)concentrationsis moreambiguous.Arecent with mildtomoderatelyraised TSHandborderlinefree neurodevelopmental outcomeswhentreatinginfants for detectingsevereCHisunequivocal,thebenefit to insight intothis( recent functionalMRIstudieshaveprovidedfurther myelination of the infant brain isundisputed and more region specific( even withintheUnitedKingdomwheretheyremain subject ofdiscussion,exhibitingwidespreaddisparity spot TSHscreeningcutpointsremainacontinued screen aged4 weeksifthefirstTSHisnegative. undergo a repeat TSH infants born atless than 32 weeks negative screeningresultsatbirth.Accordingly, intheUK, old,inordertodiagnoseCHcaseswithfalse- 1 month screening isrecommended,whentheinfantaround newborn screening programmes, a strategy of second TSH risemaythereforeevadedetectiononTSH-based becomes elevated ( hypothyroidismbutlater initially normaldespiteprimary may alsoresultinadelayedTSHrise,whichtheis axisinprematureinfants hypothalamic–pituitary–thyroid than T4measurements( TSH levelsareusedtorecallprematureinfants,rather attributing adefinitivediagnosis( month before and repeats the measurements at age 1 from newbornswithbirthweight simultaneous TSH/FT4systemdefinespositiveresults ( for 8%falsepositivesintheDutchscreeningprogramme) positive diagnosesonT4-basedprogrammes (accounting T4 withnormalTSH),whichmayresultinmanyfalse includes transienthypothyroxinemiaofprematurity(low low birthweight.Thyroiddysfunctioninpreterminfants screening programme,especiallyininfantswithvery financial andworkloadconstraints( is onlymeasuredincaseswithT4 which enables diagnosis of TBG deficiency. However, TBG strategy includesmeasurementofTBGaswellTSH, period) ( deficiency (36%offalsepositivecasesovera1-year total T4incaseswiththyroxine-bindingglobulin(TBG) from theNetherlandsattributesprimarilytosubnormal this approach is the high false-positive rate, which data initially orsimultaneouslywithTSH.Adisadvantageof 8 ). Inordertoovercome this problem,theJapanese Review In TSH-basedscreeningsystems,newbornblood Premature birthposesproblemsforbothtypesof 8 ). Accordingly, theNetherlandsscreening 118 119 117 ). Theimportanceofthyroxineinthe ). However, althoughtherationale ). Since primary CH with delayed ). Since primary 8 ). Delayedmaturationofthe 120 C Petersandothers 116 − ). However, conversely, 1.6 7 < ). IntheNetherlands, , 2 8 kg as preliminary kg aspreliminary ). s . d . orlessdueto prolonged neonatal jaundice (central adrenal insufficiency) prolonged neonataljaundice(centraladrenalinsufficiency) (hypogonadotropic hypogonadism),hypoglycaemiaor hormonedeficits,e.g.micropenis additional pituitary suggesting hypothyroidismorduetomanifestationsof severe CCHmaybediagnosedclinically, duetosigns detect CCHatbirth.Therefore,althoughmoderate-to- for future,long-termneurodevelopmentalstudiesisclear. the ageofchildassessmentandstudydesign,butneed in termsofthechosendevelopmentalassessmenttool, all, screeninglaboratories.Bothstudieshavelimitations likely to be below the screening cutpoints of most, if not newborn infantswouldsuggestthatthe75thcentileis given, thedistributionofTSHconcentrationsinscreened ( TSH increasedfromthe75thcentileofscreening neonatal TSH.Therewasadecreaseinattainmentasthe a relationshipbetweeneducationalattainmentand a largeepidemiologicalstudyinAustraliadidsuggest newly diagnosedmoderate CCHinelderly 124 diagnosis of moderate-severe CCH is concerning ( neurodevelopmental outcomes,thepotentialfordelayed hormonedeficienciesresults inadverse additional pituitary such asinthecontextof it isunequivocal that misseddiagnosis of severeCCH, exhibit moderateorseverehypothyroidism( demonstrating thatmorethan50%ofchildrenwithCCH mild havebeenrefutedbydatafromtheNetherlands Moreover, previous perceptions that CCHisusually in newbornscreeningprogammes,e.g.phenylketonuria. regions iscomparabletothatofotherconditionsincluded CH,theincidenceofCCHinsome common thanprimary also beimplicated( screening approach although differences in ethnicity may likelyreflectingalesssensitive to1:160 000), (1:31 000 whereas Japanesestudieshavereportedalowerincidence 000inDutchneonates( 400to1:21 CCH of1:16 TBG evaluationhasyieldedanincidenceofpermanent mild) arebecomingquestionable.CombinedT4/TSH/ rarity ofCCHandtheperception thatitisusually most frequentlycitedcounterarguments(therelative measurement intheCHscreeningstrategyand treatment areoftensignificantlydelayed( or postnatalgrowthfailure(GHdeficiency),diagnosisand early investigationand detection ofconcomitant benefit ofscreeningforCCH isitspotentialtotrigger with obviousdevelopmental sequelae( mutation carriers,doesnot seem tohavebeenassociated update Congenital hypothyroidism: 121 ). However, insomecontexts(e.g.IGSF1deficiency), There are strong arguments for including T4 Primary TSH-based screening strategies do not TSH-basedscreeningstrategiesdonot Primary ). Although absolute TSH concentrations were not 116 Downloaded fromBioscientifica.com at10/05/202110:01:11AM , 123 TSHB ). Therefore,althoughless mutations,orCCHwith 179 :6 111 9 , 122 ). Afurther 124 ). ). Since R312 IGSF1 8 , 98 via freeaccess 9 ) ,

European Journal of Endocrinology work ingeneratingthemodelsforTSH andTRHRusedin Council InstituteofMetabolicScience, Addenbrooke’s Hospital, forhis Metabolic ResearchLaboratories, Wellcome Trust-Medical Research The authorsacknowledgeDrErikSchoenmakers, UniversityofCambridge Acknowledgements Biomedical ResearchCentreCambridge(NS). (100585/Z/12/Z toNS)andtheNationalInstituteforHealthResearch Our researchissupportedbyfundingfromtheWellcome Trust Funding perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcould be Declaration ofinterest novel insightsintothyroiddevelopment. the mechanismsunderlyingCHaswellproviding addition toenvironmentalmodifiers,mayhelpelucidate contributions ofgeneticandepigeneticvariation,in is poorlyaccountedfor. Furtherinvestigationofthe in geneticallyascertainedCH,phenotypicvariability TD inparticularremainslargelyuncharacterizedand andcentralCHhasimproved,thebasisfor primary Although ourunderstandingofthegeneticbasisfor screening stepforcentralCHinlightofcurrentevidence. be encouragedtorevisitthecost-benefitsofanadditional TSH-basedscreeningsystemsshould operating primary optimal TSHscreeningcutpoints.Additionally, countries CH andtoprovideanevidencebasefordetermining the benefitsofearlydetectionandtreatmentmild delay. Inthefuture,furtherstudiesareneededtoaddress elimination ofassociatedsevereneurodevelopmental represents amajorpublichealthsuccess,achievingnear years,neonatalscreeningforCH Over thelast40 Conclusions barriers toimplementation. biochemical methodologyaswellcostareallpotential Increased complexityoftheclinical workload and given theneedforearlydetectionoffalsepositiveresults. CH,isnotaninsignificantundertaking,especially primary CCH whilstmaintainingahighsensitivityfordetecting TSH-based screeningstrategy, toonewhichidentifies be underestimated( hormone deficiencies,thesignificanceofthisshouldnot Since 75%ofCCHcasesexhibitcombinedpituitary treatment may prevent life-threatening consequences. andGHdeficiencies,forwhich pituitary-adrenal Review 5 ). However, changingfromaprimary C Petersandothers Fig. 4 . References

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