European Journal of 10.1530/EJE-16-0107 genetic defect;(iii)avoidsambiguous termslike‘pseudo’and(iv)eliminatestheclinical ormolecularoverlap This terminology:(i)defines thecommonmechanismresponsibleforalldiseases; (ii) doesnotrequireaconfirmed these disorders,weproposed togroupthemundertheterm‘inactivatingPTH/PTHrP signallingdisorder’(iPPSD). Results andconclusions signalling pathway. about anew, moreeffective andaccuratewaytodescribedisorderscausedbyabnormalitiesofthePTH/PTHrP Design andmethods classification thatencompassesalldisorderswithimpairments inPTHand/orPTHrPcAMP-mediatedpathway. genetic/epigenetic backgroundofthedifferent subtypes. Therefore,theEuroPHPnetworkdecidedtodevelopanew such asacrodysostosis(ACRDYS)orprogressiveosseous heteroplasia(POH),aswellrecentfindingsofclinicaland of an absence ofspecificclinicalandbiochemicalsignstogether withan heterogeneous diseaseswithdemonstrated(epi)geneticcauses.Theactualclassificationisbasedonthepresence or classified underthetermpseudohypoparathyroidism(PHP),whichencompassesrare,relatedandhighly Objective Abstract hospital, LeKremlinBicêtre,France Istanbul, Turkey, Paris, France, Hospital, Birmingham,UK, Basque Country, Leioa,Spain, University Hospital,Madrid,Spain, Université Paris-Saclay, LeKremlinBicêtre,France, Bicêtre ParisSud,LeKremlinBicêtre,France, Phosphate Metabolism,filièreOSCARandPlateformed’ExpertiseMaladiesRaresParis-Sud,Hôpital Hospital, Vitoria-Gasteiz,Spain, Belgium, Cardiovascular Sciences,CenterforMolecularandVascular Biology, UniversityofLeuven, 4 Milan, Italy, and DiabetologyUnit,DepartmentofClinicalSciencesCommunityHealth,UniversityMilan, Lübeck, Germany, 1 Serap Turan Benedetta Izzi Luisa De Sanctis Susanne Thiele the EuroPHP network (iPPSD), anovelclassificationproposed by inactivating PTH/PTHrPsignallingdisorder From pseudohypoparathyroidism to Department ofPublicHealthandPediatricSciences,UniversityTorino, Torino, Italy, Division ofExperimentalPediatricEndocrinologyandDiabetes,DepartmentPediatrics,University DOI: 10.1530/EJE-16-0107 www.eje-online.org Open Access Position Statement in vitro 6 Molecular (Epi)GeneticsLaboratory, BioArabaNationalHealthInstitute,OSIArabaUniversity : Disorderscausedbyimpairmentsintheparathyroidhormone(PTH)signallingpathwayarehistorically 3 APHM, HôpitallaConception,LaboratoryofMolecularBiology, Marseille,France, 13 Department ofPediatrics,DivisionEndocrinologyandDiabetes,MarmaraUniversity, assaytomeasureGsaproteinactivity. However, thisclassificationdisregardsotherrelateddiseases 13 14 APHP, DepartmentofPaediatricEndocrinologyandDiabetology, BicêtreParisSud

, Alessia Usardi 5 , Olaf Hiort 1 , Giovanna Mantovani 4 , Francesca MElli : Extensivereviewoftheliteraturewasperformed.Several meetingswereorganisedtodiscuss 2 12 Fondazione IRCCSCa’GrandaOspedaleMaggiorePoliclinico,Endocrinology APHP, ServicedeBiochimieetGénétiqueMoléculaires,HôpitalCochin, : Afterdeterminingthemajorandminorcriteriatobe considered forthediagnosisof 11 Department ofEndocrinologyandDiabetes,BirminghamChildren’s 7 APHP, ReferenceCenterforraredisordersoftheCalciumand 10 1 Department ofBiochemistryandMolecularBiology, Universityof , Beatriz Lecumberri 7 , S Thieleandothers 14 , Ralf Werner 8 INSERM U1169,HôpitalBicêtre,LeKremlinet Published byBioscientifica Ltd 2 , Kathleen Freson 9 Department ofEndocrinologyandNutrition,LaPaz 2 , Anne Barlier © 2016Theauthors 1 , Guiomar Perez deNanclares 9 , Arrate Pereda 5 3 , Intza Garin , Valentina Boldrin for PHP iPPSD, anovelclassification in vivo 5 Department of 6 , 10 6 , Vrinda Saraff , Virginie Grybek responsetoexogenousPTHandtheresults 2 , Paolo Bordogna 6 Attribution 3.0Unported License This workislicensed under aCreativeCommons

and Downloaded fromBioscientifica.com at10/07/202105:23:32AM Agnès Linglart 11 , Caroline Silve 7 , 8 [email protected] Email to ALinglart should beaddressed Correspondence , Patrick Hanna 175 175 :

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via freeaccess Position Statement S Thiele and others iPPSD, a novel classification 175:6 P2 for PHP

between diseases. We believe that the use of this nomenclature and classification will facilitate the development of rationale and comprehensive international guidelines for the diagnosis and treatment of iPPSDs.

European Journal of Endocrinology (2016) 175, P1–P17

Introduction

Pseudohypoparathyroidism (PHP) encompasses a and its signal transduction pathway (Fig. 1) (5, 6). group of rare, related, highly heterogeneous and deeply PTH1R, through its activation by two ligands, the impairing disorders characterised by end-organ resistance PTH and the PTH-related peptide (PTHrP), regulates to the action of (PTH) and in most skeletal development, turnover and mineral instances associated with a demonstrated (epi)genetic ion homeostasis. In the kidney, binding of PTH to component (1, 2, 3). PHP is historically the first hormone- PTH1R stimulates the production of 1,25-dihydroxy resistance syndrome described by Albright et al. (4). D3, and inhibits phosphate reabsorption A better understanding of the PHP pathophysiology in the proximal tubule, while it increases followed the identification of the PTH receptor (PTH1R) reabsorption in the distal nephron. In the growth plate, European Journal European of Endocrinology

Figure 1 Schematic transduction of PTH1R/Gsa/cAMP/PKA pathway. Upon ligand binding (PTH or PTHrP is mentioned in the figure), the receptor (PTH1R) activates the . Then, the Gsa subunit triggers the activation of the adenylate cyclase leading to cAMP synthesis. cAMP binds to the regulatory 1A subunits (R1A) of the PKA, the most common effector of cAMP. Upon cAMP (grey diamonds) binding, the catalytic subunits (Cat) dissociate from the R1A subunits, and phosphorylate numerous target proteins including CREB (cAMP-responsive binding elements) and the phosphodiesterases (PDEs). CREB activates the transcription of cAMP-responsive genes. Intracellular cAMP is then deactivated by PDEs, among which are PDE4D and PDE3A. PTH1R: transmembrane convolutional black line; G protein: trimer α, β, γ; cAMP: grey diamond; PKA: tetramer R1A (regulatory subunit 1A) and Cat (catalytic subunit); phosphodiesterases: ovals PDE4D or PDE3A; DNA: scale bar.

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Downloaded from Bioscientifica.com at 10/07/2021 05:23:32AM via free access European Journal of Endocrinology of PHP1Chasallthecharacteristics ofPHP1A,exceptthat and calcitonin( resistance toseveralhormones, includingTSH,GHRH obesity, degreesofintellectualdisabilityand varying extensively associatedwith PHP1Aindividuals,include features thatmaynotdirectlyrelatetoAHO,yet and subcutaneous ossifications ( brachydactyly, roundedface,shortstature, stockybuild encompasses heterogeneousclinicalfindingssuch as initially describedtogetherwithPHPin1942,which (AHO)( (PHP1B; OMIM #603233) ( and #612462respectively)( on thepresence(PHP1AandPHP1C;OMIM#103580 subclassification (seebelow). allowed thediagnosisofPHP, andcontributedtoPHP was demonstrated extractedfrompatientsaffectedwithPHP1 erythrocytes seen in patients with acrodysostosis type 1 (ACRDYS1) ( ( of thephosphaturicresponsetoPTHinsomepatients and vitaminDsupplementationresultedinnormalisation tovitaminDdeficiency( defect secondary been hypothesised that PHP2 could either be an acquired responsible forthisvariantisstillunknown.Ithasalso PHP2 caseshavebeenreported,andthemoleculardefect response isdeficient( butthephosphaturic where cAMPincreaseisconserved fromPHPtype2(PHP2), cAMP responseisobserved, differentiation ofPHPtype1 (PHP1), in which a blunted cAMPlevelspermitsthe of serumandurinary to exogenouslyadministeredPTHthroughmeasurement (Gsa), leadingtocAMPformation.Renaltubularresponse deficiency ( circulating levelsofPTHintheabsencevitaminD as hypocalcaemia,hyperphosphataemiaandelevated to PTHisthehallmarkofallformsPHP. Itmanifests mutations of disease (OMIM#600002),shortstature,elevatedPTHand milder phenotypeinlivingchildrenaffectedwithEiken PTH1R associated withbiallelicloss-of-functionmutationsofthe a lethal form of dwarfism ( to PTH1R( PTHrP promotesendochondralossification,bybinding 14 Position Statement , PHP type1(PHP1)isfurthersubdividedbased In 1980,deficiencyintheGsaproteinactivity Gprotein PTH receptorcoupleswiththestimulatory A defectintheresponseofproximalrenaltubule The Blomstrandchondrodysplasia(OMIM#215045), 15 gene( ), or due to defects downstream the Gsa protein, as ), orduetodefectsdownstreamtheGsaprotein,as 7 5 ). , PTH1R 9 7 ). Subsequently, onereporthasdescribeda , 23 12 in vitro , ). ( 24 10 , 13 , Table 1 25 ( 11 ). To date,onlyahandfulof 17 , ). 6 26 , , 6 18 8 , 20 , ). AHOisaclinicalentity ), was the first disorder 27 ). Foryears,thisbioassay 17 S Thieleandothers ) of Albright hereditary ) of Albright hereditary 4 , , , 28 18 21 ). The subcategory ). Thesubcategory , , 19 22 14 ) orabsence ). Additional ), as calcium ), ascalcium 16 ).

including partorthewhole ( different frequency, withadetection rate ofabout70% mutations have been identified in allofits13 exonswith PHP1A, wasdescribed( in thegenecodingforGsa( growth ( PTHrP atthegrowthplateduring foetal andpostnatal inAHOislargelymediatedbytheresistanceto observed an isolated defect. It is possible that the ‘bone phenotype’ #612463) maybepresenteitherinkindredswithPHPoras pseudopseudohypoparathyroidism (PPHP;OMIM their first report of PHP. This new syndrome, named also described by Albright of AHOwithoutanyevidencePTHresistancewere controls ( was found comparable to Gsa activity in erythrocytes the renalproximaltubules,hencePTHresistance( which could lead to a decreased expression of Gsa in A/B: GNAS A/B pattern of cytosine methylation within the maternal common toallPHP1Bpatientsisapaternal-specific PHP1B wascharacterised.Themostconsistentdefect ( maternal allele through a yet unexplained mechanism tubule ( gland and most likely in the proximalthyroid, pituitary differentially methylatedregions(DMRs)( to the control of their expressionby parent-specific the alternative splicing.Inmosttissues,exceptforGsa, tissues ( ossifications expandingintodeepmusclesandconnective OMIM #166350),adisordercharacterisedbyheterotopic lead toPPHPorprogressiveosseousheteroplasia(POH, or occurring Remarkably, similarmutationswhenpaternallyinherited, at STX16 maternal alleleof methylation (LOM))associated withdeletionsonthe to the Most AD-PHP1Bshowloss ofimprinting(LOI)limited inheritance (AD-PHP1B)throughthematernallineage. with an autosomal dominant modeoffamilial history Fifteen totwentypercent ofthePHP1Bcasespresent for PHP iPPSD, anovelclassification 33 48 GNAS , , In 1990,thefirstheterozygousinactivatingmutation Interestingly, patientsshowingthephysicalfeatures GNAS TSS-DMR; previouslyknownasexonA/Bor1A), GNAS 34 49 or , ). In the early2000, molecular defect of 45 GNAS A/B have been recentlyreported ( 36 31 35 29 isalocusencodingseveraltranscriptsthrough , : transcriptionalstartsite(TSS)-DMR( transcriptsareofmonoallelicorigindue NESP55 ), Gsa ispredominantly expressed from the ). , 46 , 36 de novo 30 ). , ). 37 ( :TSS-DMR (moreprecisely alossof , 51 onthepaternalalleleof cis 38 , 32 -acting controlelementswithin , Downloaded fromBioscientifica.com at10/07/202105:23:32AM 52 ). Sincethen,severalGsa-coding 39 , ). Casesofdeletions20q, GNAS 53 t al. et , 54 GNAS) gene,andaninversion , ( 55 175 21 40 ), although other , responsiblefor www.eje-online.org ) 10 years after :6 , 41 Fig. 2 , 42 GNAS , ) ( 43 47 GNAS , may P3 ). In 50 44 via freeaccess ). ). ). Position Statement S Thiele and others iPPSD, a novel classification 175:6 P4 for PHP

Table 1 Former classification of PHP along with the other disorders affecting the PTH/PTHrP signalling pathway; note the overlap of phenotypes and molecular defects of the patients. Diseases included in the former classification are PHP1A, PHP1B, PHP1C and PPHP.

2q37.3 Deletion Blomstrand Eiken PHP1A PHP1C PHP1B PPHP POH Syndrome PHP2 Acrodysostosis dysplasia disease Clinical AHO AHO No AHO AHO in some AHO in very Mental BWS No AHO AHO AHO Subcutaneous AHO No AHO Severe AHO AHO Severe AHO Lethal Epiphyseal presentation patients few retardation ossifications dwarfism dysplasia (brachydactyly, patients reported in subcutaneous 2 patients, ossification) lambdoid and/or obesity synostosis, early-onset obesity, macrocephaly Obesity Obesity No obesity Obesity Obesity No obesity may be present Cognitive Cognitive No cognitive impairment impairment impairment Subcutaneous Subcutaneous Subcutaneous Subcutaneous Cognitive Hypocalcaemia, Cognitive Hypertension ossifications ossifications ossifications ossifications impairment osteomalacia impairment in some patients Hormone Resistance to Resistance to PTH resistance PTH resistance, PTH PTH resistance, PTH PTH No Mild No No PTH resistance PTH PTH No Elevated resistance PTH, TSH, PTH, TSH, ± TSH resistance, ± TSH resistance resistance, resistance, resistance, PTH in one GHRH, epinephrine resistance ± TSH resistance ± TSH and TSH in and TSH in patient calcitonin, and resistance resistance some some epinephrine, gonadotropins patients patients glucagon and gonadotropins In vitro Significantly Similar to Similar to Mildly Mildly Similar to Significantly Significantly activity of below controls controls controls decreased decreased controls below below Gsa when when controls controls compared with compared controls with

European Journal European of Endocrinology controls LOI at the LOM at the Broad LOI Broad LOI Broad LOI Broad LOI GNAS DMRs GNAS A/B:TSS-DMR Genetic lesion Heterozygous Heterozygous Heterozygous Recurrent 3-kb Unknown UPD(20)pat MLID Maternal Heterozygous Heterozygous Heterozygous Deletion of None Heterozygous Heterozygous Heterozygous Biallelic Biallelic mutation in mutation in mutation in STX16 deletion including deletion of mutation in mutation in mutation in the 2q37.3 mutation in mutation in mutation in inactivating inactivating the coding the coding the coding or 4.2-kb GNAS NESP and/ the coding the coding the coding chromosomal the coding the coding the coding mutation in mutation in sequence of sequence of sequence of deletion of or AS or sequence of sequence of sequence of region sequence of sequence of sequence of the coding the coding GNAS GNAS GNAS STX16 duplication GNAS GNAS GNAS including PRKAR1A or PRKAR1A PDE3A sequence of sequence (maternal (p.E392K, (p.Ile382del) of GNAS (paternal (paternal (paternal HDAC4 PDE4D PTH1R of PTH1R allele) p.E392X, (maternal allele) allele) allele) or no p.L388R and allele) mutation p.Y391X, all in identified exon 13) (maternal allele) References (32, 33, 34, 35, (29, 30, 78) (112) (50, 51, 52, 113) (50, 51, 63, (59, 60, 61, 62, (114) (53, 54, 58, (34, 36, 44, (77) (39, 45, 46, (116) (14) (16, 82, 90, (90, 91) (92) (9, 11) (10) 36, 37, 38, 39) 74) 63) 115) 100) 79, 80) 91, 117, 118, 119)

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Downloaded from Bioscientifica.com at 10/07/2021 05:23:32AM via free access References Genetic lesion LOI atthe In vitro Hormone Clinical PHP1C andPPHP. overlap ofphenotypesandmoleculardefectsthepatients.DiseasesincludedinformerclassificationarePHP1A,PHP1B, Table 1 GNAS Gsa activity of resistance presentation DMRs

Former classificationofPHPalongwiththeotherdisordersaffecting thePTH/PTHrPsignallingpathway;note ( Heterozygous Significantly Resistance to Subcutaneous Cognitive Obesity AHO PHP1A 32 36 allele) (maternal GNAS sequence of the coding mutation in below controls gonadotropins glucagon and epinephrine, calcitonin, GHRH, PTH, TSH, ossifications impairment , , 33 37 ,

, 34 38 , , 35 39 , ) ( Heterozygous Similar to Resistance to Subcutaneous Cognitive Obesity AHO PHP1C 29 allele) (maternal exon 13) p.Y391X, allin p.L388R and p.E392X, (p.E392K, GNAS sequence of the coding mutation in controls gonadotropins and epinephrine PTH, TSH, ossifications impairment , 30 ,

78 ) ( Heterozygous Similar to PTH resistance No cognitive No obesity No AHO 112 allele) (maternal (p.Ile382del) GNAS sequence of the coding mutation in controls impairment )

( Recurrent 3-kb LOM atthe Mildly PTH resistance, AHO insome 50 STX16 deletion of or 4.2-kb STX16 A/B:TSS-DMR GNAS controls compared with when decreased resistance ± TSH and/or obesity ossification) subcutaneous (brachydactyly, patients , 51 ,

deletion 52 , 113 ) ( Unknown Broad LOI Mildly PTH Obesity AHO invery 50 74 controls with compared when decreased resistance ± TSH resistance, present may be patients few , ) 51 , 63 PHP1B , ( UPD(20)pat Broad LOI PTH resistance, Mental 59 63 GNAS including resistance ± TSH macrocephaly obesity, early-onset synostosis, lambdoid 2 patients, reported in retardation , ) 60 , 61 , 62

, ( MLID Broad LOI PTH Obesity BWS 114 resistance ) ( Maternal Broad LOI Similar to PTH No obesity No AHO 53 115 of duplication or AS NESP and/ deletion of controls resistance ± TSH resistance, , GNAS 54 ) , 58

,

European Journal of Endocrinology ( Heterozygous Significantly No Subcutaneous AHO 34 100 allele) (paternal GNAS sequence of the coding mutation in controls below ossifications pseudohypoparathyroidism; PPHP, pseudopseudohypoparathyroidism. AHO, Albright’s hereditary osteodystrophy;BWS,Beckwith–Wiedemannsyndrome;MLID,multilocusimprintingdefect;NA,notavailable;PHP, , Position Statement 36 ) ,

44 , PPHP ( Heterozygous AHO Significantly Mild Subcutaneous 77 allele) (paternal GNAS sequence of the coding mutation in controls below ossifications )

Heterozygous ( No Subcutaneous POH 39 allele) orno (paternal GNAS sequence of the coding mutation in 79 identified mutation ossifications , , 45 80 ,

) 46 , S Thieleandothers Deletion of ( No Cognitive AHO Syndrome Deletion 2q37.3 116 HDAC4 including region chromosomal the 2q37.3 impairment ) ( None Hypocalcaemia, No AHO PHP2 PTH resistance 14 osteomalacia ) for PHP iPPSD, anovelclassification ( Heterozygous Cognitive Severe AHO PTH 16 1 91 PDE4D PRKAR1A sequence of the coding mutation in in some impairment patients some and TSHin resistance, patients 19 , , 82 ) 117 , 90 , 11 , or 8, Acrodysostosis ( Heterozygous AHO PTH 90 PRKAR1A sequence of the coding mutation in patients some and TSHin resistance, , 91 ) Downloaded fromBioscientifica.com at10/07/202105:23:32AM ( Heterozygous Hypertension Severe AHO No 92 PDE3A sequence of the coding mutation in ) 175 Lethal dysplasia Blomstrand ( Biallelic www.eje-online.org 9 :6 dwarfism PTH1R sequence of the coding mutation in inactivating , 11 ) ( Biallelic Elevated Short stature Epiphyseal disease Eiken 10 of sequence the coding mutation in inactivating patient PTH inone dysplasia P5 ) PTH1R via freeaccess Position Statement S Thiele and others iPPSD, a novel classification 175:6 P6 for PHP

Figure 2 The imprinted human GNAS locus (Hg19-chr20:57,414,795-57,486,250), on , close to the STX16 gene (Hg19- chr20:57,226,309-57,254,5812) (source UCSC, Hg19). The centromeric/telomeric orientation of the chromosome is indicated. The maternal (NESP), paternal (AB, AS and XL) and biallelic (Gsa) transcripts are depicted as arrows. Maternal- and paternal-expressed transcripts are drawn above and below the horizontal line respectively. Black boxes: coding exons; grey boxes: noncoding exons; arrows: transcription (direction and parental origin). The brackets delimit the imprinting control element deletions, which have been reported. STX16 gene: full brackets: the recurrent STX16 deletion of 3.3 kb (38); large dotted brackets: the STX16 deletion of 4.4 kb (39); small dotted brackets: the STX16 deletion of 29.5 kb (42). GNAS locus: full brackets: the 4.7 and 4 kb deletions removing the NESP exon and exons 3 and 4 of GNAS-AS1 (40); large dotted brackets: the 4.2 kb deletion removing exons 3 and 4 of GNAS-AS1 (43); deletions of 40 pb (*) and 33 pb (#) in introns of NESP and GNAS-AS1 (44); small dotted brackets: the NESP and GNAS-AS1 deletion (41). cen, centromeric; Mat, maternal; Pat, paternal; tel, telomeric.

maternally inherited deletions have been identified Methodology affecting all four DMRs (GNAS-NESP:TSS-DMR, GNAS- AS1:TSS-DMR, GNAS-XL:Ex1-DMR and GNAS A/B:TSS- The EuroPHP network met on three different occasions DMR) (56, 57, 58). (October 2014, May 2015, November 2015) to discuss The remaining cases of PHP1B are sporadic. They and agree on a novel classification. The aims of these present with broad LOI at GNAS, including the GNAS meetings were (i) to identify the limitations in the current A/B:TSS-DMR. The molecular basis of this broad LOI PHP classification; (ii) to formulate mandatory criteria for is yet to be identified, with an exception of less than the new classification; (iii) to propose a comprehensive 10% of the patients who are affected by paternal definition gathering all the disorders; (iv) to analyse the European Journal European of Endocrinology complete or segmental uniparental disomy (UPD) of classifications used in other genetic/epigenetic conditions the chromosome 20, comprising the GNAS locus (59, and (v) to generate a novel classification. The methodology 60, 61, 62, 63). comprised a thorough review of the current literature to To summarise, the existing classification of PHP facilitate comparison and form basis for the proposal of a (Table 1) is based on the following criteria: (i) presence new classification. or absence of AHO differentiates PHP1A/PHP1C from We have carefully considered a series of classifications PHP1B; (ii) presence or absence of hormonal resistance proposed for various rare genetic/epigenetic disorders, differentiates PHP1 from PPHP; (iii) in vivo response including the reporting manuscripts that were taken to exogenous PTH as for nephrogenic cAMP synthesis into consideration for the design of a novel classification and phosphaturia separates PHP1 from PHP2 and (iv) (summarised in Table 2). In brief, methodologies were in vitro assay measuring the Gsa protein activity from similar. A group of experts in the field identified the erythrocyte membranes differentiates between PHP1A deficiencies in the existing classification/terminology and PHP1C. and the need for an update. Subsequently, agreement on As described above, the existing PHP classification a novel terminology and classification was reached and does not include molecular defect as a criterion and fails reported (64, 65, 66, 67, 68, 69, 70). to stratify PHP and AHO as well as include conditions such as acrodysostosis, POH and PTH1R-related Challenges and limitations of the chondrodysplasia. In this manuscript, we therefore current classification propose to review the rationale of this nomenclature and recommend a novel classification for disorders impairing Recent clinical and molecular data gathered for these the PTH/PTHrP signalling pathway. complex disorders have questioned the distinction

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Downloaded from Bioscientifica.com at 10/07/2021 05:23:32AM via free access European Journal of Endocrinology 4. 3. 2. 1. limits ofthecurrentclassification: classification ( of thedifferent PHP andAHOsubtypesintheexisting Diabetes mellitus Endocrine diseases( Autosomal dominant Skeletal dysplasia( Primary Table 2 ( (MODY) ( kidney disease( tubule interstitial diseases ( immunodeficiency 64 Position Statement mediated activation( independent activation but disruptedreceptor- adenylylcyclasereceptor- leading toaconserved of-function mutationsinthe patients withPHP1C,i.e.LOI at Different moleculardefectshavebeenidentifiedin mutations. is notonlyassociatedwithmaternallyinherited mutation ( patients affectedwithPPHP, apaternal carrying Recently, mildresistancetoPTHwasdescribed in PHP1A andPPHP( in patients with yet lesssevere–tothatobserved membranes, reminiscent– Gsa activityinerythrocyte PHP1B patientspresentwithamoderatereductionin confirmed ( overlap betweenthetwosubtypes( been reported,suggestingamolecularandclinical of AHO,LOI degree In a subset of patients with PHP1A and varying ) Nonexhaustive reviewofclassificationsusedinotherconditions. 69 70 ) ) 77 al 1 Table 72 67 ), showingthatthehormonalresistance 66 , ) 68 73 ) GNAS ) , 76 74 ). We haveselectedthefollowing Literature review Meetings, agreementon Literature review Meeting, agreementon Meeting, extensive 2-days meeting build theclassification Methodology usedto ). 29 , the manuscript the manuscript the manuscript circulation ofdrafts literature, and review ofthe identicaltothatofPHP1Bhas 75 , 30 ). , 78 GNAS S Thieleandothers ). GNAS carboxyl-terminus andfourloss- 71 ), further Groups ofdiabetesby Groups ofdiseasesby Classification basedon Agreement onanovel Groups ofdiseases Groups ofdiseases Mode ofclassification Phenotypes on diseases’ mechanism organ defect: ADTKD-gene the underlyinggenetic name: ADTKD radiographic criteria biochemical and/or defined bymolecular, format presented asatable fundamental defect according tothemost clinics andgenetics evolution, radiology, GNAS GNAS

6. 5. for PHP iPPSD, anovelclassification 60–70% ofacrodysostosis patients witha Resistance to PTH and/or TSH is present in about by moregeneralisedosseous abnormalities( ( dysmorphism and, in some cases, mental retardation characteristic features,includingbrachydactyly, facial of rare diseases characterised by skeletal dysplasia and 83 been foundinpatientswithacrodysostosis( PDE4D subunit of the protein kinase A (PKA) – and regulatory Heterozygous mutationsin PPHP is,therefore,debated( hypothesis thatPOHshouldbeconsideredasaformof progressive deepeningheterotopicossifications.The mutationsonthematernalallelepresentwith carrying AHO featuresand,conversely, somePHP1Apatients a fractionofPOHpatientsexhibitssomethetypical with PHP1A and/or PPHP ( ( osseous heteroplasiaareusuallytruncatingmutations Paternal hormone resistancesarefound onlyinasmaller mutation, while,incaseof a 84 79 ). Acrodysostosisreferstoaheterogeneousgroup , ), yettheyareidenticaltothosefoundinfamilies 85 –codingforphosphodiesterasetype4have , Provide informationon Provide informationon Disorders arecausedby Allows apractical Advantages Provide informationon Allow numberingof the diseasemechanism the disease included number ofconditions gene networks,Sheer metabolic pathwaysor disturbances inrelated PID diagnosis clinical frameworkfor and genetics the diseasemechanism MODY3, MODY4…) (MODY1, MODY2, genes forMODY identification ofnew new diabetesafter 86 GNAS , 87 mutationsassociatedwithprogressive , 88 ). AcrodysostosisdiffersfromPHP Downloaded fromBioscientifica.com at10/07/202105:23:32AM 45 PRKAR1A 80 ). Also noteworthy is that , PDE4D Very largegroupsof Use incommunication The ‘hybrid’natureof The complexitiesof Limitations Confusing asone 81 disease (type2diabetes be easy with patientsmaynot clinical, notmolecular the classification,not format the limitedtable easily becapturedin these conditionscannot different categories causing genemaybein for example) 175 ). www.eje-online.org :6 –codingforthe mutation,such PRKAR1A 87 16 , , P7 89 82 via freeaccess ). ,

Position Statement S Thiele and others iPPSD, a novel classification 175:6 P8 for PHP

subset of 10–20%. Interestingly, few patients bearing receptor or in the FSH receptor. All nomenclature based a PRKAR1A mutation have been described in patients on the cAMP signalling were carefully considered and with a phenotype indistinguishable from PHP1A rejected due to their generic nature. (90, 91). 7. Heterozygous mutations in PDE3A have been identified in patients affected with hypertension and Identification of mandatory criteria for the brachydactyly type E (hypertension and brachydactyly new classification syndrome (HTNB): OMIM #112410) (92). 8. Disorders associated with an impaired function of Basis for the newly proposed classification of iPPSD are: PTH1R, i.e. the Blomstrand and Eiken skeletal dysplasia, are currently not included in the classification. •• to provide patients with an unambiguous diagnosis; •• to base nomenclature on pathophysiology, i.e. the Over the past two decades, it became obvious that PTH1R/Gsa/cAMP/PKA pathway, and a standardised diagnostic pathway; clinical features such as AHO or in vitro assays such as Gsa •• to formulate basis to develop new therapeutic bioactivity fail to differentiate between PHP subtypes. In approaches; addition, mutations of genes different from GNAS have •• to be sufficiently flexible and adaptable to include been shown to lead to PTH and/or PTHrP resistance and emerging clinical and molecular information; GNAS mutations might trigger diseases different •• to be simple and usable for the caregivers. from PHP/PPHP (i.e. POH). These disorders are not It is, therefore, of significant importance to define encompassed by the current classification system. the category of iPPSD a patient belongs to, based on For all these reasons, different independent studies the characterisation of clinical/biochemical criteria, to from the authors of the present paper, as well as the facilitate a definitive diagnosis and, if possible, through ‘EuroPHP network’ concluded and agreed that a uniform molecular analysis, a more specific denomination within terminology is required to create a functional working the classification. classification that reflects the current knowledge of the We suggest three key clinical features as major criteria diseases (29, 93, 94). for the diagnosis of iPPSD. The proposed major criteria have minimum or no overlap with other conditions Terminology due to different mechanisms (Table 3, especially for the differential diagnoses). We propose the term of ‘inactivating PTH/PTHrP signalling We also propose a list of minor criteria that are associated European Journal European of Endocrinology disorder’, abbreviated as iPPSD, which encompass all with iPPSD. These are less specific to iPPSD compared with disorders related to this pathway. We also propose that major criteria and can occur in other clinical conditions. numbering will allow for both clinical features and Therefore, minor criteria need to be combined with one molecular and genetic findings to be included. The or more major criteria to establish the diagnosis of iPPSD. advantages of this terminology are as follows: (i) it describes the common mechanism responsible for the diseases; Major criteria (ii) it does not require a confirmed genetic defect; (iii) it avoids the ambiguous term like ‘pseudo’; (iv) it eliminates PTH resistance the clinical or molecular overlap between diseases and (v) it is flexible to incorporate new evolving information. The hallmark of inactivating PTH/PTHrP signalling We recognise that the nomenclature ‘inactivating disorders is the resistance of the renal proximal tubule PTH/PTHrP signalling disorder’ might be initially difficult to the action of PTH. All genetic defects leading to a for patients and caregivers to remember. It would, deficient PTH1R signalling in the kidney will, therefore, therefore, be helpful to rely on the abbreviation iPPSD. be named iPPSD. Equally, the former terms ‘pseudohypoparathyroidism’ and ‘pseudopseudohypoparathyroidism’ were also long Ectopic ossifications and challenging to use for communication. PTH/PTHrP- specific pathway was deliberately included in the name Ectopic ossifications are superficial, subcutaneous nodules, of the classification to avoid the misperception with defined as ectopic bone formation in the adipose or dermal disorders resulting from the inactivation of G protein- tissue. Progressive osseous heterotopic calcifications often coupled receptors, i.e. inactivating mutations in the TSH begin in the dermal and subcutaneous tissues and later

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Downloaded from Bioscientifica.com at 10/07/2021 05:23:32AM via free access European Journal of Endocrinology Brachydactyly type E (BDE, OMIM #113300) encompasses Brachydactyly refers toshortening offingers, toesorboth. Brachydactyly an inactivating In children,ectopicossificationsarehighlysuggestive of progress to the deeper tissues, such as muscles and tendons. reduce theriskofoverdiagnosingpatientswithiPPSD. BDE through screeningforcongenitalhypothyroidism; † II. Minorcriteria I. Majorcriteria Table 3 iPPSD clinicaldiagnosis US inadultswithhypothyroidismandnoevidenceforautoimmunity;thyroid imagingthrough thyroid scintigraphyandUSinneonatesdiagnosed Position Statement +

obesity orBDE Definition ofmajorandminorcriteriaforiPPSDdifferential diagnoses. GNAS +

cognitive impairmentwouldnotberelevantforourclassification.Byraising thenumberofminorcriteriafrom1to2,wewill mutation,i.e.iPPSD. 6.  5. Obesity/overweight 4.  3.  2.  1. TSHresistance 3.  2. Ectopicossification 1. PTHresistance (b) Presenceofmajorcriterianumber3andatleast2minor (a) Presenceofonemajorcriteria,eithernumber1or2; round face hypoplasia and/or and/or maxillar Flat nasalbridge retardation postnatal growth Intrauterine and impairment retardation or Motor andcognitive resistances Other hormonal (comprises theIV) Brachydactyly typeE S Thieleandothers ‡ Minor criteriaarenonspecific(obesity/cognitiveimpairment);forinstance, theassociationof Weight SDS,BMIpercentile, Clinical inspection IUGR: gestationalage,birthweight, Computed tomographyscanand/or IGF-1 (GHstimulationtestif TSH, T4l,antibodies,imaging Clinical inspection(fist),handand X-rays Detailed physicalexam PTH infusiontestinchallenging Urinary phosphate Urinary calcium Creatinine (25OHD) PTH Magnesium Phosphate Ionized calcium,totalcalcium Assessment z-score determination oftheboneage X-ray ofthelefthandfor post-natal growth:growthcharts, comparison toreferencecharts; birth length,headcircumference, for age rating scales adjusted logical MRI ofthebrain,psychopatho GnRH test necessary), calcitonin,LH,FSH, feet X-rays cases are short as in acrodysostosis since early childhood. early puberty. Brachydactyly can be overlooked when all childhood, andtendstobecome moreevidentduring of whichareincludedamongiPPSD( present inisolationoraspartofageneticdisorder, most with theinvolvementofphalanges( variable shorteningofthemetacarpals/metatarsals,often for PHP iPPSD, anovelclassification Brachydactyly canbechallenging toidentifyinearly †

- , Fibrodysplasia ossificans Vitamin Ddeficiencyor Renal failure Normocalcaemic Differential diagnosis Mutations intheTSH #190351) and TRPS-III,(OMIM TRPS-II (OMIM#150230) (OMIM #190350), syndrome (TRPS),TRPSI, tricho-rhino-phalangeal cutis post-traumatic osteoma OMIM #135100), progressiva (FOP, any kindofsecondary hyperparathyroidism receptor ‡ Downloaded fromBioscientifica.com at10/07/202105:23:32AM

175 95 Fig. 3 www.eje-online.org ). :6 ). Itcaneither ( References ( ( ( ( ( ( 16 4 23 16 24 2 26 104 86 99 , , ) 84 , , , 27 , , , 40 105 25 27 , 102 100 , , 120 , 86 , 78 ) 92 , 34 , , , 106 , ) 116 101 , 90 98 , P9 103 85 ) ) , ) ) via freeaccess , , Position Statement S Thiele and others iPPSD, a novel classification 175:6 P10 for PHP

Figure 3 European Journal European of Endocrinology Patterns of brachydactyly type E associated with iPPSD. A, B, C, D and E, brachydactylies associated with coding mutations in the Gsa subunit of the G protein (iPPSD2). F and G, bone phenotype associated with the loss of imprinting at the GNAS locus (iPPSD3). H, I and J, brachydactylies associated with the molecular defect in PRKAR1A (iPPSD4) and PDE4D (iPPSD5). Note the phenotypic overlap between A, H, J and B, C, G, I respectively.

While PTH resistance and ectopic ossifications are especially in countries where screening for congenital considered major criteria for iPPSD, brachydactyly is less hypothyroidism is routinely performed (96). specific and should, therefore, be combined with at least one major or two minor criteria to trigger the diagnosis of iPPSD. Other hormone resistances Very few other hormone resistances have been demonstrated so far. Resistance to growth hormone- Minor criteria releasing hormone (GHRH), leading to growth hormone deficiency, is the most frequent additional resistance Thyroid-stimulating hormone (TSH) resistance found in PHP1A, affecting as many as 60% of patients In iPPSD, TSH resistance is often mild and characterised (97, 98, 99). Calcitonin resistance has been described by elevated TSH levels associated with free thyroxine without clinical features in patients affected with PHP1A

(T4) levels in a normal or low-normal reference range. (27). Elevated follicular-stimulating hormone (FSH) and This occurs in the absence of goitre and markers luteinizing hormone (LH) levels were reported both of autoimmune disease (26, 27). TSH resistance by us and Namnoum et al. (78, 100). Glucagon and can sometimes be the first detected sign of iPPSD, adrenaline resistances were demonstrated in patients

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Downloaded from Bioscientifica.com at 10/07/2021 05:23:32AM via free access European Journal of Endocrinology with mutations in ( with patients ( frequent featureinpatients affectedwithacrodysostosis on thematernalalleleof the developmentofobesity inpatientswithmutations decreased restingenergyexpenditure ( impaired lipolyticresponseofadrenaline( different subtypes.Growthhormonedeficiency, pathway andmayhelptodifferentiatebetweenthe disorders withanimpairedPTH/PTHrPsignalling minor sign;however, frequentlyin itoccursvery maybethe most nonspecificObesity oroverweight Obesity/overweight dysplasia ( exceptional cases( inPHP1B,althoughonly has alsobeenobserved in shortstature( deficiency andprematureclosureoftheepiphysisresult in PHP1Aandacrodysostosis.Growthhormone increased intrauterinegrowth( maternal with mutationsin when affecting harbouring mutationsonthepaternal However, IUGRismorepronouncedinpatients inherited inactivating in both maternal and paternal frequently observed Intrauterine growthretardation(IUGR)hasbeen Intrauterine andpostnatalgrowth retardation seem unaffected( of in thesepatients( 86 in somepatientsaffectedwithacrodysostosis( maternal codingmutationof described in about 40 to70%of the patients with a Psychomotor andcognitivealterationshavebeen Motor andcognitiveretardation orimpairment in vivo with features of PHP and low Gsa bioactivity through 103 16 Position Statement ). Psychiatricmanifestationshavealsobeenreported GNAS , Postnatal growthretardationisafrequentsign ). IUGR has also been described in acrodysostosis 90 testing( , 108 orepigeneticmodificationsofthe GNAS A/B: 10 ). ). 6 GNAS , 25 16 101 102 PDE3A PRKAR1A 71 , TSS-DMR has been associated with , 63 GNAS ). Patientswithpaternalmutations ). , exon2–13mutations,compared 82 ). 74 , GNAS ( ), andinpatientswithEiken 97 exon1/intron1mutations GNAS 16 or , , 105 ( 104 GNAS 82 23 S Thieleandothers PDE4D codingmutations. , ). Growthretardation ). , 90 107 ( GNAS , 25 106 ). Obesityisalsoa 92 , and in patients , ). ALOIatthe 34 ) contributeto allele,mainly GNAS ), aswell 101 83 DMRs , ) or 85 ,

disorders are: diseases andsyndromes( suggest iPPSD,asitisacommonfeatureofseveralother associated withatleastonemajorortwominorcriteriato criteria. However, brachydactylytypeE(BDE)shouldbe diagnosis ofiPPSDwithorwithoutthepresenceminor PTH resistance or ectopic ossifications may lead to the for the clinical diagnosis of iPPSD. criteria is mandatory We proposethataminimumofonethemajor Diagnosis ofiPPSD hypoplasia) orwithPHP1A(roundface)( with acrodysostosis(flatnasalbridgeand/ormaxillar Elements offacialdysmorphismhavebeenassociated round face Flat nasalbridgeand/ormaxillarhypoplasia • • • classification ( The EuropeanPHPnetworkproposesthefollowing The novelclassificationofiPPSD numbered iPPSDsubtypesstartingwith mechanism (responsibleforthepathology).We have while thenumberwillrefertounderlyingmolecular pathophysiology ofthePTH/PTHrPsignallingabnormalities, genetic defect. Therefore, the term iPPSD will refertothe subtype iPPSDbasedontheunderlyingmolecular(epi) (using criteriadescribed solely onthephenotype,onceiPPSDhasbeenidentified • • • • • • for PHP iPPSD, anovelclassification • • • • • • • • • iPPSD2: loss-of-functionmutation inGsa; iPPSD1: loss-of-functionmutation in of geneticinvestigation; major/minor criteriaasdefined above,intheabsence iPPSD: clinical/biochemical diagnosisbasedonthe heterozygous mutationsof heterozygous mutationsof heterozygous mutationsof methylation changesoftheDMRs sequence of inactivating heterozygousmutationsinthecoding inactivating mutationsof – – – The knownmolecularcausesofPTH/PTHrPsignalling In contrast to the former diagnostic classification based In contrast to the former diagnostic classification based – – – unknown mechanism(s); paternal UPDofchromosome20q; GNAS deletions orduplicationsatICRs( -AS1); Fig. 4 GNAS ): -Gsa Downloaded fromBioscientifica.com at10/07/202105:23:32AM Table 3 al 3 Table ; PTH1R PDE3A PDE4D PRKAR1A ). ), we propose to further ), weproposetofurther ; 175 . ; PTH1R www.eje-online.org ; :6 GNAS PTH1R 4 , STX16; NESP; 86 mutations. ). causedby ; P11 via freeaccess Position Statement S Thiele and others iPPSD, a novel classification 175:6 P12 for PHP

•• iPPSD3: methylation change(s) at one or more GNAS DMRs, associated with or without a genetic (deletion) or cytogenetic (UPD) defect; •• iPPSD4: PRKAR1A mutation; •• iPPSD5: PDE4D mutation; •• iPPSD6: PDE3A mutation; •• iPPSDx: lack of genetic/epigenetic defect identified following molecular investigation of known genes described above; •• iPPSDn+1: the identification of a novel gene/molecu- lar defect will lead to a disease named iPPSD7, then 8 and so on.

iPPSD3 encompasses all disorders associated with changes in the methylation patterns of the DMRs of GNAS, including UPD(20)pat and deletion within STX16, NESP etc. Of most significance is the common mechanism shared by these patients, i.e. the LOM at the GNAS A/B:TSS-DMR. Grouping them under iPPSD3 highlights this common mechanism. Secondly, we anticipated the difficulties in integrating the multiplicity of the epigenetic mechanisms within the classification system as this adds no further diagnostic value. However, the further specification of the epigenetic defect can remain part of a private exchange between the molecular laboratory, the patient and his/ her physician. We recommend the use of Arabic numerals to avoid the confusion with letters (II with the number 11 for example). The advantages of this new nomenclature are: (i) it European Journal European of Endocrinology stratifies the disorders into clusters caused by the same mechanism; (ii) it is flexible and open to accommodate Figure 4 new defects to be discovered in the future and (iii) it Schematic representation of the new classification proposed simplifies the concept of the overlapping disorders under by the European PHP network. According to the suggested a single umbrella. new classification Blomstrand and Eiken chondrodysplasia, This classification, however, bears some limitations. PHP type 1 and 2, PPHP, AHO, POH and acrodysostosis We deliberately did not include the parental origin of clinically/biochemically diagnosed without genetic the genetic/epigenetic defect, although some iPPSD are investigation are named iPPSD; Blomstrand and Eiken imprinting disorders – namely iPPSD2 and iPPSD3 – chondrodysplasia due to PTHR1-inactivating mutations are and their phenotypic expression depends on their named iPPSD1; PHP1A, PHP1C, PPHP and POH clinically parental inheritance. The main reason behind this is diagnosed and characterised by Gsa-inactivating mutations the association of PTH resistance and POH with both are termed iPPSD2; PHP1B clinically diagnosed and due to maternal and paternal inactivating GNAS mutations. methylation changes at the GNAS DMRs is classified as iPPSD3; Therefore, the mechanism of the two allelic GNAS in the presence of acrodysostosis type 1 or PRKAR1A mutations can be considered alike. However, in daily mutations, the disease is classified as iPPSD4. Acrodysostosis practice, the parental origin of the GNAS defect should type 2 or PDE4D mutations are termed iPPSD5; PDE3A be considered, particularly for genetic counselling. In mutations are categorised as iPPSD6; patients lacking genetic fact, AHO and multiple hormone resistance including or epigenetic defects at the known genes fall under the PTH resistance are largely associated with maternal GNAS category of iPPSDx; any newly discovered genetic/molecular coding defects, whereas isolated AHO and/or POH are defects will be labelled as iPPSDn+1. more often associated with paternal GNAS coding defects.

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Downloaded from Bioscientifica.com at 10/07/2021 05:23:32AM via free access European Journal of Endocrinology perceived asprejudicingtheimpartiality oftheresearchreported. All theauthorsdeclarethatthereis noconflictofinterestthatcouldbe Declaration ofinterest of theiPPSDsinnearfuture. international guidelinesforthediagnosisandtreatment patients affectedbydifferentiPPSDsand(iii)develop (ii) validatethemajor/minorcriteriainaseries of enriched by the clinical and scientific community; disseminate thisalternativeclassificationtobepositively classification, wehaveidentifiedtheneedto (i) the bestinterestofpatients. scientific purposeswillallowappropriate amendmentsin experts inbuildingaglobalresearch networkinthefield. the causativemechanismandprovedchallengingfor dispersed research advance, adding undue complexity to PPHP, POH, ACRDYS, TRPS, BDE, AHO) have diluted and for similar diseases and patients with phenocopies (PHP, andresearchfuture observational studiesinthefield. organisations inamorehomogenousway, andenable into localcataloguesusedbythedifferenthealthcare type E.Itwouldallowfortheclassificationofpatients PTH resistance,ectopicossificationsandbrachydactyly of iPPSD,increaseawarenessthered-flagsigns approachtothediagnosis facilitate amorestraightforward We believethattheuseofnewnomenclaturewill Perspectives difference inresearch goals inthetwodiseasegroups. defects in PTH1R signalling respectively and (iii) the difference inthetherapyofhypoparathyroidismand responsible forhypoparathyroidism;(ii)thedramatic different biochemicalpatternincludinglowlevelsofPTH exclude themduetoseveralotherissuessuchas(i)their classification maybeargued.However, wedecidedto in and brachydactyly type E with short stature (mutations main ligandsofthePTH1R,i.e.( as iPPSD. specific number, werecommendthattheyareclassified such patientscannotbeclassifiedasiPPSDxorwitha of iPPSDandlackcomplete(epi)genetictesting.While to subclassifyindividualswithapureclinicalsuspicion Position Statement PTHLH While producingthisnovelnomenclatureand Regular useoftheclassificationindailypracticeorfor We stronglybelievethattoomanydenominations The inclusionofthedisordersinvolvingtwo Another limitationofthisclassificationistheinability the gene encoding PTHrP ( S Thieleandothers 110 , 111 )) to the 109 ) EUCID.net (COSTactionBM1208onimprintingdisorders; Rares Paris-Sud.AllmembersoftheEuroPHPnetworkare C S, V G, P H and A U) as well as the Plateforme d’Expertise Maladies A L, Center for Rare Disorders of the Calcium and Phosphate Metabolism (to (CP03/0064; SIVI1395/09toGPdN),theAPHPBicêtreParis-SudReference 48198) (to A P), the I3SNS Programme of the Spanish Ministry of Health Health (GV2014111017toGPdN),theUniversityofBasqueCountry(Ref: Development, FEDER,(PI13/00467toGPdN),theBasqueDepartmentof Policlinico), theInstitutodeSaludCarlosIIIandEuropeanfundforRegional Ricerca CorrenteFunds(toFondazioneIRCCSCa’GrandaOspedaleMaggiore of Luebeck(H02-2011),theItalianMinistryHealth(GR-2009-1608394), Society forPaediatricEndocrinology (ESPE) ResearchUnit,theUniversity network (EuroPHP)wassupportedbygrantsobtainedfromtheEuropean This workand/ormembersofthenetworkEuro-Pseudohypoparathyroidism Funding

References in alphabeticalorder. equally tothemanuscript;allothermembersofEuroPHParelisted S Thiele,GMantovani,PerezdeNanclaresandALinglartcontributed Author contributionstatement disorders.eu

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40 52 51 49 48 47 46 45 43 42 41 50 39 44 Position Statement Linglart A, Gensure RC,Olney RC,Jüppner H &Bastepe M.Anovel Bastepe M, Fröhlich LF, Hendy GN,Indridason OS,Josse RG, Liu J, Litman D,Rosenberg MJ,Yu S, Biesecker LG&Weinstein LS. A Mantovani G, Ballare E,Giammona E,Beck-Peccoz P&Spada A. Yu S, Yu D, Lee E, Eckhaus M,Lee R,Corria Z,Accili D,Westphal H Hayward B &Bonthron D.Animprintedantisensetranscriptatthe Shore EM, Ahn J,JandeBeur S,Li M,Xu M,Gardner RJM, Adegbite NS, Xu M,Kaplan FS,Shore EM&Pignolo RJ.Diagnostic Garin I, Elli FM,Linglart A,Silve C,deSanctis L,Bordogna P, Pereda A, Mitsui T, Nagasaki K,Takagi M, Narumi S,Ishii T&Hasegawa T. Fernandez-Rebollo E, Barrio R,Pérez-Nanclares G,Carcavilla A, Fernandez-Rebollo E, García-Cuartero B, Garin I,Largo C, Geneviève D, Sanlaville D,Faivre L,Kottler M-L,Jambou M, Lin MH, Numbenjapon N,Germain-Lee EL&Pitukcheewanont P. STX16 deletioninautosomaldominant pseudohypoparathyroidism Investigation a putativeimprintingcontrolelement ofGNAS. associated withaheterozygousmicrodeletion thatlikelydisrupts et al. Koshiyama H, Körkkö J,Nakamoto JM,Rosenbloom AL,Slyper AH of ClinicalInvestigation GNAS1 imprintingdefectinpseudohypoparathyroidismtypeIB. and Metabolism human thyroidglandandgonads. The gsalphagene:predominantmaternaloriginoftranscriptionin 8715–8720. due totissue-specificimprintingofthegsalphagene. heterotrimeric Gsproteinalpha-subunit(Gsalpha)knockoutmiceis & Weinstein LS. Variable andtissue-specifichormoneresistancein (doi:10.1093/hmg/9.5.835) human GNAS1locus. (doi:10.1056/NEJMoa011262) heteroplasia. inactivating mutationsoftheGNAS1geneinprogressiveosseous Zasloff MA, Whyte MP, Levine MA&Kaplan FS.Paternallyinherited (doi:10.1002/ajmg.a.32346) A ofMedicalGeneticsPart American Journal (POH) andotherformsofGNAS-basedheterotopicossification. and mutationalspectrumofprogressiveosseousheteroplasia Metabolism of theunderlyingmechanisms. affecting the GNASlocusin pseudohypoparathyroidism: characterization Clarke JT, Kannengiesser C,Coutant R (doi:10.1002/ajmg.a.34393) A ofMedicalGeneticsPart American Journal submicroscopic deletionencompassingthewholeGNASlocus. A familyofpseudohypoparathyroidismtypeIawithan850-kb 705–712. pseudohypoparathyroidism typeIa. Garin I, Castaño L&deNanclares GP. Newmutationtypein and Metabolism pseudohypoparathyroidism type1B. loss ofexonA/Bmethylation:potentialformisdiagnosis in pseudohypoparathyroidismtype1Aresultinganapparent de Nanclares G.IntragenicGNASdeletioninvolvingexonA/B Martínez F, Garcia-Lacalle C, Castaño L,Bastepe M&Pérez Human Genetics retardation andintractablefeedingdifficulties. in twogirlspresentingwithseverepre-andpost-natalgrowth Paternal deletionoftheGNASimprintedlocus(includingGnasxl) Gosset P, Boustani-Samara D,Pinto G,Ozilou C,Abeguilé G and Metabolism osteodystrophy.with Albrighthereditary Progressive osseousheteroplasia,asanisolatedentityoroverlapping 585–590. osteodystrophy andPHP1A. Autosomaldominantpseudohypoparathyroidism typeIbis (doi:10.1111/cen.2008.69.issue-5) (doi:10.1055/s-0034-1395678) 2015 2003 New England Journal ofMedicine New EnglandJournal 2015 2010 2002 2005 100 112 E681–E687. 28 2000 87 95 Human MolecularGenetics 1255–1263. 13 911–918. 765–771. 4736–4740. 1033–1039. 106 Hormone andMetabolicResearchHormone Journal of Clinical Endocrinology and ofClinicalEndocrinologyand Journal 1167–1174. (doi:10.1210/jc.2014-3098) (doi:10.1515/jpem-2014-0435) (doi:10.1210/jc.2009-1581) (doi:10.1172/JCI19159) Journal ofClinicalEndocrinology Journal Clinical Endocrinology et al. (doi:10.1210/jc.2002-020183) Journal ofClinicalEndocrinology Journal S Thieleandothers (doi:10.1038/sj.ejhg.5201448) Journal of Pediatric Endocrinology ofPediatricEndocrinology Journal Novel microdeletions Novelmicrodeletions 2008 2012 (doi:10.1172/JCI10431) 2002 2000 146A 158A Journal ofClinical Journal European Journal ofEuropean Journal 346 PNAS 9 1788–1796. 261–264. 99–106. 835–841. 2008 1998 2015 et al. Journal Journal 69 95 47

for PHP iPPSD, anovelclassification 54 62 56 55 57 53 58 64 63 61 60 59 Chillambhi S, Turan S, Hwang D-Y, Chen H-C,Jüppner H& Elli FM, deSanctis L,Peverelli E,Bordogna P, Pivetta B,Miolo G, Richard N, Abeguilé G,Coudray N,Mittre H,Gruchy N, Rezwan FI, Poole RL,Prescott T, Walker JM, KarenTemple I & Bastepe M, Fröhlich LF, Linglart A,Abu-Zahra HS,Tojo K, Takatani R, Molinaro A,Grigelioniene G,Tafaj O, Watanabe T, Van Dijk FS,Pals G,Van Rijn RR,Nikkels PGJ&Cobben JM. Maupetit-Méhouas S, Azzi S,Steunou V, Sakakini N,Silve C, Takatani R, Minagawa M, Molinaro A,Reyes M,Kinoshita K, Dixit A, Chandler KE,Lever M,Poole RL,Bullman H,Mughal MZ, Fernández-Rebollo E, Lecumberri B,Garin I,Arroyo J,Bernal- Bastepe M, Lane AH&Jüppner H.Paternaluniparentalisodisomyof Metabolism of GNASmethylationincis. causes pseudohypoparathyroidismtypeIbandbiparentaldefects Bastepe M. DeletionofthenoncodingGNASantisensetranscript (doi:10.1210/jc.2013-3704) of ClinicalEndocrinologyandMetabolism ablating STX16causeslossofimprintingattheA/BDMR. pseudohypoparathyroidism typeIb:anovelinheriteddeletion Beck-Peccoz P, Spada A&Mantovani G.Autosomaldominant (doi:10.1210/jc.2011-2804) of ClinicalEndocrinologyandMetabolism autosomal dominantpseudohypoparathyroidismtypeIb. NESP55 causeslossofmaternalimprintA/BGNASand Andrieux J, Cathebras P&Kottler ML.Anewdeletionablating (doi:10.1038/ng1560) pseudohypoparathyroidism typeIb. methylated regioncauseslossofmaternalGNASimprintsand Ward LM &Jüppner H.DeletionoftheNESP55differentially 804–814. element ofGNAS. type Ibredefinestheboundariesofacis-actingimprintingcontrol Research maternally inheritedGNASdeletion. pseudohypoparathyroidism typeIb(PHP1B)revealsonlyonenovel Analysis ofmultiplefamilieswithsingleindividualsaffectedby Reyes M, Sharma A,Singhal V, Raymond FL,Linglart A Genetics pseudohypoparathyroidism type1b. Mackay DJG. Very smalldeletionswithintheNESP55genein of MedicalGenetics Classification ofOsteogenesisImperfecta revisited. 1172–1180. pseudohypoparathyroidism type1b. and differentmechanismofmultilocus methylationdefectin subset ofpatientswithGNASepimutationsunderliesacomplex Simultaneous hyper-andhypomethylationatimprintedlociina Reynes C, Perezde NanclaresG,Keren B,Chantot S,Barlier A bone.2015.05.011) type Ib(sporPHP1B). patients affectedbysporadicpseudohypoparathyroidism chromosome 20q(patUPD20q)inJapaneseandCaucasian et al. Takatani T, Kazukawa I,Nagatsuma M,Kashimada K, Sato K jc.2012-2639) Endocrinology andMetabolism paternal uniparentaldisomyofchromosome20q. Steggall M &Suri M.Pseudohypoparathyroidismtype1bdueto Endocrinology associated withpseudohypoparathyroidism. Nanclares GP. Newmechanismsinvolvedinpaternal20qdisomy Chico A, Goñi F, Orduña R,SpanishPHPGroup,Castaño L&de of HumanGenetics as aplausiblecauseofpseudohypoparathyroidism. chromosome 20q–andtheresultingchangesinGNAS1methylation– Similarfrequencyofpaternaluniparentaldisomyinvolving 2015 2016 (doi:10.1086/429932) 2010 (doi:10.1002/humu.22352) 2010 23 31 494–499. 796–805. 95 2001 2010 American Journal ofHumanGenetics American Journal 163 3993–4002. Bone 953–962. 68 53 2015 Downloaded fromBioscientifica.com at10/07/202105:23:32AM 1283–1289. (doi:10.1038/ejhg.2014.133) 1–5. (doi:10.1002/jbmr.2731) 2013 Journal ofClinicalEndocrinologyand Journal (doi:10.1016/j.ejmg.2009.10.007) 79 (doi:10.1210/jc.2009-2205) (doi:10.1530/EJE-10-0435) 98 15–20. Nature Genetics European Journal ofHuman European Journal Human Mutation Journal ofBoneandMineral Journal E103–E108. 2014 2012 175 (doi:10.1016/j. European Journal of European Journal 99 www.eje-online.org 97 :6 E724–E728. E863–E867. (doi:10.1210/ Journal ofClinical Journal European Journal European Journal 2005 American Journal American Journal 2013 2005 et al. 37 Journal Journal 34 76 Journal

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Downloaded from Bioscientifica.com at 10/07/2021 05:23:32AM via free access European Journal of Endocrinology 107 106 105 104 103 102 101 100 99 97 96 95 94 98 Position Statement de Sanctis L,Bellone J,Salerno M,Faleschini E,Caruso-Nicoletti M, Mantovani G, Maghnie M, Weber G, DeMenis E, Brunelli V, Cappa M, Germain-Lee EL, Groman J,Crane JL,JandeBeur SM&Levine MA. Romanet P, Osei L,Netchine I,Pertuit M,Enjalbert A,Reynaud R Pereda A, Garin I,Garcia-Barcina M, Gener B,Beristain E, Ibañez AM Bastepe M. Geneticsandepigeneticsofparathyroid and Metabolism pseudohypoparathyroidism type1A. Stallings VA Harrington J, Sochett E,Tershakovec A, Zemel BS, 2013 pseudohypoparathyroidism type1a. & Cone RD.Energyexpenditureinobesechildrenwith Endocrinology Reviews deficiency inpseudohypoparathyroidismtype1a. (doi:10.1210/jc.2014-4047) of ClinicalEndocrinologyandMetabolism exon A/Bisassociatedwithincreasedintrauterinegrowth. Linglart A, Kottler ML&Jüppner H.LossofmethylationatGNAS 2013 in fetaldevelopment. growth retardation(IUGR)andprovideevidenceforaroleofXL Kottler M-L. PaternalGNASmutationsleadtosevereintrauterine 37 pseudohypoparathyroidism type1A. Janiri L. Clinicalinsightsbythepresenceofbipolardisorderin (doi:10.1210/jcem.84.11.6145) ofClinicalEndocrinologyandMetabolism Journal action ofepinephrine:anewfeatureproteinGsdeficiency. Adnot P, Garabédian M&Bougnères P. Resistancetothelipolytic (doi:10.1210/jcem.83.3.4652) ofClinicalEndocrinologyandMetabolism Journal dysfunction inwomenwithAlbright’s osteodystrophy. hereditary (doi:10.1007/BF03347406) type Ia. secretion inacohortofchildrenwithpseudohypoparathyroidism Cicchetti M, Concolino D,Balsamo A,Buzi F, Ghizzoni L Metabolism imprinting oftheGsalphagene. resistance inpseudohypoparathyroidismtypeia:newevidencefor Loli P, Beck-Peccoz P&Spada A.Growthhormone-releasinghormone (doi:10.1210/jc.2003-030028) of ClinicalEndocrinologyandMetabolism 1a: anothermanifestationofmultihormoneresistance. Growth hormonedeficiencyinpseudohypoparathyroidismtype (doi:10.1542/peds.2014-2806) congenital hypothyroidism. & Barlier A.CasereportofGNASepigeneticdefectrevealedbya (doi:10.1186/1750-1172-8-141) of asyndrome. & Perezde NanclaresG.BrachydactylyE:isolatedorasafeature (doi:10.1159/000342494) hormone resistance. Roizen JD, Danzig J,Groleau V, McCormack S,Casella A, Shoemaker AH, Lomenick JP, Saville BR,Wang W, Buchowski MS Germain-Lee EL. Shortstature,obesity, andgrowthhormone Bréhin A-C, Colson C,Maupetit-Méhouas S,Grybek V, Richard N, Richard N, Molin A,Coudray N,Rault-Guillaume P, Jüppner H& Kadilli I, Colicchio S,Guglielmo R,Vollono C, DellaMarca G & Carel JC, LeStunff C,Condamine L,Mallet E,Chaussain JL, Namnoum AB, Merriam GR,Moses AM&Levine MA.Reproductive 497.e3–497.e5. 37 98 Journal ofEndocrinologicalInvestigation Journal 1147–1153. E1549–E1556. 2003 et al. 2015 Orphanet Journal ofRare Diseases Orphanet Journal 88 Restingenergyexpenditureisdecreasedin (doi:10.1016/j.genhosppsych.2015.06.008) 4070–4074. Endocrine Development 2006 (doi:10.1038/ijo.2012.200) 101 Journal ofClinicalEndocrinologyandMetabolism Journal (doi:10.1210/jc.2013-1667) 880–888. 3 (Supplement2)318–327. Pediatrics (doi:10.1210/jc.2002-022028) Journal of Clinical Endocrinology and ofClinicalEndocrinologyand Journal (doi:10.1210/jc.2015-3895) International Journal ofObesity Journal International Journal ofClinicalEndocrinology Journal General HospitalPsychiatry S Thieleandothers 2015 2015 2003 2013 135 100 88 2007 1999 1998 2013 e1079–e1083. 4059–4069. 24 E623–E631. Pediatric 11–24. 30 84 83 8 97–103. 141. 4127–4131. 824–829. Journal Journal et al. Journal Journal GH 2015 α s

111 110 108 Accepted 7July2016 Revised versionreceived5July2016 Received 8February2016 120 118 113 112 117 116 115 109 119 114 for PHP iPPSD, anovelclassification Bilezikian JP, Khan A,Potts JT, Brandi ML,Clarke BL,Shoback D, Lindstrand A, Grigelioniene G, Nilsson D, Pettersson M, Hofmeister W, Bakker B, Sonneveld LJH,Woltering MC, Bikker H&Kant SG. Agirlwith Journal of Medical Genetics Part A ofMedicalGeneticsPart Journal associated withbrachydactylytypeEandliteraturereview. Silve C &deNanclares GP. ReportoftwonovelmutationsinPTHLH Genetics of PTHLHcausebrachydactylytypeE. Gillerot Y, Weigel JF, Krüger G Bone andMineralResearch involvement, treatment,andchallengesforfutureresearch. in theadult:epidemiology, diagnosis,pathophysiology, target-organ Jüppner H, D’Amour P, Fox J,Rejnmark L (doi:10.1002/humu.22222) gene causingacrodysostosis. Identification ofnovelmutationsconfirmsPDE4Dasamajor Campeau PM, Lee B,Bacino CA,Michaud JL,Bernier FP 2014 acrodysostosis type2. as aphenotypicvariationofpseudohypoparathyroidismand Soneda S, Keino D,Matsubayashi S 45–54. disorders withmirrorphenotypes. et al. Anderlid B-M, Kant SG,Ruivenkamp CA,Gustavsson P, Valta H (doi:10.1016/j.cellsig.2014.07.025) pathology ofacrodysostosis. protein kinaseA(PKA)providenewinsightsintothemolecular mutations incyclicAMPphosphodiesterase-4D(PDE4D)and Ohta T, Nishimura G,Mastuura N,Kim OH 1b. Cinacalcet asadjunctivetherapyinpseudohypoparathyroidismtype Biological Chemistry uncouples cellsurfacereceptorsfromadenylylcyclase. osteodystrophy alpha mutantinapatientwithAlbrighthereditary ajmg.a.37490) Clinical Genetics mutations ofthePRKAR1Ageneinpatientswithacrodysostosis. Lankes E, Henn W, Gruber-Sedlmayr U,Seifert W 146 breakpoint regionon2q37.3. association withschizophrenicpsychosis,andshareddeletion two caseswithhighlydistinctivefacialphenotype,discordant Bubendorff V, Mannhart A&Müller S.2q37.3deletion syndrome: (doi:10.1371/journal.pone.0117691) duplications intheGNASlocus. Pseudohypoparathyroidism typeIbassociatedwithnovel and Metabolism 1B duetomultipleimprintingdefects. Beckwith-Wiedemann syndromeandpseudohypoparathyroidism type 3271-7) Thomas-Teinturier C, Pereda A,Garin I,Diez-Lopez I,Linglart A, Klopocki E, Hennig BP, Dathe K,Koll R,deRavel T, Baten E,Blom E, Lynch DC, Dyment DA,Huang L,Nikkel SM,Lacombe D, Mitsui T, Kim O-H,Hall CM,Offiah A,Johnson D,Jin D-K, Toh TH, Kaname T, Ki C-S,Niikawa N,Baillie GS,Day JP, Yamamura K-I, Srivastava T, Krudys J,Mardis NJ,Sebestyen-VanSickle J &Alon US. Schwindinger WF, Miric A,Zimmerman D&Levine MA.AnovelGs Muhn F, Klopocki E,Graul-Neumann L,Uhrig S,Colley A,Castori M, Mehraein Y, Pfob M,Steinlein O,Aichinger E,Eggert M, Perez-Nanclares G, Velayos T, Vela A, Muñoz-Torres M &Castaño L. Pediatric Nephrology 33–38. Different mutations in PDE4D associated with developmental DifferentmutationsinPDE4Dassociatedwithdevelopmental 164A (doi:10.1136/jmedgenet-2013-101937) 2010 2529–2534. (doi:10.1159/000431389) 86 2015 2013 434–439. 1994 100 84 American Journal of Medical Genetics Part A ofMedicalGeneticsPart American Journal 2016 3963–3966. (doi:10.1002/ajmg.a.36669) 531–538. 2011 269 Downloaded fromBioscientifica.com at10/07/202105:23:32AM (doi:10.1016/j.ajhg.2010.01.023) Cellular Signalling Human Mutation 31 25387–25391. Cytogenetic andGenomeResearch et al. 26 795–800. 2016 PLoS ONE 2317–2337. Journal ofMedicalGenetics Journal (doi:10.1111/cge.2013.84.issue-6) Deletionandpointmutations et al. (doi:10.1210/jc.2015-2260) Journal of Clinical Endocrinology ofClinicalEndocrinology Journal 170 American Journal ofHuman American Journal Acroscyphodysplasia et al. (doi:10.1007/s00467-015- 2015 734–742. 175 et al. 2013 Hypoparathyroidism Hypoparathyroidism (doi:10.1002/jbmr.483) 2014 www.eje-online.org :6 10 Heterozygous et al. e0117691. 34 26 (doi:10.1002/ Novel Novel 97–102. 2446–2459. Journal of Journal et al. 2014 Journal of of Journal American

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