European Journal of Endocrinology 10.1530/EJE-17-0074 reported referral-basedcohorts. rate ofmetastaticdiseaseandarelativelyhighnumber of headandneckparagangliomascomparedwithpreviously Conclusions of thetwofounder orpheochromocytomas,norintheoccurrence ofmetastaticdiseaseorothertumorsbetweencarriers showed nosignificantdifferences inthenumberand locationofheadandneckparagangliomas,sympathetic non-paraganglionic tumors.Atstudyclose,therewere111 (57.2%)unaffected mutationcarriers.Statisticalanalyses sympathetic paragangliomas.Fifteenpatients(7.7%)developed metastaticparagangliomaand17(8.8%)developed or multipleheadandneckparagangliomas,4(2.1%)hadapheochromocytoma26(13.4%)onemore carried theexon3deletionand46(23.7%)c.423 Mean agewas44.8 Results Methods Design clinical phenotypesrelatedtospecific phenotypical characteristicsofalargeDutchcohort carcinoma, gastrointestinalstromaltumorandpituitaryneoplasia).Theaimofthisstudywastodetermine sympathetic paragangliomas,headandneckparagangliomasnon-paraganglionictumors(e.g.renalcell Objective Abstract Leiden, theNetherlands 10 9 the Netherlands, 7 Otorhinolaryngology/Head andNeckSurgery, RadboudUniversityMedicalCenter, Nijmegen,theNetherlands, Leiden UniversityMedicalCenter, Leiden,theNetherlands, University ofGroningen,MedicalCentertheNetherlands, Otorhinolaryngology/Head andNeckSurgery, VUUniversityMedicalCenter, Amsterdam,theNetherlands, 1 Erik F Hensen Jean-Pierre Bayley Peter H Bisschop Anouk van Berkel Anouk N A van der Horst-Schrivers Nicolasine D Niemeijer carriers: anationwidestudy The phenotypeof Department ofClinicalGenetics,ErasmusMC,UniversityMedicalCenter, Rotterdam,theNetherlands, Department ofEndocrinologyandMetabolism,AcademicMedicalCenter, UniversityofAmsterdam, Department ofEndocrinologyandMetabolicDiseases,LeidenUniversityMedicalCenter, Leiden,theNetherlands, Department ofHumanGenetics,and DOI: 10.1530/EJE-17-0074 www.eje-www.eje-online.org Clinical Study : Retrospectivedescriptivestudy. : We included194 online.org : Retrospectivedescriptivestudyinsevenacademiccenters. : SuccinatedehydrogenaseBsubunit( : Inthisnationwidestudyofdisease-affected andunaffected 8 Department ofEndocrineOncology, UniversityMedicalCentreUtrecht,theNetherlands, 2

and 7 , Koen M A Dreijerink 5 ± 10 SDHB , Henri J L M Timmers Eleonora P M Corssmit

16.0 years. Mediandurationoffollow-upwas2.6 years(range:0–36).Sixtypersons(30.9%) , Alberto M Pereira 1 (exon3deletionvsc.423 , Johannes A Rijken SDHB © 2017EuropeanSociety ofEndocrinology © 2017EuropeanSociety ofEndocrinology 11 mutationcarriersconsisting65(33.5%)indexpatientsand129(66.5%)relatives. Department ofOtorhinolaryngology, LeidenUniversityMedicalCenter, N DNiemeijerandothers 3 SDHB , Michiel N Kerstens 1 Printed inGreatBritain 8 , Jeroen C Jansen , Marieke F van Dooren 5 mutations. , Henricus P M Kunst 1 5 2 Division ofEndocrinology, DepartmentofInternalMedicine, SDHB , Karin Eijkelenkamp SDHB ) genegermlinemutationspredisposetopheochromocytomas, + 1G SDHB >

A .Fifty-fourmutationcarriers(27.8%)hadone 3 , Carli M J Tops germlinemutationcarriersandassessdifferences in germlinemutation 11

mutation carriers Phenotype of + 1G , Frederik J Hes Published byBioscientifica Ltd. 6 > , C René Leemans A). 9 , 3

, 4 Department ofClinicalGenetics, SDHB SDHB 4 , mutationcarriers,weobservedalower 4

, 3 Department ofEndocrinology, 2 Downloaded fromBioscientifica.com at09/27/202106:40:41AM , 2 Department of 6 (2017) Endocrinology European Journal of to NDNiemeijer should beaddressed Correspondence [email protected] Email Department of 177

177 : 2 177 :2 , 115–125

115 –125 via freeaccess European Journal of Endocrinology subunits ofsuccinatedehydrogenase(alsomitochondrial SDHA cases.The mutations areresponsibleformosthereditary Netherlands, succinatedehydrogenase( germlinemutations.Inthe 10–20% ofsporadiccasescarry syndrome. Most familial cases of PCC and/or PGL and PGLs canoccurspontaneouslyoraspartofahereditary The aimofthisstudywasto obtainabetterimpression mutation, alsoannotatedas adeletionofexon3( mutation andthec.201-4429_287-933del, p.(Cys68fs) in DutchPGLfamilies,the c.423 tumor spectrum( neuroendocrine tumorsmaybepartoftheSDH-related stromal tumors. We also found that pancreatic neoplasia, renaltumorigenesisandgastricgastrointestinal the etiologicalassociationofSDHgeneswithpituitary paraganglionic tumors. In a recent study we strengthened carriers withmanifestdisease( PGL, and23%instudiesthatincludedonlymutation mutation carriersandwithmanifest 13% inpopulationsincludingbothasymptomatic that thepooledprevalenceofmetastaticdiseasewas analysis reportedbyVan Hulsteijn were considerablylower. Asystematicreviewandmeta- risks ofmetastaticdiseasein SDHB malignancy ratesashigh31–97%werereportedfor other subunitsofthe and metastaticdiseasethanmutationcarriersinthe mutation carriersmorefrequentlydevelopsPGLs,PCCs diagnosed asasingletumor( of malignancy. Incontrast, located intheheadandneckregionwithalowfrequency are usuallycharacterizedbymultiplePGLs,predominantly have distinctphenotypiceffects. activity( essential forflavinationoftheSDHAproteinandSDH encodesSDHcomplexassemblyfactor2(SDHAF2), cycle andtheelectrontransportchain( enzymethatlinkstheKrebs complex II),akeyrespiratory parasympathetic tissueoftheheadandneck(HNPGL)( locations (alsotermedsympatheticPGL(sPGL))orfrom termed (PCC))andextra-adrenal sympathetic chromaffintissueoftheadrenalmedulla(also tumors ofparaganglia.Theyderivefromeither Paragangliomas (PGLs)arerarevascular, neuroendocrine Introduction www.eje-online.org Clinical Study Two foundermutationsin SDH -related PGL ( , SDHB mutations have also been linked to non- , SDHC 11 3 ). Thesevariousgermlinemutations and ). 5 , SDH 6 SDHD , gene( 7 , SDHB SDHB 8 , 10 SDHB encode for the four 9 N DNiemeijerandothers 5 SDHD ). 4 ), we recently reported -related diseaseisoften , ). Furthermore, mutationcarriersthat 6 havebeenidentified , t al. et + 7 1G -related PGL/PCCs ). Althoughinitial 2 SDH > ). The demonstrated

A splicesite ) germline SDHAF2 12 SDHB SDHB , 13 1 ). ).

the genetic,clinical,radiologicalandbiochemicaldata andnecksurgeon.Weotolaryngologist/head evaluated the dateoflastcontactwithendocrinologistor Follow-up endedonJuly1,2014or, whenlosttofollow-up, written informed consent was obtained from their parents. yearsofage, consent andincaseofpersonsunder18 the analysis.Allincludedpersonsgavewritteninformed mutation carriersdiagnosedbefore2014wereincludedin In thisretrospectivenationwidestudy, all Subjects andmethods the Netherlands. in anationwidestudysevenacademiccenters affected andunaffected the clinicalandbiochemicalcharacteristics of disease- of thetwofoundermutations.Therefore,weinvestigated of thephenotype In thismanuscriptwereport pathogenicorlikely as intheinternationalguidelines byPlon the Netherlands). using theP226MLPA (MRCHolland, Amsterdam, multiplex ligation-dependent probe amplification (MLPA) ABI 377 Genetic Analyser (Applied Biosystems) and by by directsequencing using theSangermethodonan Screening forgermline and DNA testing for the family-specific patients aresubsequentlyinvitedforgeneticcounseling gene isidentified,at-riskfamilymembersoftheindex all patientswithanHNPGL.Ifamutationinthe years), and PCC/sPGL at an early age (younger than 50 for HNPGLorPCC/sPGL,patientswithanisolated to patientswithPCC/sPGLandapositivefamilyhistory DNA testingformutationsinthe previously describedbyvanHulsteijn carriers fromtheLeidenUniversityMedicalCenterare SDHB reasons. However, theyonlyhadidentifiedonegermline Medical Centerwasnotabletoparticipatefortechnical Medical Center Utrecht (Utrecht). Maastricht University Academic MedicalCenter(Amsterdam)andUniversity (Amsterdam), ErasmusMedicalCenter(Rotterdam), Medical Center (Nijmegen), VU University Medical Center Center Groningen(Groningen),RadboudUniversity University MedicalCenter(Leiden), eight clinicalgeneticscentersoftheNetherlands:Leiden of mutation carriers Phenotype of SDHB In theacademiccenters,geneticcounselingand mutationcarrier. Datafrom47 mutationcarriersidentified insevenofthe SDHB

SDHB SDHB SDHB Downloaded fromBioscientifica.com at09/27/202106:40:41AM germlinevariantsareclassified SDHB mutationcarriers,especially germlinemutationcarriers mutationsisperformed SDH 177 et al. genesareoffered SDHB :2 SDHB SDHB ( 14 t al. et mutation. ). mutation germline ( SDHB 116 15 via freeaccess ).

European Journal of Endocrinology disease, i.e.HNPGL,sPGLand/or PCC. carrier wasdefinedasagermline mutationcarrierwith HNPGL, sPGLand/orPCC). Adisease-affectedmutation germline mutationcarrierwithout evidenceofdisease(i.e. resection werepossibletreatmentoptions. characteristics. Wait andscanpolicy, radiotherapyor the clinicalsymptoms,tumorcharacteristicsandpatient of choice.IncaseanHNPGL,treatmentwasguidedby a PCCorsPGLanoperationwasthepreferredtreatment was offered,guidedbytheclinicalcourse.Ingeneral,for or HNPGL,treatmentintensifiedperiodicexamination varied betweencenters.IncaseofadiagnosissPGL,PCC inthisagecategory ofsurveillance method andinterval yearsofage.Therefore,the carriers youngerthan18 in structured protocolsforsurveillance performed inordertoconfirmthediagnosis. doubt, additionalnuclearmedicineimagingstudieswere specific characteristicsonCTand/orMRI.Whenin tumors wereclassifiedasparaganglionicbasedontheir neck region.Incaseswithoutavailabletumorhistology, excessive catecholamineproductionoutsidetheheadand scans wereperformedtoidentifypotentialsources of scans/ 2-deoxy-2-[fluorine-18]fluoro- (MIBG)-scans/positron emissiontomography(PET)with abdomen andpelvisand/or radiological assessment byMRIorCTscansofthorax, secretion (i.e.anyvalueabovetheupperreferencelimit), metanephrine. Incaseofexcessivecatecholamine measurement(s) weredone),and/orplasmafree(nor) (depending ontheacademiccenterwhichurinary samples 3-methoxytyramine (3-MT)intwo24-hurinary acid (VMA),dopamine,(nor)metanephrineand/or the measurementof(nor)epinephrine,vanillylmandelic two years. Annual biochemical screening included every tomography (CT)scansofthorax,abdomenandpelvisonce threeyears,andMRIorcomputed neck regiononceevery of magneticresonanceimaging(MRI)theheadand yearsofage,screeningconsisted carriers olderthan18 andendocrinology.of otorhinolaryngology Formutation forPGLatthedepartments annual clinicalsurveillance oncoline.nl/familiair-paraganglioom). Theywereoffered care intheNetherlandsforpatientswithaPGL(www. according tostructuredprotocolsusedforstandard germline mutations. regions that are likely pathogenic, as highly conserved pathogenic variants,includingmissensemutationsin Clinical Study An unaffectedmutation carrier was defined asa At the time of this study, there were no national, All 18 SDHB F- l -dihydroxyphenylalanine ( germlinemutationcarrierswereinvestigated 123 d I metaiodobenzylguanidine -glucose ( N DNiemeijerandothers 18 SDHB F-DOPA) PET- 18 F-FDG PET)- mutation index patients and relatives Kaplan–Meier curves (One index patients and relatives Kaplan–Meier curves exact was employed. For comparison of disease risks for expected cellsizewaslessthanfive,inwhichcaseFisher’s proportions differedsignificantly, exceptwhenan analysis. Chi-squaretestswereusedtotestwhether IBM SPSSStatisticsversion20·0(SPSS)wasusedfordata Data analysis with theirlocalmedicalethicscommitteerequirements. (LUMC; numberP13.161),participatingcenterscomplied Committee of the Leiden University Medical Center distinguish benignfrommalignantPGLs. tumorthatreliably histological featuresoftheprimary tumor,distant fromtheprimary becausethereareno locoregional lymphnodesorinnon-chromaffinorgans metastases, that is, the presence of chromaffin tissue in carriers, 104havehadcomplete radiologicalscreening mutation carriers.Fromthe 111unaffectedmutation affected mutationcarriers and 111(57.2%)unaffected three duetoprogressivedisease duetoamalignantsPGL. HNPGL (jugularbodytumor)withbonemetastases,and infarction), oneduetoprogressivediseaseofamalignant (lung cancer, metastasizedbreastcancerandmyocardial persons (3.6%)died:threebecauseofintercurrent disease the follow-upinanon-participatinghospital.Seven pursue anyfollow-up,oneemigratedandcontinued to follow-up: six for unknown reasons, three chose not to years(range:0–36).Elevenpersons(5.7%)werelost 2.6 were included.Themediandurationofthefollow-upwas sity MedicalCenterUtrecht(Utrecht). Medical Center(Amsterdam)andfourfromtheUniver­ Medical Center(Rotterdam),fourfromtheAcademic sity MedicalCenter(Amsterdam),18fromtheErasmus Medical Center(Nijmegen),17fromtheVUUniver­ Groningen (Groningen),29fromtheRadboudUniversity Center (Leiden), 61 from the University Medical Center included: 61 from the Leiden University Medical A totalof194 Results significant at as mean wereplotted.Resultsarepresented Minus CumSurvival) mutation carriers Phenotype of The study wasapproved by the Medical Ethics Malignant disease was defined as thepresence of In total,ourcohortconsisted of83(42.3%)disease- In total,83men(42.8%)and111women(57.2%) ±

s . d SDHB . Differenceswereconsideredstatistically P .5 (two-sided). ≤0.05 SDHB

germlinemutation carriers were Downloaded fromBioscientifica.com at09/27/202106:40:41AM 177 www.eje-online.org :2 117 via freeaccess European Journal of Endocrinology www.eje-online.org (range: 11–77).Carotidbody tumorswerethemost Mean ageofdiagnosis of HNPGL was45.9 were clinicallyaffectedwith oneormultipleHNPGLs. and c.653G mutations (deletionexon3,c.423 cohort asawholeand for fourmost prevalent Dutch of theirrelatives. comprised of65(33.5%)indexpatientsand129(66.5%) was 44.8 The meanageatfirstevaluationtheoutpatientclinic Clinical features mutation in11persons(5.7%). 19 persons(9.8%)andthec.653G The c.654G 46 (23.7%)werecarriersofthec.423 Sixty (30.9%)werecarriersoftheexon3deletionand Details of Genetics non-functioning adrenaladenoma). was thoughttohaveaPCC,butthisturnedoutbe reversed tonoevidenceofatumorandthefourthpatient during radiologicalfollow-upthediagnosisofHNPGLwas tumor (GIST),onewasthoughttohaveanHNPGL,but carcinomas (RCCs)and a gastricgastrointestinalstromal multiple congenitalanomalies,onewithtworenalcell these patientshadDNAtestingforotherreasons(onewith were notaffectedwithHNPGL,PCCorsPGLbecause were unaffectedmutationcarriers.Fourindexpatients index patients.Ofthe129relatives,109persons(84.5%) scans/ body) imagingstudy(i.e. radiological screeningbyCT/MRI,didhadanother(total the mutationcarriers,whodidnothavehadcomplete abdomen/pelvis (seven mutation carriers). However, all region (two mutation carriers) or a CT/MRI of the thorax/ carriers have hadeither a CT/MRIof the headand neck have hadcompleteradiologicalscreening.Ninemutation carriers). Fromthe83disease-affectedmutationcarriers,74 a CT/MRIofthethorax/abdomen/pelvis(fivemutation of theheadandneckregion(twomutationcarriers)or thorax/abdomen/pelvis). SevenhavehadeitheraCT/MRI (CT/MRI oftheheadandneckregionCT/MRI Clinical Study There were65indexpatientsand129relativesof Of thewholecohort,54mutation carriers(27.8%) Clinical characteristicsattheendoffollow-up 18 F-DOPA PET-scans). ±

16.0 years (range11–76).Intotal,ourcohort 16.0 years SDHB > >

C) areoutlinedin A, p.(Trp218*) mutationwaspresentin mutationsareoutlinedin 123 I MIBG-scans/ Table 2 N DNiemeijerandothers + 1G + > . 1G , p.(Trp218Ser) C, > , c.654G A, > 18 mutation. A ± F-FDG PET- 42 years 14.2 al 1 Table SDHB > A .

and biochemicalphenotypes aredetailedin to progressivemetastaticdisease. Clinicalcharacteristics sPGLs hadmetastaticdisease andthreeofthemdieddue mutation. Twelve ofthe 26carrierswithoneormore c.343C 3deletion,fivethec.423 were onlythreethoracicPGLs.Eightpersonscarriedthe located intheabdominal/pelvicregion(28tumors);there levels. FivecarriershadtwosPGLs.ThesPGLsweremainly half ofthepatientswithansPGLhadelevatedhormone 26 mutationcarrierssufferedfromanHNPGL.Morethan of sPGLwas33.4 affected withoneormoresPGLs.Meanageofdiagnosis in (range 19–56).Clinicalcharacteristicsaredetailed PCC. Mean age of diagnosis of PCC was 36.2 HNPGL and15(27.8%)receivedradiotherapy. Twenty-seven carriers (50.0%) had an operation for their tumors (in7.2%)andvagalbody6.2%). prevalent HNPGLs(in11.3%),followedbyjugularbody Exon 1deletion Exon 2deletion Deletion promotertill Deletion promoter c.292T c.343C c.686_725del c.590C c.649C c.725G c.418G c.328A c.137G c.200 +1G c.574T c.653G c.654G c.119A c.1A c.325A c.380T c.626C c.761C c.727T c.713delT c.423 +1G Exon 3deletion DNA mutation Table 1 mutation carriers Phenotype of exon 8 and exon1 Table 3 Twenty-six mutationcarriers(13.4%)wereclinically Four patients(2.1%)wereclinicallyaffectedwitha > G > > > > > > > > > > > > > > > > > > C C C A T G T T T A T C A C A C C

T mutation and another two the c.200 SDHB > > . A A SDHB germlinemutations. ±

12.7 years (range:10–66).Noneofthe 12.7 years p.? p.? p.0 p.? p.(Cys98Arg) p.(Arg115*) p.(Glu229fs) p.(Pro197Arg) p.(Arg217Cys) p.(Arg242His) p.(Val140Phe) p.(Thr110Pro) p.(Arg46Gln) p.? p.(Cys192Arg) p.(Trp218Ser) p.(Trp218*) p.? p.(Lys40Thr) p.? p.(Asn109His) p.(Ile127Thr) p.(Pro209Leu) p.(Pro254Leu) p.(Cys243Ser) p.(Phe238fs) p.? change SDHB predicted Downloaded fromBioscientifica.com at09/27/202106:40:41AM + 1G >

A mutation,twothe 177 :2 Table 4 ± subjects Number of 16.3 years 16.3 years 11 (6) 19 (10) 46 (24) 60 (31) 1 (0.5) 1 (0.5) 1 (0.5) 1 (0.5) 1 (0.5) 1 (0.5) 1 (0.5) 1 (0.5) 2 (1) 2 (1) 2 (1) 1 (0.5) 2 (1) 3 (1.5) 3 (1.5) 3 (1.5) 3 (1.5) 3 (1.5) 4 (2) 4 (2) 4 (2) 6 (3) 8 (4) + 1G . 118 (%) > via freeaccess A European Journal of Endocrinology PRL, prolactinoma;sPGL,sympathetic ;Tymp, tympanicumbodytumor;VBT, vagalbodytumor. tumor; HNPGL,headandneckparaganglioma; JBT, jugularbody tumor;LTF, losstofollow-up;NED,noevidenceofdisease; PCC,pheochromocytoma; AWD, alivewithdisease;ca.,carcinoma;CBT, carotidbodytumor;DID,deadofintercurrent disease;DOD,deadofGIST, gastrointestinalstromal and ovariancancer, onepatientwiththreeRCCaswellaGIST. renal cellcarcinomas(2fociontheleft sideenoneontherightside)aswellagastrointestinalstromaltumor (GIST); renal cellcarcinoma(RCC)ontheleftsideandoneRCCrightside. Theother2patientsbothhad1fociofaRCC; Of these 26patients,fivepatientshad2sPGLs; a DID DOD LTF AWD NED Disease statusatlastfollow-up Micro-PRL Melanoma Other tumors Left Table 2 Malignant PGL/PCC Operation sPGL Left sPGL Right PCC Radiotherapy HNPGL Operation HNPGL Age HNPGL Other (HNPGL) Bilateral Right Left Tymp Bilateral Right Left JBT Bilateral Right VBT Bilateral Right Left CBT HNPGL Family historypositive Age (mean Woman Man Gender Mean ageatpresentationtheoutpatientclinicinanacademichospital; Pituitary incidentaloma Gastric GIST Ovarian ca. Synovial sarcoma Meibomian gland Colon ca. Prostate ca. Lung ca. Basal cellca. Renal cellca. Mamma ca. 3 HNPGL 2 HNPGL 1 HNPGL Clinical Study c Clinical phenotypesofspecific ± b

s d . d . ) a Total cohort

N DNiemeijerandothers 1 (righttonsil) 133 (68.6%) 129 (66.5%) 111 (57.2%) 43 (22.2%) 26 (13.4%) 15 (27.8%) 27 (50.0%) 22 (11.3%) 54 (27.8%) 83 (42.8%) 45.9 44.8 11 (5.7%) 17 (8.8%) 15 (7.7%) 10 (5.2%) 14 (7.2%) 12 (6.2%) 3 (1.5%) 4 (2.1%) 4 (2.1%) SDHB d number ofpatients(somedevelopedmultipletumors); 25 11 47 3 2 ± ± 1 1 1 1 2 1 1 2 2 1 1 1 3 0 5 5 1 5 8 0 6 6 2 9 1 6 e f 14.2 16.0 ( n germlinemutations. =194) Exon 3deletion 13 (21.7%) 42 (70.0%) 18 (30.0%) 40 (66.7%) 31 (51.7%) 29 (48.3%) 43.2 47.0 7 (11.7%) 6 (10.0%) 8 (13.3%) 8 (44.4%) 8 (44.4%) 8 (100%) 2 (3.3%) 3 (5.0%) 5 (8.3%) 5 (8.3%) 4 (6.7%) 4 (6.6%) 1 (1.7%) 15 ± ± 0 1 0 0 0 1 0 0 0 0 1 0 2 0

1 1 1 5 0 2 2 0 4 3 1 2 0 1 0 0 3 b age atdiagnosisHNPGL; 15.3 14.8 mutation carriers Phenotype of ( n =60) c.423 +1G

SDHB 32 (69.6%) 11 (23.9%) 35 (76.1%) 28 (60.9%) 18 (39.1%) 7 (15.2%) 51.0 50.6 9 (19.6%) 5 (10.9%) 5 (10.9%) 4 (36.4%) 4 (36.4%) 5 (100%) 2 (4.3%) 1 (2.2%) 2 (4.3%) 1 (2.2%) 1 (2.2%) 3 (6.5%) 3 (6.5%) 10 ± ± 0 0 1 1 0 0 2 0 1 1 1 1 1 1 0 2 3 0 3 0 0 0 3 0 1 0 0 0 0 > A c total cohort:26patientswith1ormoresPGLs.

14.5 11.2 ( n g =46) Downloaded fromBioscientifica.com at09/27/202106:40:41AM e there wasonepatientwithtwofociof c.654G 16 (84.2%) 18 (94.7%) 11 (57.9%) 44.0 8 (42.1%) g 1 (5.3%) 1 (5.3%) 1 (5.3%) 1 (5.3%) 1 (5.3%) 1 (5.3%) f one patientwithrectalcancer one patientdevelopedthree 27.2 > A ± 0 0

0 0 0 0 1 0 1 0 0 1 0 0 0 0 18.1 ( 177 n =19) www.eje-online.org :2 c.653G 49.1 44.8 3 (27.3%) 8 (72.7%) 2 (18.2%) 3 (27.3%) 8 (72.7%) 9 (81.8%) 2 (18.2%) 1 (33.3%) 1 (100%) 1 (9.1%) 1 (9.1%) 1 (9.1%) 1 (9.1%) > C ± ± 0 0 0 0 1 0 0 0 0 0 0 1 0 1 1 0 0 3 14.3 11.7 119 ( n =11) via freeaccess European Journal of Endocrinology www.eje-online.org tumors (allthreepatientshad anHNPGL). tumors, only three patients had also paraganglionic biopsy orsurgically-resectedmaterial. radiological follow-up without available underwent incidentaloma, both ofwhich functioning pituitary a microprolactinoma and one person had a non- cell tumor). had arectalcancerandoneovarian(granulosa (metastasized) synovialsarcoma. Inaddition,twopatients meibomian gland(adeno)carcinoma andonewitha breast cancer, one with prostate cancer, one with a squamous celllungcarcinoma, onewith(metastasized) basal cellcarcinoma, two withamelanoma,one gastric GIST. Furthermore,thereweretwopatientswitha ( deficient gastricGISTandhasbeendescribedpreviously carcinomas). Thislatter patientalsodevelopedanSDH- and oneontherightside(allthreeSDH-deficientrenal one patientdevelopedtwofociofaRCContheleftside cell carcinoma and one SDH-deficient carcinoma), and 17 and classifiedasSDH-deficientrenalcarcinomas ( tumors. Fourofthosetumorsweredescribedpreviously developed a total of five (histology confirmed) renal total of21non-paraganglionictumors.Threepatients publication in2014( previously havedevelopedmetastaticdiseasesinceour all patients.Noneofthe47mutationcarriersdescribed Treatment in tumorexistedofsurgery oftheprimary with metastaticdiseasearedisplayedindetail characteristics, treatment andoutcomeofthepatients carriers, 15/194(7.7%)developedmetastaticPGL.Clinical F, female;M,male;MN,metanephrine;NA,notassessed;NAV, notavailable;NED,noevidenceofdisease;NMN,normetanephrine. a 4 3 2 1 Case Table 3 Age atdiagnosisofpheochromocytoma. 11

Clinical Study ). Two patientsdevelopedaRCCononeside(oneclear ). TherewasoneotherpatientwithanSDH-deficient Of these 17 mutation carriers with non-paraganglionic Besides thesemalignancies,onepersondeveloped Seventeen mutationcarriers(8.8%)developeda Out ofthewholecohort F F F M Sex

Clinical characteristicsofthe4patientswithapheochromocytoma. c.653G Exon 3deletion c.343C Exon 2deletion SDH B mutation > > T C

14 ). Left Left Left Right Location

SDHB N DNiemeijerandothers Hypertension, flushes None, brotherwith Collaps Hypertension, flushes, Presenting symptoms mutation palpitations germlinemutation Table 5 11 , 16 SDHB

. ,

carriers ofthetwomostcommon related tothespecificmutationswithin in risk forindexpatients(probands)vsrelativesisoutlined relatives are outlined in of whomwereindexpatients and85persons(69%) carriers included124 by theFrenchnetworkon PGL/PCC in sPGL ormalignantdisease.Arecentlypublishedstudy overestimation oftheriskdevelopingHNPGL,PCC, This mayresultinascertainmentbiasandtherefore studies include a high proportion of index patients. in theliterature.Themajorityofpreviouslypublished difficult to directly compare our results with those reported respectively ( for developingPCCandsPGLs,18–52%59–84% metastatic disease. one ormoresPGLs.Fifteenpatients(7.7%)developed were clinicallyaffectedwithaPCCand26(13.4%) one ormultipleHNPGLs.Onlyfourpatients(2.1%) Fifty-four carriers(27.8%)wereclinicallyaffectedwith carriers and 111 (57.2%) unaffected mutation carriers. cohort consistedof83(42.8%)disease-affectedmutation phenotypes of194 In thisnationwidemulticenterstudyweassessedthe Discussion tumors. PCCs, norintheoccurrenceofmalignantdiseaseorother differences innumberandlocationofHNPGLs,sPGLsor compared. Statisticalanalysesshowednosignificant Netherlands (exon3deletionandc.423 mutation carriers Phenotype of Age 19 56 28 40

Fig. 1

To explorepotentialdifferencesinclinicalphenotypes The clinicalcharacteristicsoftheindexpatientsvs Previous studieshavereportedmuchhigherrates a NAV M, NMN,3-MTslightly NA NMN elevated,Mnormal (urinary measurements) Biochemical phenotype elevated .

SDHB 5 , 6 ,

8 SDHB , 18 SDHB Table 6 ). Forvariousreasons,itisquite Downloaded fromBioscientifica.com at09/27/202106:40:41AM germlinemutationcarriers.Our mutationcarriers,39(31%) and the age-related disease NAV NA NA NA (blood) phenotype Biochemical SDHB

177 mutationsinthe :2 SDHx + AWD (vagal NED NED NED Outcome 1G body tumor) SDHB mutation > ) were A) gene, 120 via freeaccess European Journal of Endocrinology study aremorecomparable totheresultsinourcurrent prevalences of PCC (1.6%) and sPGL (6.5%) found in their to resembletheproportions ofourstudycohort,andthe were relativesofindexpatients ( 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 Case Table 4 NA, not assessed;NE,norepinephrine;NMN,normetanephrine;PGL,paraganglioma; RFA, radiofrequencyablation;VMA,vanillylmandelicacid. patients withprogressivemalignantpheochromocytomaandparaganglioma; HNPGL,headandneckparaganglioma;M,male;MN,metanephrine; blind, phaseII,international,multicenterstudywhichisdedicatedtodetermine theefficacy of sunitinibontheprogression-freesurvivalat12 monthsin 3-MT, 3-methoxytyramine;CVD,cyclophosphamide,vincristine,dacarbazine;D,dopamine;E,epinephrine; F, female;Firstmappp,randomized,double- primary tumor. developed withlymphnodemetastases,notattimeofprimarytumor;***catecholamine excessdevelopedattimeofmalignantdisease,not a 26 25 Age atdiagnosisofsympatheticparaganglioma;*catecholaminemeasurements attimeofprimarytumornotavailable;**catecholamineexcess 9 8 7 6 5 4 3 2 1 Clinical Study

F F M F M F F F M M M M M M F M F F F M F M M M F F Sex

Characteristics of26patientswithsympatheticparagangliomas. c.686_725del c.343C c.727T c.574T c.200 +1G c.325A c.423 +1G Exon 3deletion Exon 3deletion c.653G c.423 +1G c.423 +1G c.725G c.423 +1G Exon 3deletion Exon 1deletion Exon 3deletion Exon 3deletion c.200 +1G Exon 3deletion c.343C SDH Exon 3deletion c.654G Exon 3deletion c.423 +1G c.626C B mutation > > > > > > > > > A C T T T A C C A > > > > > > > A A A A A A A

Para-vertebral Bladder Presacral Pararenal Bladder Para-aortic abdominal Thoracic Retroperitoneal hilum Bladder Para-aortic abdominal Para-aortic abdominal Bladder and Retroperitoneal Retroperitoneal Para-aortic abdominal Para-iliac (2lesions) Para-adrenal Retroperitoneal Para-aortic abdominal Renal hilum Thoracic (vertebraTh6) Retropancreatic Retroperitoneal Para-aortic Retroperitoneal and Location sPGL abdominal (Th3/Th4) and para-vertebral (para-aortic) retroperitoneal and intra-abdominal (pararenal) presacral N DNiemeijerandothers 19 ). Thiscohortseems

Age 10 and32 27 37 66 31 19 40 36 42 28 11 42 41 31 33 19 28 31 42 39 14 52 24 45 30 38 a (year)

No Yes Yes No No Yes No No No Yes No Yes No No disease Malignant Yes Yes Yes No Yes No No Yes No Yes Yes No other studiesarelikelytobe theresultofascertainment indicate that the high percentages described in several of PCC/sPGLsreportedinFrance andinthepresentstudy study (2.1%and13.4%respectively). Thelowpercentages mutation carriers Phenotype of

Surgery Surgery Surgery, Surgery Surgery Surgery, Lutetium Surgery Surgery Surgery Surgery, chemotherapy Surgery Surgery, Surgery (non-radical) Surgery Tumor reduction therapy Surgery, Surgery (primarybladder Surgery, Surgery Radiotherapy, Firstmappp Follow-up Surgery Surgery, radiotherapy Surgery Surgery, radiotherapy, Surgery, Surgery octreotate therapy therapy, RFA radiotherapy radiotherapy radiotherapy (metastases) PGL) sunitinib radiotherapy trial (startedJune2014) chemotherapy (CVD) SDHB 131 131 131 131 131

I-MIBG therapy I-MIBG therapy, I-MIBG therapy, I-MIBG therapy, I-MIBG therapy

131 Downloaded fromBioscientifica.com at09/27/202106:40:41AM I-MIBG No evidenceofdisease Alive atage40,with Alive atage78,with No evidenceofdisease No evidenceofdisease Alive atage51,with No evidenceofdisease No evidenceofdisease No evidenceofdisease Alive atage37, No evidenceofdisease Alive atage52,with Alive withdisease No evidenceofdisease Outcome Dead ofdisease:died Dead ofdisease:died Dead ofdisease:died No evidenceofdisease Alive atage52,with Alive withdisease Loss tofollow-up Died atage63,dueto No evidenceofdisease Alive atage47,with Alive atage46,with No evidenceofdisease disease disease disease disease without evidenceof disease progressive disease at age37dueto progressive disease at age62dueto progressive disease at age32dueto disease intercurrent disease disease disease 177 www.eje-online.org :2 121 via freeaccess European Journal of Endocrinology Relatives (129) Index patients(65) Table 6 RFA, radiofrequency ablation;Th6,6ththoracicvertebra. malignant pheochromocytomaandparaganglioma;HNPGL,headneck PGL;LTF, losstofollow-up;M,male;PGL,paraganglioma; multicenter studywhichisdedicatedtodeterminetheefficacy ofsunitinibontheprogression-free survivalat12 monthsinpatientswithprogressive CBT, carotidbodytumor;CVD,cyclophosphamide,vincristine,dacarbazine;F, female;Firstmappp,randomized,double-blind,phaseII,international, a 15 14 13 12 11 10 Case Table 5 www.eje-online.org number oftumorsdividedbythetotalpatients mentioned inmoststudiesarecalculatedusingthetotal bias. Furthermore,itshouldbenotedthatthepercentages Age atdiagnosisofparaganglioma; 9 8 7 6 5 4 3 2 1 Clinical Study

F F M M F M M M F F M F F M M Sex

Clinical characteristicsofindex patientsandrelatives. Clinical characteristicsofpatientswithmetastaticparagangliomas. Exon 3deletion c.654G Exon 3deletion c.626C c.727T c.200+1G c.325A Exon 3deletion c.653G Exon 3deletion c.423+1G c.725G c.418G Exon 3deletion c.200+1G SDH B mutation > > > > > > > A T A C C A T > > > Age A A A 45.4 43.6 (mean

± ± Para-vertebral Bladder Presacral Bladder Retroperitoneal Bladder Para-aortic Retroperitoneal Retroperitoneal Carotid body Jugular body Para-adrenal Right tonsil Thoracic Retroperitoneal Location PGL 16.6 14.8 abdominal (para-aortic) abdominal (vertebra Th6) (pararenal) ± b s age atdiagnosisofmalignantdisease. . d .) N DNiemeijerandothers Follow-up

Age (median,year) 2.0 4.5 a 33 19 28 42 52 45 30 37 66 35 48 40 18 10 42 (years)

(years) Age 70 66 57 45 20 13 45 33 58 28 46 55 45 39 38

b HNPGL

16 (12.4) 38 (58.5) carriers fromour cohort (111subjects) would givea persons intoaccount.Removalofallunaffectedmutation with anytumor, therebytakingonlydisease-affected mutation carriers Phenotype of Lymph nodes, Lymph nodes, Bone (vertebra) Lymph nodes, Lymph nodes, Intra-thoracic Bone metastases Location Lymph nodes, Lymph nodes, Bone Lymph nodes, Bone Lymph nodes, Lymph nodes, Lymph nodes bone bone (vertebra) bone bone bone bone bone, lung bone, lung bone (%)

SDHB PCC 1 (0.8) 3 (4.6) 131 None (notwithin None Surgery and Surgery, radiotherapy Surgery, Surgery, disease Treatment malignant Surgery, sunitinib Surgery, Radiotherapy, Radiotherapy Surgery, radiotherapy, 131 Surgery (%)

study period) octreotate therapy 177 RFA 131 radiotherapy chemotherapy radiotherapy therapy, radiotherapy therapy, radiotherapy therapy, (started June2014) Firstmappp trial (CVD) chemotherapy I-MIBG therapy I-MIBG therapy Lutetium I-MIBG therapy, Downloaded fromBioscientifica.com at09/27/202106:40:41AM 131 131 131 I-MIBG I-MIBG I-MIBG 21 (32.3) sPGL 5 (3.9) (%) 177 Alive atage78, Alive atage66, Died atage57,due Alive atage51, LTF, follow-uptill Alive atage37, Alive atage52, Outcome Died atage37due Died atage62due Died atage32due Alive atage52, Died atage63,due Alive atage47, Alive atage46, Alive atage40, with disease malignant disease progressive to rapidly with disease disease age 22,alivewith of disease without evidence with disease disease to progressive disease to progressive disease to progressive with disease disease to intercurrent with disease with disease with disease with disease Malignant PGL/PCC :2 15 (23.1) 0 122 via freeaccess European Journal of Endocrinology malignancy. paraganglioma/pheochromocytoma; malignancy, riskof neck paraganglioma;sPGL/PCC,riskofsympathetic paragangliomas/pheochromocytoma; HNPGL,riskofheadand patients (probands)vsrelatives.PGL/PCC,riskof(all) Comparison ofageatonsetin Figure 1 identifies arelativelyhigh numberofasymptomatic of personswitha testing ofrelativesandstructured follow-upprotocols and hadnotyetcometomedical attention.Thegenetic The large majority of these patients had no symptoms (i.e.non-indexHNPGLpatients) is29.6%(16/54). history proportion ofHNPGLpatientswithapositivefamily that in ourstudythe be explainedbytheobservation in disease-affectedsubjects( cohort, nearlydoublethefrequencyreportedpreviously prevalence ofHNPGLwasashigh54/83(65.1%)inour affected mutationcarriersweretakenintoaccount,the of theFrenchnetwork(14.5%)( (3–31%) ( SDHB relatively highfrequencyofHNPGLs(27.8%)among in previous studiesthathaveassessedclinicalcharacteristics into account,ourfiguresaresubstantiallylowerthanin for sPGL.Evenifwetakeonlydisease-affectedindividuals figure forPCCof4in83(4.8%)and26(31.3%) Clinical Study SDHB mutationcarrierscomparedwithotherstudies mutationcarriers.Bycontrast,wefounda 5 , 6 , 8 , 18 ) andevenwhencomparedwiththat SDHB mutationintheNetherlands SDHB 5 , 6 N DNiemeijerandothers , 19 mutationscarriers:index 8 ). Ifonlythedisease- ). Thismightinpart more accurate representation of the phenotype of mutation carriers,withorwithouttumors,allowingfora This meansthatthemalignancyriskforpatients already HNPGL patients,thismalignancyratewas5.6%(3/54). the malignancyriskisashigha46.2%(12/26).For patients. Taking intoaccountonlythesPGLpatients, of metastatic disease by 18.1% (15/83) in PGL/PCC mutation carriers(111subjects)resultsinaprevalence tumorwasansPGL.Removalofallunaffected primary (including one in the tonsil) and in 12 patients (80%) the tumorwasanHNPGL patients (20%)theprimary carriers, developedmetastaticPGL.Inthreeofthese including bothdisease-affectedandunaffectedmutation region in importance ofradiologicalscreeningtheheadandneck patients developanHNPGLfurthermoreunderlinesthe mutation carriers. shorter follow-up of relatives compared to index patients. However, thefollow-uptimeisrelatively shortduetoa inthisstudy,2.6 years whichisalimitationofthisstudy. mutation carriers.Themedian durationoffollow-upis with an underscore the need foranextendedfollow-upinpatients reported widerangesoftimetometastatictransformation metastatic diseaseispresent,thecurrentandpreviously tumor,based onhistopathologyoftheprimary onlyif ( ( results. Timmers years).Thisisinlinewithpreviouslypublished (0–39.2 PGL, wefoundawiderangeoftimetometastaticdisease reported ( 23% respectively( a pooledriskfordevelopingmetastaticPGLof13and carriers withmanifestnon-malignantPGLdocumented asymptomatic systematic reviewofprevalencestudiescomprisingboth also bearesultofvariablefollow-uptimes( Alternatively, thediscrepancyinmalignancyratesmay inflated becauseofselectionbiasinreferral-basedstudies. reported malignancyratesarehowevermostlikelyalso from31to97%( subjects andvary in theliteraturearecalculatedbasedondisease-affected cohort was16%(5/32).Theratesofmalignancyreported subjects ( reported metastaticPGLinfiveof16(31%)disease-affected for thefollow-upofthosepatients.Srirangalingam suffering fromansPGLishigh,whichhasimplications mutation carriers Phenotype of 8 7 ). Becauseitisnotpossibletodiagnosemalignancy ) andSrirangalingam Only fifteenpatients(7.7%)intheentirecohort, that the majority of The observation 8 SDHB SDHB 20 ). However, themalignancy rate forthe , SDHB 21 SDHB mutation,especiallyindisease-affected mutationcarriers. ). Inthefifteenpatientswithmetastatic et al

10 mutationcarriersand ), alsomuchlowerthanpreviously . found a range from 0 to 17 years . foundarangefrom0to17 years Downloaded fromBioscientifica.com at09/27/202106:40:41AM t al et ewe . n 5 years . between1.5and25 177 5 , www.eje-online.org 6 :2 , SDHB 7 7 , , SDHB 8 8 , ). Arecent mutation 9 ). These -linked SDHB 123 entire et al. via freeaccess

European Journal of Endocrinology www.eje-online.org analysis and preparation of the manuscript. Johannes A Rijken helped in Nicolasine DNiemeijerhelpedin study design,datacollection, Author contributionstatement the public,commercialornot-for-profit sector. This researchdidnotreceiveanyspecificgrantfromfundingagency in Funding perceived asprejudicingtheimpartialityofthisstudy. The authorsdeclarethatthereisnoconflictofinterestcould be Declaration ofinterest mutation carriers. include radiologyoftheheadandneckregionin importance ofthoroughtumorscreeningprotocolsthat of germlinemutations.Itfurthermorehighlightsthe unaffected individualsinstudiesthatassessthephenotype the importanceofincludingbothdisease-affectedand inclusion ofunaffectedmutationcarriers,underlining phenomenon buttheresultofmorecomprehensive based cohorts.Thisismostprobablynotaregional of HNPGLscomparedwithpreviousreportsreferral- rate ofmetastaticdiseaseandarelativelyhighnumber carriers identifiedintheNetherlands,wefoundalower allowed fortheinclusionof first-degree relatives. analyses thatexcludedindexpatientswhileincluding cumulative lifetimerisksofbreastcancerfollowedfrom being pathogenic of unaffectedmutationcarriers,onewell-knownexample other genetictumorsyndromesfollowingtheinclusion Lower lifetimecancerriskshavealsobeenestablishedfor and DNA testing for the family-specific patients, whoareadvisedtoundergogeneticcounseling the Netherlandsofat-riskfamilymembersindex in ourstudyseemstoreflectanactivetestingprotocol ( tumor risks than series that include mainly index patients carriers should provide better information on actual population andtheinclusionofunaffectedmutation providesamorehomogeneousstudy a singlecountry Netherlands ( altitude andtherefore relatively highoxygenlevels in the hypothesize thatthiscouldbeassociatedwiththelow of needed tovalidateourresults. Future studieswithalongerdurationoffollow-upare 18 Clinical Study ). Thehighproportionofunaffectedmutationcarriers SDHB In conclusion, in this nationwide study which Our findings show a relatively mild phenotype mutationsintheNetherlands.Onemight 22 ). However, studyingalargecohortfrom BRCA1/2 genevariants( SDHB N DNiemeijerandothers germlinemutation SDHB 23 mutation. ). Lower SDHB

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