Arch Metab. Endocrinol 2019;63/4 (1). without agender difference tofifthdecadeoflife beinginthethird of occurrence been estimatedtobe1/300,000 withthepeakage The combinedannualincidence ofPGL/PCChas medulla,respectively. ganglia and adrenal adrenal system that occur in the extra- autonomic nervous P INTRODUCTION investigation for treatment, mutationof germline paraganglioma: implications and Pheochromocytoma; paraganglioma;germlinemutation;succinatedehydrogenase complex;screening Keywords geneticcounseling. records, andallpatientsreceived sequencing panelsincluding analysis ofpatientsdiagnosedwithPGL/PCC.Germlinemutationswerestudiedusingnext-generation their families of making an opportune genetic diagnosis. in which hereditarysyndromescanbesuspectedandtoemphasize theimportance for patientsand a hereditarysyndrome. We aimedtocharacterize PGL/PCCfamiliestoexemplifythedifferent scenarios genes over thelastdecade,itiscurrently estimatedthatupto40%ofcasescan occur inthecontextof were considered to be predominantly sporadic. However, with the identification of novel susceptibility Objective: ABSTRACT https://orcid.org/0000-0002-1187-1384 NirvanaMaria Formiga https://orcid.org/0000-0001-6894-1219 Isabel Achatz Maria https://orcid.org/0000-0003-3185-9187 Daniele Paixão Pereira https://orcid.org/0000-0002-1631-0105 Alexandre André Balieiro Costa https://orcid.org/0000-0002-1279-9302 Diogo Cordeiro Soares https://orcid.org/0000-0002-4739-5260 Ana MilenaGómez screening, andsurveillance diagnose theseinheritedcancerpredispositionsyndromes. undergo geneticcounseling.For allthesereasons,itiscriticalthatmedicalstaff cansuspectand should undergolifelongclinical,biochemical andimagingsurveillancetheirfamiliesshould withgermlinemutationsassociatedPGL/PCC theoverlapping phenotypes.Individuals given should undergogeneticriskevaluation.NGSmultigenepaneltestingisacost-effective approach a germlinemutationthananywiththesetypesoftumors othercancertype,therefore,allindividuals being atypicalaccordingtotheliterature. . The clinicalpresentationofthepatientsandtheirfamilieswas heterogeneous,withsome PCC andgermlinemutationsinSDHcomplexgenes.2familieshave (PCC) are rare neuroendocrine tumorsofthe neuroendocrine rare (PCC) are araganglioma (PGL)andpheochromocytoma Paraganglioma (PGL) and pheochromocytoma that (PCC) are rare neuroendocrine tumors 1 3 2 2 2 SDHA , 2 SDHB Conclusions: , SDHC and SDHD PGL/PCC are more commonly associated with PGL/PCCaremorecommonlyassociatedwith Results: Arch EndocrinolMetab. 2019;63(4):369-75 . Clinical data were collected from clinical . Clinicaldatawerecollectedfromclinical Materials and methods: We describe4familieswithPGL/ with parasympathetic nervous system structures and systemstructures with parasympathetic nervous generally associated PGLs oftheskullbaseandneck are (2).Meanwhile, sweating, andanxiety)ormass effects headache, palpitations, excessive hypertension, (i.e., attributable tocatecholamine hypersecretion computed tomography. generally PCC symptoms are imaging (MRI) or as a mass on magnetic resonance incidentally sympathetic PGLandmaybediscovered SDHB PCCs, which can be described as a form of PCCs, whichcanbedescribedasaform mutationsand2 Retrospective Retrospective SDHD

Sírio-Libanês, SãoPaulo, SP, Brasil 3 São Paulo, SP, Brasil A.C. CamargoCancerCenter, 2 Ignacio, Bogotá, Colombia 1 DOI: 10.20945/2359-3997000000145 Accepted onMar/18/2019 Receivedon Aug/26/2018 [email protected] 01509-900 –SãoPaulo, SP, Brasil Rua Prof. Antonio Prudente, 211 FormigaMaria Nirvana Correspondence to: Centro de Oncologia, Hospital Centro deOncologia,Hospital deOncogenética, Departamento UniversitarioSan Hospital original article original 369

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. ( (SDH)complexsubunit genes dehydrogenase Neoplasia type2(MEN2),respectively. type1(NF1),andMultipleEndocrine neurofibromatosis described in the literature include described inthe literature significance ofthesefindings isunclear. hyperplasia, andtesticularseminoma (20),thoughthe cancer, thyroid adrenal neuroblastoma, non-medullary tumors, have alsobeenfoundinpatients withpituitary mutationsin (19).Germline described recently mutations in triadpatientswithgermline sporadic condition,Carney's tobea hasbeenconsidered chondroma) pulmonary triad(PGL/PCCandGIST,the Carney's together with some familieswith whichhasbeendescribedin cellcarcinoma, and renal to GIST related (dyadofPGL/PCCand syndrome Carney-Stratakis tumors (GISTs) stromal including gastrointestinal in risks associated with SDH complex gene mutations, otherstumor are exceptions(14-16).There with rare inherited head andneckPGL.Interestingly, onlypaternally SDHD with ahighriskofmetastasis(12,13),followedby sympathetictumors mainlyinextra-adrenal resulting Of thesegenes, complex factorgenes( 370 to PGL/PCC with variable risks (11). predisposition Von genesare three Hippel-Lindaudisease(VHL), associatedwithmutationsinthese The syndromes NF1 syndromes: genes thatcausewell-knowncancersusceptibility three tomutationsin PCC developmenthasbeenrelated implicated PGL/PCCsusceptibilitygenes(7-10).PGL/ oneof16 affecting 11–24% haveagermline sporadic withnofamilyhistory, studieshaveshownthat tobe (3-6). Even among cases considered syndrome linkedtoanautosomal-dominanthereditary cases are PCC susceptibilitygenes.Itappearsthatsome40%of methodology hasledtotheidentificationofnovelPGL/ expanded availability of next generation sequencing sporadic.However,to bepredominantly therecently bymasseffects. produced symptoms are Thustheir oncatecholaminesecretion. without effects Implications ofgermlinemutations for PGL/PCC SDHA, SDHB, SDHC, SDHD Other putativePGL/PCC susceptibilitygenes Additionally, succinate mutationsaffecting Previously, considered PGL/PCCtumorswere (neurofibromin 1), and (neurofibromin , which has been associated with parasympathetic , whichhasbeenassociatedwithparasympathetic SDHD VHL SDHA SDHB SDHB mutations cause a disease phenotype, mutations cause a disease phenotype, (von hippel-lindau tumor supressor), (von hippel-lindau tumor supressor), SDHB , is the most commonly mutated, isthemostcommonlymutated, , SDHAF2 SDHB SDHC mutations (17,18). Although mutations(17,18).Although RET , and , and ) and one of the SDH ) andoneoftheSDH ) are associated with a associatedwitha ) are (ret proto-). proto-oncogene). (ret MAX SDHC SDHD and have been havebeen TMEM127 mutations) mutations) SDH ,

biochemical phenotypetoguidetheselectionofgenes algorithm basedontumorlocationandcatecholamine patients withPGL/PCCaclinicalfeature-driven consideringgenetictestinginall Society recommends (23).The Endocrine tumorsandfamilyhistory adrenal malignant tumors,multiple PGL/PCC orbilateral or recurrent findings: earlyonset(<45yearsold), and/or PCC,prioritizingthosewiththefollowing inallindividualswithPGL should beconsidered syndromes associated withPGL/PCC,hereditary mutations, asdescribedabove. similarto effects genes exhibitparent-of-origin contribution (6). numbers ofcaseswithapossiblymodestpathogenic EPAS1 (21,22). Mutationsin foundinassociationwithPCC both of which were 5 (clearlypathogenic) (24,25). significance), class4(likely tobepathogenic),andclass class 2(unlikelytobepathogenic), class3(unknown system:class 1 (clearlynotpathogenic),five-category of MedicalGeneticsand Genomics, includingtheir classified basedonguidelinesofAmericanCollege were inBrazil.VariantsLaboratory foundintarget genes SDHB, SDHC basicpanelincluding with aphysician-ordered analyses inanext-generationsequencingplatform submitted tomutation were allprobands obtained from Center, thisstudy. whoseEthicsCommittee approved ofOncogeneticsatA.C.Camargo Cancer Department followed-upinthe PGL/PCC. Thepatientswere phenotype andgenetic data of patients diagnosed with We analysis,collectingclinical conductedaretrospective MATERIALS ANDMETHODS for patientsandtheirfamilies. geneticdiagnosis ofmakinganopportune importance canbesuspected.Wesyndromes emphasizethe scenariosinwhichhereditary was toexemplifydifferent and mutationsinSDHcomplexsubunitgenes.Ouraim fourfamilieswithPGL/PCC of thistopic,we present single-gene testinginmostcenters. itisreplacing costeffective, testing isbecomingmore aspanelgene to thebetested.(23)Nevertheless, Given thehighrateofinheritedmutations DNA extracted from peripheralbloodsamples DNA extractedfrom Based ontheabove,andconsideringimportance ,

and KIF1B ,

and

Mutations in SDHD havealsobeenfoundinsmall FH , EGLN1 Arch Metab. Endocrinol 2019;63/4 at a commercial Genetics at acommercial SDHAF2 , EGLN2 and , MDH2 SDHA, SDHD MAX ,

Arch Metab. Endocrinol 2019;63/4 Figure 1. tested negativeforthemutation. asymptomaticbrother PGL/PCC (26).Theproband’s families withearly-onset,multifocal,and/ormalignant in individuals and be pathogenic and has been observed in c.689G>Apointmutation(p.Arg230His) heterozygous a geneticcounselingandtestingthatrevealed underwent bodyPGLat33years ofage.She with acarotid 1). was asymptomaticattheageof9years(Figure the mutation, but to carry daughter was also confirmed sister’syoungest PGL at8 years old. The proband’s son waspositiveforthemutationanddiagnosedwith at43yearsofage.Thatsister’soldest was unaffected sisterwaspositiveforthemutationbut The proband’s PGLintheson,whowas12yearsold. retroperitoneal a Imagingstudiesrevealed both foundtobecarriers. stop codon.Herasymptomaticsonanddaughterwere apremature frameandcreated shifted thereading in c.393delAmutation(p.His132Thrfs*4) heterozygous a genetic counseling and testing, which revealed died at40yearsold.Theindexcasepatientunderwent diagnosed withmetastaticPCCat37yearsoldand hadbeen at40yearsofage.Herbrother that appeared In family1,theindexcasepatienthadajugularPGL RESULTS wt SDHB:wild-typeSDHBgene -: non-carrier mut SDHB:mutationinSDHBgene : Carrier SDHB SDHB In family 2, the index case patient was diagnosed In family2,theindexcasepatientwasdiagnosed Pedigree offamily with mutationin . This mutation has been reported previously to to previously . Thismutationhasbeenreported that resulted in an adenine deletionthat that resulted 3 Undefined cancer 2 etroperitoneal PGL,12 3 mut SDHB SDHB gene 15 ugular PGL,40 2 Breast cancer mut SDHB mut SDHB 12 mut SDHB PGL, 8 stop signalinthelastexonof in c.361C>T (p.Gln121*) a heterozygous geneticcounselingandtestingthatrevealed underwent body PGLsattheageof13years.Thproband carotid alungattheageof11yearsandbilateral PCC affecting years old,andhissonwasdiagnosedwithmetastatic 2). havenotbeentestedyeteither(Figure proband ofthe for themutation.Theasymptomaticchildren ages of 39 years and 45 years; neither has been evaluated PGLs at the cousins had bilateral cervical Two paternal SDHD c.3G>Cpointmutation(p.Met1Ile)in a heterozygous geneticcounselingandtestingthatrevealed underwent bilaterallyat35yearsold.She she experiencedPGLrelapse excisionsurgery. Subsequently,diagnosis, sheunderwent body PGLsat25yearsofage.Atthetimethat carotid available to confirm this information (Table thisinformation available toconfirm 1). were records been diagnosedwithPGL,butnohistory mother, cousinhad uncle,andamaternal amaternal indicated thathis for themutation.Theproband son have been tested aforementioned the proband’s jugular PGLat38yearsofage,butneithershenor sisterhad year aspathogenic(Class5).Theproband’s inlast likely pathogenic(class4),andwasreclassified previously as identified mutation had been classified 71 SDHD In family4,theindexcasepatienthadaPCCat38 In family3,theindexcasepatienthadbilateral , which had been described as pathogenic (27). , whichhadbeendescribedaspathogenic(27). mut SDHB wt SDHB 12 that resulted in a premature translational inapremature thatresulted mut SDHB Implications ofgermlinemutations for PGL/PCC 9 3 Metastatic PCC,37 40 2 SDHD mRNA.The 74 371

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 372 in allpatientswiththesetumors should beconsidered of heritabilityamongneoplasias (28).Genetictesting PGL/PCCshowthehighestdegree Although rare, DISCUSSION investigations orfollowups. biochemicalfindingsatinitial patients hadabnormal catecholamine biochemical parameters, none of our Regarding cellcarcinoma. diagnosed withGISTorrenal respectively. orfamilymemberswere Noprobands 33.3%, 16.7%,and16.7%ofthecasesinfamilies1–4, in8.3%, prevalent multiple, andmalignanttumorswere bilateral, people youngerthan40yearsold.Recurrent, diagnosedin four studyfamilies(11/12,92%)were ID: identification;PCC: pheochromocytoma;PGL: paraganglioma;(M): metastases;HN: headandneck. * Unusualfor Table 1. Figure 2. Implications ofgermlinemutations for PGL/PCC F4 F3 F2 F1 ID Family Most ofthePGL/PCCcasesidentifiedin 2 Comparison offamilieswithgermlinemutationsinSDHcomplexgenes Pedigree offamilywithmutationin SDHB Mutated SDHD SDHD SDHB SDHB gene genemutation. **Uniquepresentationinthefamily, morefrequentinsporadicscenario. 2 mut SDHD:mutationinSDHDgene -: non-carrier +: Carrier c.689G>A c.361C>T c.393delA Mutation c.3G>C Bilateral cervicalPGL,45 (DNA) p.His132ThrfsX4 Prostate cancer,70 p.Arg230His p.Gln121* Mutation (protein) p.Met1Ile SDHD gene Bilateral cervicalPGL,39 onset (yr) Earliest age of Colorectal cancer,80 11 25 33 8 Colorectal cancer,60 diagnosis (yr) 11, 13, 38, 38 8, 12, 37, 40 patients at Ages ofall 25, 39, 45 2 33 phenotype correlations (30,31). Overlappingof phenotype correlations testing prioritization based on established genotype- and clinicalphenotypecanguidegene profile (11). confirmation formolecular gene testing isrecommended direct manifestations, ofothercardinal based onthepresence (e.g.VHL,NF1,orMEN2)canbemade syndrome clinical diagnosisofanestablishedcancersusceptibility tothedisease(5,23,29). related and mortality early, relatives affected and treat morbidity reducing inapatientmakesit possible to diagnose syndrome SDHB 50% ofmetastaticPGL/PCCmaybeassociatedwith mutations,andupto PCC havepathogenicgermline because atleast30~40%ofallpatientswithPGL/ Bilateral cervicalPGL,25,35 8 Prostate cancer,67 In non-syndromic forms, the patient’s biochemical forms, In non-syndromic Types oftumors HN PGLPCC(M) PCC(M), HNPGL Abdominal and mut SDHD mutations. The confirmation of a hereditary ofahereditary mutations.Theconfirmation in family HN PGL HN PGL 70 39 8 + 62 6 Unusual malignantPCCandmaternallyinherited Typically presentationandpaternallyinherited 34 Unexpected ClinicalFeatures Index casewithHNPGL** Index casewithHNPGL* Arch Metab. Endocrinol 2019;63/4 Colorectal cancer,59 2 transmission transmission 90 3 53 2

If Arch Metab. Endocrinol 2019;63/4 mutations (16). However, to remains thisinformation inherited paternally through predominantly oftumordevelopmentoccurring prior reports from transmission,differing was compatiblewithmaternal in family4,thedistribution ofindividualswithtumors ofthegene,asinfamily4(34,35).Interestingly,portion when the mutation is in the 5’ develop PCC, particularly tendency for isa there genotype-phenotype association wherein SDHD with individuals 24 of developing a skull base or neck PGL compared SDHD with Bennandcols.’sfindingthatindividuals this familyhadmultipleheadandneckPGLs,consistent 3 hada offamily insporadiccases(32).Theproband presents and cols.’ssuggestionthat for site frequent The mutationsitewasnotaparticularly PGLandhadnofamilyhistory. diagnosed withacervical inallsuchfamilies. of mutationscreening the importance tumors infamilies1and4underscores withPGL/PCC mutationsamongchildren germline of with malignantPGL/PCC(13,29).Theprevalence inpersons survival ashorter mutations mayalsopredict versus only3%in malignant PGLsin of A meta-analysisshowedthatthepooledprevalence PGL/PCCsyndromes. genes associatedwithhereditary thehighestriskofmalignancyall neck. Theycarry glands,head, and at anylocationincluding the adrenal the abdomenandpelvis,butwithpotentialtooccur in tumorspredominantly associated withextra-adrenal respectively.being affected, between the two families with differed in both families. Themutated genes PCC occurring neck PGLsandindividualswithPCCs,metastatic Sanger sequencingmethods(25,30). used mutationdetectionthanpreviously cost-effective analysis ofmultiplegenesthatallowsfasterandmore simultaneous providing PGL/PCC syndromes, molecular diagnostics,includingthoseforhereditary sequencing isbeingintegratedwithrapidityintoclinical However,gene-to-gene approaches. next-generation clinical phenotypes may complicate prioritization in The findingofaPCCinpatientwithmutated The Families 1and4includedindividualswithhead SDHB (family4)canbeexplainedbyanestablished mutationshaveanoddsratioofapproximately SDHD SDHB mutations, butconsistentwithTimmers SDHD mutation and all affected individualsof mutationandallaffected -mutated proband infamily2was -mutated proband SDHB SDHD SDHB -nonsense mutation carriers to -nonsense mutationcarriers -mutation carriers was 23%, was23%, -mutation carriers SDHB -mutation carriers; -mutation carriers; mutations(33). SDHB mutations have been mutationshavebeen -related PGLoften -related

SDHB and

SDHD SDHD SDHB

not availableforourcases. time, andcosts(30,37,38). testingeffort, toreduce testing; ithasbeenreported sporadic PGL/PCCtohelpguidemoleculargenetic has alsobeenusedinbothfamilialand(apparently) used to reveal encoding genes(2).IHCforSDHAhasbeenalso mutationinanyofthe inactivated duetoagermline SDHB, SDHC,SDHD,orSDHAF2iscompletely IHCforSDHBisnegativewheneverSDHA, Therefore, indegradationoftheSDHBsubunit. unstable, resulting complex becomes completely inactivated, the entire When anycomponentofmitochondrialcomplexIIis can helptoidentifytumorsin notphenocopies. thattheyare toensure be performed infamily4,andgenetictestingshould of theproband relatives for maternal by clinical reports be corroborated screening of catecholamine metabolites, known as screening individuals shouldbesubjected toannualbiochemical Secondly,monitoring, shouldbeperformed. at-risk and physical examination, including blood pressure facets.Firstly,include three history annualcareful with all personswith at10yearsofage,diseasewouldbedetectedin started years ofage;ithasbeenestimatedthatifscreening shouldbeginbetween5and10 complex, surveillance opinion(30,41). practices basedonexpert susceptibility genes, which leaves variance in screening of mutations in lower-frequency carriers for screening isnotyetaclearconsensus PGL/PCC cases,there (VHL,NF1,andMEN2) forsyndromic surveillance (2). Although whohavenotyetundergone genetictesting history atriskbasedonfamily andrelatives mutation carriers andaffected tounaffected up shouldbeoffered (30,40). biochemical, andimagingsurveillance with PGL/PCCshouldundergo lifelongclinical, mutations (2). andmetastasisriskinpatientswith recurrence urgency tominimize withgreat should beresected to underlyingmutations.Mostimportantly, PGL/PCC However, shouldbepersonalized thesurgical approach blockade established in published guidelines (23,30,39). perioperative PGL/PCC following appropriate Surgical resection is the mainstay treatment for isthemainstaytreatment Surgical resection (IHC)ofSDHsubunits Immunohistochemistry For patients with mutations affecting theSDH For patientswithmutationsaffecting mutationsassociated Individuals withgermline SDHB mutations (33).

there are establishedguidelinestoguide are there SDHA SDHD Implications ofgermlinemutations for PGL/PCC mutations (36). IHC for SDHB mutationsand96%ofpersons

However, thisstrategywas SDH

Surveillance should Surveillance mutation carriers. mutationcarriers.

Follow- SDHB 373

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 374 associated with PGL/PCCshouldundergo genetic (42). hypoxemia duetocyanoticcongenital cardiopathy of fiveevaluatedpatients(80%) diagnosedwithchronic to oxygenconcentrationchanges –inPGL/PCCsoffour transcription factorinvolved in thephysiologicalresponse function somaticmutationof data showing a gain-of- by recent was reinforced genes or smoking) shouldbeavoidedinindividualswithSDH lungdiseases(e.g. onetochronic and thatpredispose tohypoxia(e.g.livingatahigh exposure (34). PGL/PCCsyndromes penetranceofhereditary increase germline a been casesofPGL/PCCinindividualscarrying SDHD of effect parent-of-origin paternal aforementioned istheirmother, parent despite the whom the affected includes individuals for (40). This recommendation forconfirmed imaging, beprovided medicalevaluation,including suggested thataprimary hasagermline parent person whose the age of18 years to every from inpatientswith performed shouldbe screening cellcarcinoma or anemiaandrenal symptoms, obstruction, in patientswithgastrointestinal other tumors,evaluationforGISTs shouldbeperformed 123 levels and may include functional studies, suchas ofelevatedmetanephrine inthepresence be increased (2,11,33,39). as forpatientswithmutationsin theSDH with mutationsaffecting 2yearsforallthepatients full bodyifavailable)every theskullbasetopelvis(or MRIfrom recommended patients with 2yearsfor and MRIoftheskullbaseneckevery 2yearsforpatientswith pelvis every MRIoftheabdomen,thorax,and recommended (11,41).Someauthorshave limit radiationexposure imagingmodalityto MRI maybethepreferable Thirdly, imagingstudiesshouldbeperformed; regular PGL. be evaluatedforearlydetectionofcervical fractionated catecholamine(dopamine)levelsshould and/or24-hoururine methoxytyramine andserum metanephrines in 24-hour urine samples. Plasma free- metane free Implications ofgermlinemutations for PGL/PCC I-metaiodobenzylguanidine scintigraphy. Regarding It is our view that all patients with germline mutations It isourviewthatallpatients with germline may hypoxiaexposure High-altitude andchronic thatgenetictestingbeoffered It hasbeenproposed

Therefore, lifestyles that promote long-term long-term lifestylesthatpromote Therefore, mutations because, although rare, there have there mutations because,althoughrare, SDHD MAX phrines, in plasma and/orfractionated

SDHC The frequency ofimagingstudiesshould The frequency mutations (2). This recommendation mutations(2).Thisrecommendation mutation on the maternal (40). mutationonthematernal or SDHD SDHD SDHB EPAS1 – mutation, and further mutation,andfurther mutations;othershave mutations(2). TMEM127

complex, aswell SDHB which encodes a which encodesa SDHD mutations or altitude) altitude) carriers carriers

MAX

contributions to the conception and design of this work as well as contributions totheconceptionanddesignofthisworkaswell Individual contributions:A.M.G.andD.C.S.madesubstantial with aPGLorPCC. forpatientswhohavepresented protocols care routine These considerations should be incorporated into ofpatientsandtheirfamilymembers. the surveillance and screening, implicationsfortreatment, has important mutations of germline because the presence syndromes, signs of inherited cancer predisposition can recognize all medicalpersonnelinteractingwiththesepatients mutation. Itiscriticalthat associated withagermline andmetastasis(2). transformation perioperative morbidity, malignant andcanprevent tumor detectionfacilitatessurgical excision,reduces when afamilialmutationhasbeenidentified.Early testing ofasymptomaticfamilymembersbeperformed familialrisk,andthatpredictive counseling regarding 7. 6. 5. 4. 3. 2. 1. REFERENCES andhad noconflictsofinterest. pertise, ofex development ofthiswork,contributedwithintheirareas for the the study authors had no financial support Disclosure: work andisnotunderconsiderationbyanyotherjournal. ted versionofthemanuscript.Thismanuscriptdescribesoriginal ofthesubmit of themanuscript.Allauthorsgavefinalapproval ofdataandthedrafting cipated intheanalysisandinterpretation to dataacquisition.A.M.G.,A.A.B.C.,M.N.F., andM.I.A.parti In conclusion, PGL/PCC tumors are commonly In conclusion,PGL/PCCtumorsare Brito JP, Asi N,Bancos I, GionfriddoMR,Zeballos-Palacios CL, Pandit K, Sarathi R, Khadilkar V, Kasaliwal R, Goroshi M, Khare S. Fishbein L,Merrill S,FrakerDL,CohenNathansonKL. Buffet A, Venisse A, Nau V, Roncellin I, Boccio V, Le Pottier N,etal. Mannelli M,CastellanoSchiavi F, Filetti S,Giacchè M, Mori Kirmani S, Young WF. HereditaryParaganglioma- paraganglia.Baysal BE.Hereditaryparaganglioma targetsdiverse Endocrinol (Oxf). 2015;82(3):338-45. pheochromocytoma/paraganglioma: asystematicreview. Clin Leppin AL, et al. Testing for germline mutations insporadic J Endocrinol.2016;175(4):311-23. Indian patientswithpheochromocytoma andparaganglioma. Eur Germline mutationsandgenotype-phenotype correlation in Asian Oncol. 2013;20(5):1444-50. why allpatientsshouldbeoffered genetictesting. Ann Surg Inherited mutationsinpheochromocytoma andparaganglioma: and paraganglioma. HormMetabRes. 2012;44(5):359-66. A decade(2001-2010) ofgenetictestingforpheochromocytoma 2009;94(5):1541-7. or nonfunctionalparagangliomas. JClinEndocrinolMetab. italian patients with and/or functional L, etal.Clinicallyguidedgeneticscreeninginalargecohort of Ardinger HH,etal.(eds):Seattle (WA): GeneReviews(R); 2014. Pheochromocytoma Syndromes. In:Pagon RA, Adam MP, J MedGenet.2002;39(9):617-22. Arch Metab. Endocrinol 2019;63/4

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