um efeito aditivo. um efeitoaditivo. do umfenótipomaisgraveouatípiconapaciente,sugerindo que asmutaçõesnãoapresentam único ,mesmonaqueles com amesmamutaçãoidentificada napaciente.Nãofoiobserva- ciente apresentaquadroclínicotípicosemelhanteaodospacientes comSNemutaçãoemum previamente descritas: p.N308De p.R552G nos PTPN11 eSOS1, respectivamente. A pa- dos genesPTPN11, mutações levamaumaexpressãomaisgravedofenótipo.Utilizou-se sequenciamentodireto SN queapresentamutaçõesemdoisgenesdaviaRAS/MAPK afimdeestabelecerseessas Arq Bras Metab. Endocrinol 2010;54/8 N Introduction frequentes: tes genesdaviadesinalizaçãoRAS/MAPK sãoresponsáveispelasíndrome,sendoasmais clínica variável,caracterizadaporbaixaestatura,dismorfismosfaciaisecardiopatia.Diferen- A síndromedeNoonan(SN)éumadoençagênicaautossômicadominante,comexpressão SUMÁRIO Arq BrasEndocrinolMetab. 2010;54(8):717-22 phenotype waseffect. notobserved,suggestingthatthesemutationsdoexhibitanadditive gene, eventhosewiththesamemutationidentifiedinthispatient. Amore severeoratypical The patient has typical clinical features similar tothe ones with NS and mutation in only one tations in heterozygosity: p.N308D and p.R552G in the genes sequencing ofthePTPN11 , whether these mutationslead to a more severe expressionof the phenotype. We used direct nan syndrome presenting mutations in twogenesof RAS/MAPK pathway in order toestablish PTPN11, the RAS/MAPK signalingpathway areresponsibleforthesyndrome,mostcommonare: sion, characterized byshort stature,facialdysmorphismsandheart disease.Different genesof (NS)isanautosomaldominantdisorder, withvariablephenotypicexpres- SUMMARY Amanda SalemBrasil de Noonan: este achado prediz umfenótipo maisgrave? Coocorrência demutações nosgenesPTPN11eSOS1nasíndrome more severe phenotype? syndrome: doesthispredict a gene mutations inNoonan PTPN11andSOS1 Co-occurring Alexander A. L. Jorge incidence between 1/1,000and1/2,500 (1).The Luciana TurollaWanderley autosomal dominant disorder withanestimated autosomal dominantdisorder (NS;OMIM163950)isan oonan syndrome SOS1, PTPN11, RAF1, andKRAS. ofthisstudywasThe objective toreport apatientwithNoo- Arq BrasEndocrinolMetab. 2010;54(8):717-22 SOS1, SOS1, 4 1 , Alexandre C. Pereira , Alexsandra C. Malaquias RAF1 eKRAS. Foram identificadasduasmutaçõesemheterozigose SOS1, RAF1 e 1 , Chong Ae Kim RAF1, andKRAS genes. We haveidentifiedtwodescribed- mu KRAS deste estudo . foi O relatar objetivo um paciente com 1 3 , José Eduardo Krieger , Débora RomeoBertola 2 ,

PTPN11 and chidism in the males [Reviewed in ref. (2)]. chidism inthe males[Reviewedinref. andcryptor cardiomyopathy) nosis andhypertrophic ste- (especiallypulmonary abnormalities neck, cardiac include short stature, stature, include short variable, extremely whichare main clinicalfeatures, SOS1, respectively. 3 , 1 clinical casereport facial dysmorphisms,webbed São Paulo, SaoPaulo, SP, Brazil de Medicina,Universidade de dasClínicas,FaculdadeHospital HC-FMUSP, SaoPaulo, SP, Brazil LIM/25, DisciplineofEndocrinology, Sao Paulo, SP, Brazil Institute (InCor),HC-FMUSP, Molecular Cardiology, Heart's 1 Accepted onNov/15/2010 Receivedon Aug/2/2010 [email protected] [email protected] −SãoPaulo,05403-900 SP, Brazil Av. Dr. EnéasdeCarvalho Aguiar, 647 Instituto daCriança,HC-FMUSP Unidade deGenética, Amanda SalemBrasil Correspondence to: 4 3 2 HC-FMUSP, SaoPaulo, SP, Brazil Genetics Laboratory, LIM/42, Unit, HormoneandMolecular EndocrinologyofDevelopment Genetics Unit,Children’s Institute, Endocrinology-Genetics Unit– ofGeneticsand Laboratory

717 -

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. Noonan syndrome T NS –PTPN11andSOS1. for pathogenic mutationsinthemaingenesresponsible two on a single patient presenting we report Herein, the forNS(Table responsible are 1)(3-11). Mutationin genesoftheRAS/MAPKsignalingpathway Different Co-occurring mutationsCo-occurring inNoonansyndrome 718 responsible genes–PTPN11, responsible patientsforthemain ofNSsyndrome acohort screened one mutationingenesoftheRAS/MAPKpathway, we than ofmore tothepresence isduepartially drome pathogenicity). dicted tobebenign(uncertain - (pathogenic mutation),whiletheothermutationpre function theprotein toaffect the mutationspredicted genes(14,15).Inbothstudies, oneof way-related RAS/MAPKpath- senting twomutationsindifferent therapy. implicationsinGH andhasimportant stature of short diagnosis inthedifferential NSisimportant Therefore, and/orundescendedtestesinmales. delayed puberty stature, toendocrinologistsbecauseofshort referred systems. Additionally, frequently withNSare children endocrine tion of the RAS/MAPK pathway in different tostudytheimplica- opportunity aremarkable resent pathway,- rep disorders NSandrelated andtherefore, thatstimulatetheRAS/MAPK receptors act through factor1(IGF-1), (GH) (2)andinsulin-likegrowth lyzed untilamutationwasfound. the othergenessubsequentlyana- in this gene, were negativefor mutations Only in thosepatientswhowere the patientsinitiallyfor studieshavescreened NS, previous BRAF, MEK1MEK2,SHOC2andCBL(12,13). describedinNSpatients,including rarely pathway are 70% ofNS(12)cases.Mutationsinothergenesthis leading toagain-of-function,isfoundinapproximately able 1. Major genes of RAS/MAPK signaling pathway involved with mutation. a) In patients without 2p22.1 12q24.1 Locus 12p12.1 3p25.1 The molecular background was recently unveiled. wasrecently The molecularbackground To inthissyn- evaluateifthevariableexpressivity Recently,- describedNSpatientspre twogroups hormone includinggrowth Several hormones, Due tothecomplexityofmolecularanalysisin PTPN11, gene, the main gene in the syndrome. PTPN11 gene, the main genein the syndrome. PTPN11 gene mutation; b) In patients without SOS1, Mutation Gene PTPN11 SOS1 KRAS RAF1 RAF1 andKRASgenes,usually SOS1, 17 9 29-70 2 (%) b a a -17 -6 -28 b b

RAF1 andKRAS. a

PTPN11 and Reference (4,12) (9,11) (6,7) (3,5) SOS1 genes graphs ofthefather. and photo- exam of the mother or by medical history eitherbythephysical ofNSwasnotuncovered, tory Apositivefamilyhis- school, withoutmajordifficulties. ataregular exam. Attheageof10years,sheisenrolled onslit-lamp nerves corneal demonstrated prominent Ophthalmologicevaluation XI analysisandkaryotype. X-ray, boneage,hematologicalstudies,includingfactor abdominal ultrasound,spine examsshowednormal ry developmentalmilestones.Complementa- had normal ity. disclosed.She findingswere Noevidentectodermal - hepatoesplenomegaly anddistaljointshiperextensibil (pectus carinatumsuperiorlyandexcavatuminferiorly); deformity pinnae;webbedneck;sternal ate, overfolded pal- malocclusion,high arched ptosis, slightproptosis, left 1):mildhypertelorism, ed dysmorphisms(Figure - 47.2 cm(-1.5SDS).ShehadNoonansyndrome-relat was index SDS=-1.5)andherheadcircumference tall (height SDS = -1.8), weighed 11,100 g (body mass lar hypertrophy. Atthefirstevaluationshewas89 cm EKGshowedsignsofrightventricu- echocardiogram. and ostiumsecundumatrialseptaldefect(ASD)onthe stenosis ofvalvarandsupravalvarpulmonary presence dicated attheageof3yearsandmonthsdueto wasin- surgery clinicandacardiac at ourcardiology stenosiswasdisclosed. She was first evaluated monary wasaudibleandadiagnosisofpul- murmur A heart 2,710 g(-1.3SDS)andlengthof48cm(-0.5SDS). weightof byvaginaldelivery,at term, withabirth = 158cmandfather´sheight183cm).Shewasborn height(mother’s hadnormal tion, bothparents old andherfather36yearsatthetimeofconcep- Her mother was 22 years non-consanguineous parents. a10year-oldThe proband, female,istheonlychildof Case Repor dysmorphisms: hypertelorism, leftptosisandslightproptosis. Figure 1.Noonansyndromepatientshowing typicalNSfacial t Arq Bras Metab. Endocrinol 2010;54/8 Arq Bras Metab. Endocrinol 2010;54/8 T this studyincludeatoolforwholegenomecompara- likely thatitlacksanyphenotypiceffect. and3)benign:itismost functionorstructure 2)possiblydamaging: itissupposedtoaffect structure, functionor protein fidence thatitissupposedtoaffect damaging:itiswithhighcon- as follows:1)probably of themutations tion. PolyPhendefinesthepredictions - informa functionalannotationandstructural , sis ofmultiplesequencealignmentshomologous basedontheanaly- are method (16).Thesepredictions using a new version of the PolyPhen tion or structure, func- fied basedontheir potential impactonprotein classi- Missense variantsidentifiedbysequencingwere In silicopredictionofmutationeffects individuals(384 alleles). investigated in192control also Gene. NewallelicvariantsidentifiedinSOS1were usingDNASTAR SeqMan –Laser manually observed sequencer (PerkinElmer). Genotype sequences were ABI PrismGeneticAnalyser3100automaticDNA ter City, CA,USA)andanalyzedbyanautosequencer ABI PrismTMBigDyeTerminator (PerkinElmer, Fos- methodusingakit with dideoxychain-termination sequenced directly theseexonswere from products request). PCR willbesentupon plification protocols primers(primersequencesandam- ing specificintronic amplifiedus- KRAS exons2-6(NC_000012.11)were RAF1 exons7,14,and17(NC_000003.11) NC_000012.11), leukocytes usingasalting-outprotocol. peripheral drawn forgenomicDNAextractionfrom de SãoPaulo(HC-FMUSP).Briefly, venousbloodwas tee ofHospitaldasClínicasdaFaculdadedeMedicina by theInstitutional Ethics Commit- of NS, approved study This patientwasincludedinanon-goingcohort Molecular studies Subjects andmethod a) Literatureforp.N308S inPTPN11gene(10,19-23);b)Literature forp.R552Gin able 2. ofthemutationsfoundinpresently describedNoonansyndrome patient Summary PTPN11 Gene SOS1 SOS1 Another investigationofthevariationsidentifiedin sequence: PTPN11 exons2-15(Reference SOS1 exons1-23(NC_000002.11), Exon 13 10 8 Nucleotide c.A1121G c.G2122A c.A1654G SOS1 gene(9,11,24-26);PolyPhen (16);VISTA GenomeBrowser (17). Amino Acid p.N308S p.R552G p.A708T cording to reference values provided bytheassaykit. valuesprovided toreference cording asSDSforage andsexac- CA, USA)andexpressed Corporation–DPC,LosAngeles, Diagnostic Products bychemiluminescenceassays(IMMULITE, measured levels >3.3µg/L:(18).IGF-1andIGFBP-3were peakGH ciency diagnosis after stimulation test were out GH defi- levels used to rule MA, USA). Cut-off nio rerio andTrichoplax adhaerens sequences. Gallus gallus,Xenopustropicalis,Canisfamiliaris,Da- Pantroglodytes, sequence andwild-typeFugurubripes, builtusingwild-typeandmutatedhuman ments were (17).Multipleaminoacidalign- Genome Browser tive analysisofthehumangenomeusingVISTA metric assay(AutoDELFIA - byanimmunofluoro measured GH andinsulinwere evaluation Laboratory fortunately, thefatherwas notavailable. DNAfrom describedallelicvariants.Un- had noneofthesethree polymorphism inourpopulation.Thepatient’smother of1%),characterizinga zygous state(allelicfrequency - individualsinthehetero ent in4outof192control - andthisspecificgenealterationwaspres was screened group a control among species. Furthermore, served tobebenignandisnot con- SOS1 gene),ispredicted other hand,thenewalterationfound(p.A708Tin species. On the betweendifferent conserved idues are - damagingandaminoacidres tobeprobably predicted describedmutations,the alterationsare two previously tion [p.R552G(9)]andanewvariantp.A708T. Forthe described muta- zygous allelicvariants:onepreviously - twohetero sequencingofSOS1revealed (14)]. Direct state [p.N308S was identifiedintheheterozygous describedmutation inPTPN11 genes. Onepreviously No mutationwasidentifiedintheKRASandRAF1 summarized in table 2. Positive molecular findings are Molecular results Resul ts Described Yes Yes No b a Co-occurring mutationsCo-occurring inNoonansyndrome Probably damaging Probably damaging PolyPhen Benign ® , PerkinElmer, Waltham, Genome Browser No conserved Conserved Conserved VISTA 719

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 720 ofNS−short SOS1. Thepatient has typicalfeatures common genes associated with NS – simultaneous pathogenicmutations intwoofthemost studywedescribedaNSpatientwith In thepresent Discussion (30). group inotherNSpatientsour similar totheonesobserved ing outGHdeficiency. findingswere Thesehormonal - thepatienthadaGHpeakof8.5µg/L,rul secretion, -1.7 SDS).DuringtheclonidinetesttoevaluateGH to bothcorresponding and 2.0µg/mL,respectively; rangeforsexandage(61µg/L at thelowernormal ides of98mg/dL).IGF-1andIGFBP-3levelswere of40mg/dL andtriglycer mg/dL, HDS-cholesterol (Total lipidprofile an unremarkable of136 cholesterol mmol/L) and<2.5µU/mL,respectively. Shealsohad 77 mg/dL (4.2 fasting glucose and insulin were metabolicevaluationforherage: Patient hadnormal Hormonal analysis and (b)specificforNoonansyndromepatients(29). Height SDSwascalculatedusingage-andgender-specific norms(a)forgeneralpopulation(28) NS patientswithonlyoneofthegenes. (p.N308D) and T tient harboringbothmutations(Table 3). the pa- from these patients did not significantly differ mutation intheSOS1 in thePTPN11geneandonepatientwithp.R552G tified fiveotherNSpatientswithp.N308Smutation weiden- tions onlyinPTPN11orSOS1.Inourgroup phenotypethanthoseNSpatientswithmuta- severe in thePTPN11andSOS1genes,didnothaveamore mutations patient,whohasco-occurring The present Phenotype analysis mutationsCo-occurring inNoonansyndrome able 3. Clinical phenotype of NS patient with co-occurrence of Typical facialfeatures Patient(s) Pulmonary stenosis Pulmonary BMI SDS Mutation(s) Sternal deformity Height SDS Development delay Height SDS b a SOS1 (p.R552G) pathogenic mutations in comparison with (PTPN11) and p.R552G p.N308S (SOS1) -1.5 -1.8 0.2 gene (14,27).Thephenotypeof + 1 + + - -2.1 to+1.2 -1.2 to-3.9 -1.0 to0.1 (PTPN11) p.N308S 5/5 2/5 2/5 3/5 5 PTPN11 and p.R552G (SOS1) -1.5 0.4 1.3 1 + + - - PTPN11 - ing pathway, closelyconnected toSHCandGRB2 are oftheRAS/MAPKsignal - proteins ing forupstream PTPN11 gene(9-11,19,25). the phenotypeofpatientsharboringmutationsin consistentwith findings,whichismore ectodermal ASDandlackofevident stature, showedshort proband stenosis.Ontheotherhand, – valvarpulmonary lesion andthecardiac such asthetypicalfacialfeatures commontomutationsinbothgenes, by ourpatientare and tients withp.N308SorpR552GmutationsinPTPN11 to pa- with isolatemutations–evenwhencompared phenotypethanNSpatients severe findings oramore intheirpatients. stature and cols.(9)foundlessshort Ontheotherhand,Tartaglia rare. ASD wasrelatively stenosis, but of pulmonary also had a high frequency andcols.(25)showedthattheirpatients (11). Roberts keratosis pilarisandcurlyhair, intelligence andnormal signs,suchas ptosis,ectodermal this geneshowedmore mutationsin For theSOS1gene,patientspresenting tootherdescribedmutationsin PTPN11 gene. pared less special education, com- that the patients required tation p.N308D,Tartaglia andcols.(19)demonstrated and bleedingdiathesis(10,19).Specificallyforthemu- deformity sternal stature, stenosis, short of pulmonary tations in PTPN11 tend toshow a higherprevalence mu- NS hasnotbeenestablished,patientspresenting not associatedtosignificantphenotypiceffects. is polymorphism inourpopulationandmostprobably test)showedthatthisgenealterationisa group control p.A708T, additionalanalysis(insilicoanda thenovel sociated withNS(9,11,24-26).Concerning oneinthisgeneas- genic mutation,themostfrequent found inourpatient.Thep.R552Gisaknownpatho- found inseveralstudiedpatients(10,19-23). is p.N308D(10,19).Mutationp.N308Shasalsobeen mutationfoundinNS 308. Indeed,themostfrequent mutationsinexon8 mainly involveresidue spread, are exons3and13,inwhichthemutations from ferent especiallyinexons3,8,and13.Dif- (19), clustered 50%ofNSpatients foundinapproximately gene are atrial septaldefect). stenosisassociatedwith defect(pulmonary cific heart webbedneckandthespe- classicfacialfeatures, stature, The genes here involved (PTPN11 and The genes here doesnot show atypical presented here The proband in Although acleargenotype-phenotypecorrelation Regarding theSOS1 Regarding mutationsinthePTPN11 Missense heterozygous SOS1, respectively. presented Someofthefeatures gene, two gene alterations were gene, twogenealterationswere Arq Bras Metab. Endocrinol 2010;54/8 SOS1), cod - Arq Bras Metab. Endocrinol 2010;54/8 inthephenotype. We effect canspeculatethat portant event,failedtoshowanim - rare which isanextremely pathogenicmutations inourpatient, of twodifferent elucidated.Thepresence tobeproperly still remains mean. and hehasaheightof1SDabovethe problems heart of isnohistory suggestiveofNS.Besides,there tures mutations, butphotographsfailedtoshowanyfacialfea- thatthefathercomprisedoneofthese with certainty ordinary. Unfortunately, out not able to rule we were oftwomutationsinourcaseisoutthe the presence thechanceofthisoccurrence. which increases hadoneof themutations, both casesoneoftheparents described (31,32)butin (NFNS) havebeenpreviously syndrome neurofibromatosis-Noonan tients presenting oftwopathogenicmutationsinpa- er hand,thereport mutation,actingasamodifier.mild partial Ontheoth- a p.G409A mutationinthePTPN11generepresents ter genealteration.Theauthorsconcludedthatthe alsoshowedthislat- stature, onlyshort presenting (p.S2G) andPTPN11gene(p.G409A).Themother, liver haemangioma,andmutationsintheSHOC2gene hair, and gingivalhyperplasia,spinalneuroblastoma mental delay, looseanagen hoarsevoice,osteoporosis, mildpsychomotor develop- on aNSpatientpresenting in the exception, inindividualswiththep.N308Dmutation an ing disabilities,whichisnotcommon,butfarfrom - of NS andlearn typicalfeatures The patientpresented and alsothep.N85SmutationinKRASgene(14). pathogenic p.N308DmutationinthePTPN11gene modifier. the We describedaNSpatientpresenting functionsasa another genealterationthatprobably ofoneknownpathogenicmutationand the presence showed ourgroup, ies (14,15),includingonefrom stud- Two previous has notbeendescribedbefore. tations ingenesoftheRAS/MAPKpathwayNS leadingtoatypicalNSphenotype. effects, that mutationsinthesetwogenesdonothaveadditive in ourpatientwithmutationsbothgenessuggests phenotype severe amore fact thatwedidnotobserve to again-of-functionoftheRAS/MAPKpathway. The in activate theRAS-RAF-MEK-ERKcascade.Mutations that hasthefunctionofexchangingGDPforGTPto belongtothesamecomplex Alltheseproteins proteins. reported here, commonlylead here, PTPN11 andSOS1reported The great variability in the phenotype of NS patient The great lowingeneraland The rateofnewmutationsisvery oftwoknownpathogenicmu- The occurrence gene. Ekvall and cols. (15) reported PTPN11 gene. Ekvall and cols. (15) reported modulate thephenotype. factorsmay other genesassociatedwithenvironmental gle nucleotides(SNPs)ingenesofthispathwayoreven subtler genealterations,suchaspolymorphismsofsin- 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. References was reported. relevant tothisarticle nopotentialconflictofinterest Disclosure: for technicalsupport. (301477/2009-4 toA.A.L.J.).TheauthorsthankNoelyFerreira Council forScientificand Technological Development(CNPq) National (08/50184-2 and07/59555-0toA.C.M.)from àPesquisadoEstadodeSãoPaulo(FAPESP) dacao deAmparo Fun- bygrantsfrom Acknowledgments: thisworkwassupported

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