Medical complications, clinical findings, and educational outcomes in adults with Noonan syndrome
Identifieur interne : 006393 ( Istex/Corpus ); précédent : 006392; suivant : 006394Medical complications, clinical findings, and educational outcomes in adults with Noonan syndrome
Auteurs : Patroula Smpokou ; Erica Tworog-Dube ; Raju S. Kucherlapati ; Amy E. RobertsSource :
- American Journal of Medical Genetics Part A [ 1552-4825 ] ; 2012-12.
Abstract
Noonan syndrome (NS) is a heterogeneous developmental disorder caused by missense mutations in genes involved in the Ras/MAPK signaling pathway, a major mediator of early and late developmental processes. The diagnosis of NS is made on clinical grounds with molecular confirmation of a mutation found in 63% of cases. Key clinical features include short stature, cardiac defects, developmental delay, lymphatic dysplasias, bleeding tendency, and a constellation of distinctive facial features and physical exam findings. The prevalence of medical issues or the development of new ones in adults with NS is not well‐studied. This cross‐sectional study reports on the prevalence of clinical conditions and their ages of onset in a cohort of 35 adolescents and adults with NS aged 16–68 years old (mean age 28 years). In this cohort, 34 of 35 subjects (97%) had had full PTPN11 sequencing; 37% were PTPN11 positive, 23% were SOS1 positive, and 3% were BRAF positive. Mean adult height in both men and women was at the 3rd–10th centile. The most prevalent clinical findings in this cohort included pulmonary valve stenosis (71%), easy bruising (63%), GERD (60%), constipation (51%), scoliosis (54%), chronic joint pain (54%), lymphedema (49%), depression (49%), anxiety (49%), Chiari malformation (20%), and osteopenia/osteoporosis (14%). In summary, adults with NS are affected by multi‐organ morbidity and require special medical management aimed towards the most prevalent and serious known medical complications. Larger studies characterizing the clinical conditions found in NS adults are needed to provide potential genotype–phenotype correlations that may aid in clinical management. © 2012 Wiley Periodicals, Inc.
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DOI: 10.1002/ajmg.a.35639
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The diagnosis of NS is made on clinical grounds with molecular confirmation of a mutation found in 63% of cases. Key clinical features include short stature, cardiac defects, developmental delay, lymphatic dysplasias, bleeding tendency, and a constellation of distinctive facial features and physical exam findings. The prevalence of medical issues or the development of new ones in adults with NS is not well‐studied. This cross‐sectional study reports on the prevalence of clinical conditions and their ages of onset in a cohort of 35 adolescents and adults with NS aged 16–68 years old (mean age 28 years). In this cohort, 34 of 35 subjects (97%) had had full PTPN11 sequencing; 37% were PTPN11 positive, 23% were SOS1 positive, and 3% were BRAF positive. Mean adult height in both men and women was at the 3rd–10th centile. The most prevalent clinical findings in this cohort included pulmonary valve stenosis (71%), easy bruising (63%), GERD (60%), constipation (51%), scoliosis (54%), chronic joint pain (54%), lymphedema (49%), depression (49%), anxiety (49%), Chiari malformation (20%), and osteopenia/osteoporosis (14%). In summary, adults with NS are affected by multi‐organ morbidity and require special medical management aimed towards the most prevalent and serious known medical complications. 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Roberts</name><affiliations><json:string>Harvard Medical School, Boston, Massachusetts</json:string><json:string>Division of Genetics, Boston Children's Hospital, Boston, Massachusetts</json:string><json:string>Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts</json:string><json:string>Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115.</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Noonan syndrome</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Noonan spectrum</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Ras/MAPK pathway</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PTPN11</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>SOS1</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>RAF1</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>KRAS</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>BRAF</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>NRAS</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>MEK1</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>SHOC2</value></json:item></subject><articleId><json:string>AJMG35639</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>Noonan syndrome (NS) is a heterogeneous developmental disorder caused by missense mutations in genes involved in the Ras/MAPK signaling pathway, a major mediator of early and late developmental processes. The diagnosis of NS is made on clinical grounds with molecular confirmation of a mutation found in 63% of cases. Key clinical features include short stature, cardiac defects, developmental delay, lymphatic dysplasias, bleeding tendency, and a constellation of distinctive facial features and physical exam findings. The prevalence of medical issues or the development of new ones in adults with NS is not well‐studied. This cross‐sectional study reports on the prevalence of clinical conditions and their ages of onset in a cohort of 35 adolescents and adults with NS aged 16–68 years old (mean age 28 years). In this cohort, 34 of 35 subjects (97%) had had full PTPN11 sequencing; 37% were PTPN11 positive, 23% were SOS1 positive, and 3% were BRAF positive. Mean adult height in both men and women was at the 3rd–10th centile. The most prevalent clinical findings in this cohort included pulmonary valve stenosis (71%), easy bruising (63%), GERD (60%), constipation (51%), scoliosis (54%), chronic joint pain (54%), lymphedema (49%), depression (49%), anxiety (49%), Chiari malformation (20%), and osteopenia/osteoporosis (14%). In summary, adults with NS are affected by multi‐organ morbidity and require special medical management aimed towards the most prevalent and serious known medical complications. 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type="first">Patroula</forename><surname>Smpokou</surname></persName><affiliation>Harvard Medical School, Boston, Massachusetts<address><country key="US"></country></address></affiliation><affiliation>Division of Genetics, Boston Children's Hospital, Boston, Massachusetts<address><country key="US"></country></address></affiliation></author><author xml:id="author-0001"><persName><forename type="first">Erica</forename><surname>Tworog‐Dube</surname></persName><affiliation>Partners Center for Personalized Genetic Medicine, Boston, Massachusetts<address><country key="US"></country></address></affiliation></author><author xml:id="author-0002"><persName><forename type="first">Raju S.</forename><surname>Kucherlapati</surname></persName><affiliation>Harvard Medical School, Boston, Massachusetts<address><country key="US"></country></address></affiliation><affiliation>Partners Center for Personalized Genetic Medicine, Boston, Massachusetts<address><country key="US"></country></address></affiliation></author><author xml:id="author-0003" role="corresp"><persName><forename type="first">Amy E.</forename><surname>Roberts</surname></persName><email>amy.roberts@cardio.chboston.org</email><affiliation>Harvard Medical School, Boston, Massachusetts<address><country key="US"></country></address></affiliation><affiliation>Division of Genetics, Boston Children's Hospital, Boston, Massachusetts<address><country key="US"></country></address></affiliation><affiliation>Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts<address><country key="US"></country></address></affiliation><affiliation>Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115.</affiliation></author><idno type="istex">D5430EBE91CAAEC27EB4152EC09AC22B065240E5</idno><idno type="DOI">10.1002/ajmg.a.35639</idno><idno type="unit">AJMG35639</idno><idno type="toTypesetVersion">file:AJMG.AJMG35639.pdf</idno></analytic><monogr><title level="j" type="main">American Journal of Medical Genetics Part A</title><title level="j" type="alt">AMERICAN JOURNAL OF MEDICAL GENETICS</title><idno type="pISSN">1552-4825</idno><idno type="eISSN">1552-4833</idno><idno type="book-DOI">10.1002/(ISSN)1552-4833</idno><idno type="book-part-DOI">10.1002/ajmg.a.v158a.12</idno><idno type="product">AJMG</idno><imprint><biblScope unit="vol">158A</biblScope><biblScope unit="issue">12</biblScope><biblScope unit="page" from="3106">3106</biblScope><biblScope unit="page" to="3111">3111</biblScope><biblScope unit="page-count">6</biblScope><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2012-12"></date></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><abstract xml:lang="en" style="main"><head>Abstract</head><p>Noonan syndrome (NS) is a heterogeneous developmental disorder caused by missense mutations in genes involved in the Ras/MAPK signaling pathway, a major mediator of early and late developmental processes. The diagnosis of NS is made on clinical grounds with molecular confirmation of a mutation found in 63% of cases. Key clinical features include short stature, cardiac defects, developmental delay, lymphatic dysplasias, bleeding tendency, and a constellation of distinctive facial features and physical exam findings. The prevalence of medical issues or the development of new ones in adults with NS is not well‐studied. This cross‐sectional study reports on the prevalence of clinical conditions and their ages of onset in a cohort of 35 adolescents and adults with NS aged 16–68 years old (mean age 28 years). In this cohort, 34 of 35 subjects (97%) had had full <hi rend="italic">PTPN11</hi> sequencing; 37% were <hi rend="italic">PTPN11</hi> positive, 23% were <hi rend="italic">SOS1</hi> positive, and 3% were <hi rend="italic">BRAF</hi> positive. Mean adult height in both men and women was at the 3rd–10th centile. The most prevalent clinical findings in this cohort included pulmonary valve stenosis (71%), easy bruising (63%), GERD (60%), constipation (51%), scoliosis (54%), chronic joint pain (54%), lymphedema (49%), depression (49%), anxiety (49%), Chiari malformation (20%), and osteopenia/osteoporosis (14%). In summary, adults with NS are affected by multi‐organ morbidity and require special medical management aimed towards the most prevalent and serious known medical complications. Larger studies characterizing the clinical conditions found in NS adults are needed to provide potential genotype–phenotype correlations that may aid in clinical management. © 2012 Wiley Periodicals, Inc.</p></abstract><textClass><keywords xml:lang="en"><term xml:id="kwd1">Noonan syndrome</term><term xml:id="kwd2">Noonan spectrum</term><term xml:id="kwd3">Ras/MAPK pathway</term><term xml:id="kwd4"><hi rend="italic">PTPN11</hi></term><term xml:id="kwd5"><hi rend="italic">SOS1</hi></term><term xml:id="kwd6"><hi rend="italic">RAF1</hi></term><term xml:id="kwd7"><hi rend="italic">KRAS</hi></term><term xml:id="kwd8"><hi rend="italic">BRAF</hi></term><term xml:id="kwd9"><hi rend="italic">NRAS</hi></term><term xml:id="kwd10"><hi rend="italic">MEK1</hi></term><term xml:id="kwd11"><hi rend="italic">SHOC2</hi></term></keywords><classCode scheme="articleCategory">Research Article</classCode><classCode scheme="tocHeading1">Research Articles</classCode></textClass><langUsage><language ident="EN"></language></langUsage></profileDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/D5430EBE91CAAEC27EB4152EC09AC22B065240E5/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Wiley Subscription Services, Inc., A Wiley Company</publisherName><publisherLoc>Hoboken</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1552-4833</doi><issn type="print">1552-4825</issn><issn type="electronic">1552-4833</issn><idGroup><id type="product" value="AJMG"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="AMERICAN JOURNAL OF MEDICAL GENETICS">American Journal of Medical Genetics Part A</title><title type="short">Am. 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Genet.</title></titleGroup><selfCitationGroup><citation type="ancestor" xml:id="cit1"><journalTitle>American Journal of Medical Genetics</journalTitle><accessionId ref="info:x-wiley/issn/01487299">0148-7299</accessionId><accessionId ref="info:x-wiley/issn/10968628">1096-8628</accessionId><pubYear year="2004">2004</pubYear></citation></selfCitationGroup></publicationMeta><publicationMeta level="part" position="120"><doi origin="wiley" registered="yes">10.1002/ajmg.a.v158a.12</doi><idGroup><id type="focusSection" value="0"></id></idGroup><titleGroup><title type="focusSection" xml:lang="en">American Journal of Medical Genetics Part A</title></titleGroup><numberingGroup><numbering type="journalVolume" number="158">158A</numbering><numbering type="journalIssue">12</numbering></numberingGroup><coverDate startDate="2012-12">December 2012</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="160" status="forIssue"><doi origin="wiley" registered="yes">10.1002/ajmg.a.35639</doi><idGroup><id type="unit" value="AJMG35639"></id></idGroup><countGroup><count type="pageTotal" number="6"></count></countGroup><titleGroup><title type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="publisher">Copyright © 2012 Wiley Periodicals, Inc.</copyright><eventGroup><event type="manuscriptReceived" date="2012-05-18"></event><event type="manuscriptAccepted" date="2012-08-06"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:3.1.9 mode:FullText" date="2012-12-05"></event><event type="publishedOnlineEarlyUnpaginated" date="2012-11-19"></event><event type="publishedOnlineFinalForm" date="2012-11-22"></event><event type="firstOnline" date="2012-11-19"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-02"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.3.4 mode:FullText" date="2015-02-24"></event></eventGroup><numberingGroup><numbering type="pageFirst">3106</numbering><numbering type="pageLast">3111</numbering></numberingGroup><correspondenceTo>Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115.</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:AJMG.AJMG35639.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="0"></count><count type="tableTotal" number="3"></count><count type="referenceTotal" number="26"></count><count type="wordTotal" number="5756"></count></countGroup><titleGroup><title type="main" xml:lang="en">Medical complications, clinical findings, and educational outcomes in adults with Noonan syndrome<link href="#fn1"></link><link href="#fn2"></link></title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Patroula</givenNames><familyName>Smpokou</familyName></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Erica</givenNames><familyName>Tworog‐Dube</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1 #af3"><personName><givenNames>Raju S.</givenNames><familyName>Kucherlapati</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1 #af2 #af4" corresponding="yes"><personName><givenNames>Amy E.</givenNames><familyName>Roberts</familyName></personName><contactDetails><email>amy.roberts@cardio.chboston.org</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="US" type="organization"><unparsedAffiliation>Harvard Medical School, Boston, Massachusetts</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="US" type="organization"><unparsedAffiliation>Division of Genetics, Boston Children's Hospital, Boston, Massachusetts</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="US" type="organization"><unparsedAffiliation>Partners Center for Personalized Genetic Medicine, Boston, Massachusetts</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="US" type="organization"><unparsedAffiliation>Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">Noonan syndrome</keyword><keyword xml:id="kwd2">Noonan spectrum</keyword><keyword xml:id="kwd3">Ras/MAPK pathway</keyword><keyword xml:id="kwd4"><i>PTPN11</i></keyword><keyword xml:id="kwd5"><i>SOS1</i></keyword><keyword xml:id="kwd6"><i>RAF1</i></keyword><keyword xml:id="kwd7"><i>KRAS</i></keyword><keyword xml:id="kwd8"><i>BRAF</i></keyword><keyword xml:id="kwd9"><i>NRAS</i></keyword><keyword xml:id="kwd10"><i>MEK1</i></keyword><keyword xml:id="kwd11"><i>SHOC2</i></keyword></keywordGroup><supportingInformation><p>
Additional supporting information may be found in the online version of this article.
</p><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:15524825:media:ajmg35639:ajmg_35639_sm_SuppMat"></mediaResource><caption>Supporting Information</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Noonan syndrome (NS) is a heterogeneous developmental disorder caused by missense mutations in genes involved in the Ras/MAPK signaling pathway, a major mediator of early and late developmental processes. The diagnosis of NS is made on clinical grounds with molecular confirmation of a mutation found in 63% of cases. Key clinical features include short stature, cardiac defects, developmental delay, lymphatic dysplasias, bleeding tendency, and a constellation of distinctive facial features and physical exam findings. The prevalence of medical issues or the development of new ones in adults with NS is not well‐studied. This cross‐sectional study reports on the prevalence of clinical conditions and their ages of onset in a cohort of 35 adolescents and adults with NS aged 16–68 years old (mean age 28 years). In this cohort, 34 of 35 subjects (97%) had had full <i>PTPN11</i> sequencing; 37% were <i>PTPN11</i> positive, 23% were <i>SOS1</i> positive, and 3% were <i>BRAF</i> positive. Mean adult height in both men and women was at the 3rd–10th centile. The most prevalent clinical findings in this cohort included pulmonary valve stenosis (71%), easy bruising (63%), GERD (60%), constipation (51%), scoliosis (54%), chronic joint pain (54%), lymphedema (49%), depression (49%), anxiety (49%), Chiari malformation (20%), and osteopenia/osteoporosis (14%). In summary, adults with NS are affected by multi‐organ morbidity and require special medical management aimed towards the most prevalent and serious known medical complications. Larger studies characterizing the clinical conditions found in NS adults are needed to provide potential genotype–phenotype correlations that may aid in clinical management. © 2012 Wiley Periodicals, Inc.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p>How to Cite this Article: Smpokou P, Tworog‐Dube E, Kucherlapati RS, Roberts AE. 2012. Medical complications, clinical findings, and educational outcomes in adults with Noonan syndrome. Am J Med Genet Part A 158A: 3106–3111.</p></note><note xml:id="fn2"><p>The authors have no conflicts of interest to declare.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Medical complications, clinical findings, and educational outcomes in adults with Noonan syndrome</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Medical complications, clinical findings, and educational outcomes in adults with Noonan syndrome</title></titleInfo><name type="personal"><namePart type="given">Patroula</namePart><namePart type="family">Smpokou</namePart><affiliation>Harvard Medical School, Boston, Massachusetts</affiliation><affiliation>Division of Genetics, Boston Children's Hospital, Boston, Massachusetts</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Erica</namePart><namePart type="family">Tworog‐Dube</namePart><affiliation>Partners Center for Personalized Genetic Medicine, Boston, Massachusetts</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Raju S.</namePart><namePart type="family">Kucherlapati</namePart><affiliation>Harvard Medical School, Boston, Massachusetts</affiliation><affiliation>Partners Center for Personalized Genetic Medicine, Boston, Massachusetts</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Amy E.</namePart><namePart type="family">Roberts</namePart><affiliation>Harvard Medical School, Boston, Massachusetts</affiliation><affiliation>Division of Genetics, Boston Children's Hospital, Boston, Massachusetts</affiliation><affiliation>Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts</affiliation><affiliation>Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2012-12</dateIssued><dateCaptured encoding="w3cdtf">2012-05-18</dateCaptured><dateValid encoding="w3cdtf">2012-08-06</dateValid><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="tables">3</extent><extent unit="references">26</extent><extent unit="words">5756</extent></physicalDescription><abstract lang="en">Noonan syndrome (NS) is a heterogeneous developmental disorder caused by missense mutations in genes involved in the Ras/MAPK signaling pathway, a major mediator of early and late developmental processes. The diagnosis of NS is made on clinical grounds with molecular confirmation of a mutation found in 63% of cases. Key clinical features include short stature, cardiac defects, developmental delay, lymphatic dysplasias, bleeding tendency, and a constellation of distinctive facial features and physical exam findings. The prevalence of medical issues or the development of new ones in adults with NS is not well‐studied. This cross‐sectional study reports on the prevalence of clinical conditions and their ages of onset in a cohort of 35 adolescents and adults with NS aged 16–68 years old (mean age 28 years). In this cohort, 34 of 35 subjects (97%) had had full PTPN11 sequencing; 37% were PTPN11 positive, 23% were SOS1 positive, and 3% were BRAF positive. Mean adult height in both men and women was at the 3rd–10th centile. The most prevalent clinical findings in this cohort included pulmonary valve stenosis (71%), easy bruising (63%), GERD (60%), constipation (51%), scoliosis (54%), chronic joint pain (54%), lymphedema (49%), depression (49%), anxiety (49%), Chiari malformation (20%), and osteopenia/osteoporosis (14%). In summary, adults with NS are affected by multi‐organ morbidity and require special medical management aimed towards the most prevalent and serious known medical complications. Larger studies characterizing the clinical conditions found in NS adults are needed to provide potential genotype–phenotype correlations that may aid in clinical management. © 2012 Wiley Periodicals, Inc.</abstract><note type="content">*How to Cite this Article: Smpokou P, Tworog‐Dube E, Kucherlapati RS, Roberts AE. 2012. Medical complications, clinical findings, and educational outcomes in adults with Noonan syndrome. Am J Med Genet Part A 158A: 3106–3111.</note><note type="content">*The authors have no conflicts of interest to declare.</note><subject lang="en"><genre>keywords</genre><topic>Noonan syndrome</topic><topic>Noonan spectrum</topic><topic>Ras/MAPK pathway</topic><topic>PTPN11</topic><topic>SOS1</topic><topic>RAF1</topic><topic>KRAS</topic><topic>BRAF</topic><topic>NRAS</topic><topic>MEK1</topic><topic>SHOC2</topic></subject><relatedItem type="host"><titleInfo><title>American Journal of Medical Genetics Part A</title></titleInfo><titleInfo type="abbreviated"><title>Am. J. Med. Genet.</title></titleInfo><genre type="journal">journal</genre><note type="content"> Additional supporting information may be found in the online version of this article.Supporting Info Item: Supporting Information - </note><subject><genre>article-category</genre><topic>Research Article</topic></subject><identifier type="ISSN">1552-4825</identifier><identifier type="eISSN">1552-4833</identifier><identifier type="DOI">10.1002/(ISSN)1552-4833</identifier><identifier type="PublisherID">AJMG</identifier><part><date>2012</date><detail type="volume"><caption>vol.</caption><number>158A</number></detail><detail type="issue"><caption>no.</caption><number>12</number></detail><extent unit="pages"><start>3106</start><end>3111</end><total>6</total></extent></part></relatedItem><relatedItem type="preceding"><titleInfo><title>American Journal of Medical Genetics</title></titleInfo><identifier type="ISSN">0148-7299</identifier><identifier type="ISSN">1096-8628</identifier><part><date point="end">2004</date></part></relatedItem><identifier type="istex">D5430EBE91CAAEC27EB4152EC09AC22B065240E5</identifier><identifier type="DOI">10.1002/ajmg.a.35639</identifier><identifier type="ArticleID">AJMG35639</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2012 Wiley Periodicals, Inc.</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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