Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation
Identifieur interne : 007218 ( Istex/Corpus ); précédent : 007217; suivant : 007219Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation
Auteurs : Débora Romeo Bertola ; Alexandre C. Pereira ; Paulo S. L. De Oliveira ; Chong A. Kim ; José Eduardo KriegerSource :
- American Journal of Medical Genetics Part A [ 1552-4825 ] ; 2004-11-01.
Abstract
Noonan syndrome (NS) is an autosomal dominant disorder comprising short stature, facial dysmorphism, short and/or webbed neck, heart defects, and cryptorchidism in males. The gene responsible for the disorder (PTPN11) was recently identified, and explains 30–50% of the cases clinically diagnosed as NS. Cardiofaciocutaneous (CFC) syndrome, a similar but distinct entity, is characterized by relative macrocephaly, characteristic facial appearance, ectodermal abnormalities (sparse and friable hair, sparse eyebrows, hyperkeratotic skin), congenital heart defects, and growth and mental retardation. We describe on a young woman who presents clinical features of NS (short stature, triangular facies, with dowslanting palpebral fissures and apparent hypertelorism, webbed neck, pulmonary stenosis, bleeding diathesis, prominent corneal nerves), but with a more prominent ectodermal involvement (sparse and very coarse hair, sparse eyebrows and eyelashes) and developmental delay/mental retardation, which are characteristic of CFC patients. Sequencing of the PTPN11 gene showed a T411M substitution, not previously described in patients with NS. The same mutation was found in her mother and older sister, not initially considered to be affected by NS, but with very subtle clinical findings compatible with this diagnosis. Molecular dynamic studies indicate that this new mutation, similar to other previously described mutations, favors a more active protein conformation. However, the main disruptive effect is not directly in the catalytic domain, suggesting that the location of this mutation could make the protein more susceptible to gene–gene or gene–environment interactions. Atypical cases of NS should be screened for mutations in the PTPN11 gene and in the case of a positive result, first‐degree relatives should also be tested for the specific mutation. © 2004 Wiley‐Liss, Inc.
Url:
DOI: 10.1002/ajmg.a.30270
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Pereira</name><affiliation><mods:affiliation>Laboratório de Genética e Cardiologia Molecular, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil</mods:affiliation></affiliation></author><author><name sortKey="Oliveira, Paulo S L De" sort="Oliveira, Paulo S L De" uniqKey="Oliveira P" first="Paulo S. L. De" last="Oliveira">Paulo S. L. De Oliveira</name><affiliation><mods:affiliation>Laboratório de Genética e Cardiologia Molecular, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil</mods:affiliation></affiliation><affiliation><mods:affiliation>Disciplina de Informatica Médica, Medical School, University of São Paulo, São Paulo, Brazil</mods:affiliation></affiliation></author><author><name sortKey="Kim, Chong A" sort="Kim, Chong A" uniqKey="Kim C" first="Chong A." last="Kim">Chong A. Kim</name><affiliation><mods:affiliation>Genetics Clinic Unit, Instituto da Criança do Hospital das Clínicas, University of São Paulo, São Paulo, Brazil</mods:affiliation></affiliation></author><author><name sortKey="Krieger, Jose Eduardo" sort="Krieger, Jose Eduardo" uniqKey="Krieger J" first="José Eduardo" last="Krieger">José Eduardo Krieger</name><affiliation><mods:affiliation>Laboratório de Genética e Cardiologia Molecular, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><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="ISSN">1552-4825</idno><idno type="eISSN">1552-4833</idno><imprint><biblScope unit="vol">130A</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="378">378</biblScope><biblScope unit="page" to="383">383</biblScope><biblScope unit="page-count">6</biblScope><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2004-11-01">2004-11-01</date></imprint><idno type="ISSN">1552-4825</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1552-4825</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Noonan syndrome (NS) is an autosomal dominant disorder comprising short stature, facial dysmorphism, short and/or webbed neck, heart defects, and cryptorchidism in males. The gene responsible for the disorder (PTPN11) was recently identified, and explains 30–50% of the cases clinically diagnosed as NS. Cardiofaciocutaneous (CFC) syndrome, a similar but distinct entity, is characterized by relative macrocephaly, characteristic facial appearance, ectodermal abnormalities (sparse and friable hair, sparse eyebrows, hyperkeratotic skin), congenital heart defects, and growth and mental retardation. We describe on a young woman who presents clinical features of NS (short stature, triangular facies, with dowslanting palpebral fissures and apparent hypertelorism, webbed neck, pulmonary stenosis, bleeding diathesis, prominent corneal nerves), but with a more prominent ectodermal involvement (sparse and very coarse hair, sparse eyebrows and eyelashes) and developmental delay/mental retardation, which are characteristic of CFC patients. Sequencing of the PTPN11 gene showed a T411M substitution, not previously described in patients with NS. The same mutation was found in her mother and older sister, not initially considered to be affected by NS, but with very subtle clinical findings compatible with this diagnosis. Molecular dynamic studies indicate that this new mutation, similar to other previously described mutations, favors a more active protein conformation. However, the main disruptive effect is not directly in the catalytic domain, suggesting that the location of this mutation could make the protein more susceptible to gene–gene or gene–environment interactions. Atypical cases of NS should be screened for mutations in the PTPN11 gene and in the case of a positive result, first‐degree relatives should also be tested for the specific mutation. © 2004 Wiley‐Liss, Inc.</div></front></TEI><istex><corpusName>wiley</corpusName><keywords><teeft><json:string>mutation</json:string><json:string>noonan</json:string><json:string>genet</json:string><json:string>noonan syndrome</json:string><json:string>syndrome</json:string><json:string>phenotype</json:string><json:string>tartaglia</json:string><json:string>paulo</json:string><json:string>ndings</json:string><json:string>older sister</json:string><json:string>centile</json:string><json:string>sharland</json:string><json:string>hypertelorism</json:string><json:string>ectodermal</json:string><json:string>palpebral</json:string><json:string>bertola</json:string><json:string>ssures</json:string><json:string>proband</json:string><json:string>mental retardation</json:string><json:string>sparse eyebrows</json:string><json:string>short stature</json:string><json:string>costello syndrome</json:string><json:string>downslanting palpebral</json:string><json:string>neurological involvements</json:string><json:string>clinical variability</json:string><json:string>gene mutation</json:string><json:string>leopard syndrome</json:string><json:string>high forehead</json:string><json:string>prominent nasolabial folds</json:string><json:string>short neck</json:string><json:string>online issue</json:string><json:string>native protein</json:string><json:string>genetic counseling</json:string><json:string>facial features</json:string><json:string>clinical criteria</json:string><json:string>same family</json:string><json:string>hyperkeratotic skin</json:string><json:string>recurrence risk</json:string><json:string>short webbed neck</json:string><json:string>young woman</json:string><json:string>heterogeneous disorder</json:string><json:string>clinical features</json:string><json:string>triangular facies</json:string><json:string>giant cell lesion syndrome</json:string><json:string>heart defects</json:string><json:string>dowslanting palpebral</json:string><json:string>other hand</json:string><json:string>distinct entity</json:string><json:string>relative macrocephaly</json:string><json:string>apparent hypertelorism</json:string><json:string>twinning gestations</json:string><json:string>slow feeder</json:string><json:string>zygomatic areas</json:string><json:string>great volume</json:string><json:string>webbed neck</json:string><json:string>pulmonary stenosis</json:string><json:string>supraorbital ridges</json:string><json:string>posterior hair line</json:string><json:string>hyperelastic skin</json:string><json:string>follicular mucinosis</json:string><json:string>coarse hair</json:string><json:string>genet tartaglia</json:string><json:string>mild hypertelorism</json:string><json:string>younger sister</json:string><json:string>curly hair</json:string><json:string>ectodermal abnormalities</json:string><json:string>crystallographic structure</json:string><json:string>wild protein</json:string><json:string>catalytic domain</json:string><json:string>phosphopeptide binding</json:string><json:string>clinical diagnosis</json:string><json:string>friable hair</json:string><json:string>genetics clinic unit</json:string><json:string>syndrome patients</json:string><json:string>retardation syndrome</json:string><json:string>keratosis pilaris atrophicans faciei</json:string><json:string>skin lesions</json:string><json:string>wooly hair</json:string><json:string>clinical study</json:string><json:string>syndrome phenotype</json:string><json:string>amino domain</json:string><json:string>steric block</json:string><json:string>catalytic site</json:string><json:string>intramolecular interaction</json:string><json:string>dizygous twinning</json:string><json:string>dental malocclusion</json:string><json:string>large family</json:string><json:string>turner phenotype</json:string><json:string>congenital heart disease</json:string><json:string>several years</json:string></teeft></keywords><author><json:item><name>Débora Romeo Bertola</name><affiliations><json:string>Genetics Clinic Unit, Instituto da Criança do Hospital das Clínicas, University of São Paulo, São Paulo, Brazil</json:string><json:string>Av Dr. Éneas Carvalho de Aguiar, 647, Unidade de Genética Clínica do Instituto da Criança—HC‐FMUSP, CEP: 05403‐900, São Paulo, SP, Brazil.</json:string></affiliations></json:item><json:item><name>Alexandre C. 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Kim</name><affiliations><json:string>Genetics Clinic Unit, Instituto da Criança do Hospital das Clínicas, University of São Paulo, São Paulo, Brazil</json:string></affiliations></json:item><json:item><name>José Eduardo Krieger</name><affiliations><json:string>Laboratório de Genética e Cardiologia Molecular, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>PTPN11</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>autosomal dominant disorder</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Noonan syndrome</value></json:item></subject><articleId><json:string>AJMG30270</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>Noonan syndrome (NS) is an autosomal dominant disorder comprising short stature, facial dysmorphism, short and/or webbed neck, heart defects, and cryptorchidism in males. The gene responsible for the disorder (PTPN11) was recently identified, and explains 30–50% of the cases clinically diagnosed as NS. Cardiofaciocutaneous (CFC) syndrome, a similar but distinct entity, is characterized by relative macrocephaly, characteristic facial appearance, ectodermal abnormalities (sparse and friable hair, sparse eyebrows, hyperkeratotic skin), congenital heart defects, and growth and mental retardation. We describe on a young woman who presents clinical features of NS (short stature, triangular facies, with dowslanting palpebral fissures and apparent hypertelorism, webbed neck, pulmonary stenosis, bleeding diathesis, prominent corneal nerves), but with a more prominent ectodermal involvement (sparse and very coarse hair, sparse eyebrows and eyelashes) and developmental delay/mental retardation, which are characteristic of CFC patients. Sequencing of the PTPN11 gene showed a T411M substitution, not previously described in patients with NS. The same mutation was found in her mother and older sister, not initially considered to be affected by NS, but with very subtle clinical findings compatible with this diagnosis. Molecular dynamic studies indicate that this new mutation, similar to other previously described mutations, favors a more active protein conformation. However, the main disruptive effect is not directly in the catalytic domain, suggesting that the location of this mutation could make the protein more susceptible to gene–gene or gene–environment interactions. Atypical cases of NS should be screened for mutations in the PTPN11 gene and in the case of a positive result, first‐degree relatives should also be tested for the specific mutation. © 2004 Wiley‐Liss, Inc.</abstract><qualityIndicators><score>7.853</score><pdfVersion>1.3</pdfVersion><pdfPageSize>594 x 792 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>1891</abstractCharCount><pdfWordCount>4853</pdfWordCount><pdfCharCount>29363</pdfCharCount><pdfPageCount>6</pdfPageCount><abstractWordCount>265</abstractWordCount></qualityIndicators><title>Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation</title><genre><json:string>article</json:string></genre><host><title>American Journal of Medical Genetics Part 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Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><licence>Copyright © 2004 Wiley‐Liss, Inc.</licence></availability><date type="published" when="2004-11-01"></date></publicationStmt><notesStmt><note type="content-type" subtype="article" source="article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</note><note type="publication-type" subtype="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="article"><analytic><title level="a" type="main" xml:lang="en">Clinical variability in a Noonan syndrome family with a new <hi rend="italic">PTPN11</hi> gene mutation</title><title level="a" type="short" xml:lang="en">Clinical Variability in Noonan Syndrome</title><author xml:id="author-0000" role="corresp"><persName><forename type="first">Débora Romeo</forename><surname>Bertola</surname></persName><email>drbertola@attglobal.net</email><affiliation>Genetics Clinic Unit, Instituto da Criança do Hospital das Clínicas, University of São Paulo, São Paulo, Brazil<address><country key="BR"></country></address></affiliation><affiliation>Av Dr. Éneas Carvalho de Aguiar, 647, Unidade de Genética Clínica do Instituto da Criança—HC‐FMUSP, CEP: 05403‐900, São Paulo, SP, Brazil.</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Alexandre C.</forename><surname>Pereira</surname></persName><affiliation>Laboratório de Genética e Cardiologia Molecular, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil<address><country key="BR"></country></address></affiliation></author><author xml:id="author-0002"><persName><forename type="first">Paulo S.L. de</forename><surname>Oliveira</surname></persName><affiliation>Laboratório de Genética e Cardiologia Molecular, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil<address><country key="BR"></country></address></affiliation><affiliation>Disciplina de Informatica Médica, Medical School, University of São Paulo, São Paulo, Brazil<address><country key="BR"></country></address></affiliation></author><author xml:id="author-0003"><persName><forename type="first">Chong A.</forename><surname>Kim</surname></persName><affiliation>Genetics Clinic Unit, Instituto da Criança do Hospital das Clínicas, University of São Paulo, São Paulo, Brazil<address><country key="BR"></country></address></affiliation></author><author xml:id="author-0004"><persName><forename type="first">José Eduardo</forename><surname>Krieger</surname></persName><affiliation>Laboratório de Genética e Cardiologia Molecular, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil<address><country key="BR"></country></address></affiliation></author><idno type="istex">F396A0B92187C3E38F563C7EBA3D795342A1F68D</idno><idno type="DOI">10.1002/ajmg.a.30270</idno><idno type="unit">AJMG30270</idno><idno type="toTypesetVersion">file:AJMG.AJMG30270.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.v130a:4</idno><idno type="product">AJMG</idno><imprint><biblScope unit="vol">130A</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="378">378</biblScope><biblScope unit="page" to="383">383</biblScope><biblScope unit="page-count">6</biblScope><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2004-11-01"></date></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><abstract xml:lang="en" style="main"><head>Abstract</head><p>Noonan syndrome (NS) is an autosomal dominant disorder comprising short stature, facial dysmorphism, short and/or webbed neck, heart defects, and cryptorchidism in males. The gene responsible for the disorder (<hi rend="italic">PTPN11</hi>) was recently identified, and explains 30–50% of the cases clinically diagnosed as NS. Cardiofaciocutaneous (CFC) syndrome, a similar but distinct entity, is characterized by relative macrocephaly, characteristic facial appearance, ectodermal abnormalities (sparse and friable hair, sparse eyebrows, hyperkeratotic skin), congenital heart defects, and growth and mental retardation. We describe on a young woman who presents clinical features of NS (short stature, triangular facies, with dowslanting palpebral fissures and apparent hypertelorism, webbed neck, pulmonary stenosis, bleeding diathesis, prominent corneal nerves), but with a more prominent ectodermal involvement (sparse and very coarse hair, sparse eyebrows and eyelashes) and developmental delay/mental retardation, which are characteristic of CFC patients. Sequencing of the <hi rend="italic">PTPN11</hi> gene showed a T411M substitution, not previously described in patients with NS. The same mutation was found in her mother and older sister, not initially considered to be affected by NS, but with very subtle clinical findings compatible with this diagnosis. Molecular dynamic studies indicate that this new mutation, similar to other previously described mutations, favors a more active protein conformation. However, the main disruptive effect is not directly in the catalytic domain, suggesting that the location of this mutation could make the protein more susceptible to gene–gene or gene–environment interactions. Atypical cases of NS should be screened for mutations in the <hi rend="italic">PTPN11</hi> gene and in the case of a positive result, first‐degree relatives should also be tested for the specific mutation. © 2004 Wiley‐Liss, Inc.</p></abstract><textClass><keywords xml:lang="en"><term xml:id="kwd1"><hi rend="italic">PTPN11</hi></term><term xml:id="kwd2">autosomal dominant disorder</term><term xml:id="kwd3">Noonan syndrome</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/F396A0B92187C3E38F563C7EBA3D795342A1F68D/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. J. Med. Genet.</title></titleGroup></publicationMeta><publicationMeta level="part" position="40"><doi origin="wiley" registered="yes">10.1002/ajmg.a.v130a:4</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="130">130A</numbering><numbering type="journalIssue">4</numbering></numberingGroup><coverDate startDate="2004-11-01">1 November 2004</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="8" status="forIssue"><doi origin="wiley" registered="yes">10.1002/ajmg.a.30270</doi><idGroup><id type="unit" value="AJMG30270"></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 © 2004 Wiley‐Liss, Inc.</copyright><eventGroup><event type="manuscriptReceived" date="2003-08-13"></event><event type="manuscriptAccepted" date="2004-04-26"></event><event type="publishedOnlineEarlyUnpaginated" date="2004-09-21"></event><event type="firstOnline" date="2004-09-21"></event><event type="publishedOnlineFinalForm" date="2004-10-22"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.6 mode:FullText source:FullText result:FullText" date="2010-05-07"></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:4.1.7 mode:FullText,remove_FC" date="2014-10-14"></event></eventGroup><numberingGroup><numbering type="pageFirst">378</numbering><numbering type="pageLast">383</numbering></numberingGroup><correspondenceTo>Av Dr. Éneas Carvalho de Aguiar, 647, Unidade de Genética Clínica do Instituto da Criança—HC‐FMUSP, CEP: 05403‐900, São Paulo, SP, Brazil.</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:AJMG.AJMG30270.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="3"></count><count type="tableTotal" number="0"></count><count type="referenceTotal" number="43"></count><count type="wordTotal" number="5194"></count></countGroup><titleGroup><title type="main" xml:lang="en">Clinical variability in a Noonan syndrome family with a new <i>PTPN11</i> gene mutation</title><title type="short" xml:lang="en">Clinical Variability in Noonan Syndrome</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1" corresponding="yes"><personName><givenNames>Débora Romeo</givenNames><familyName>Bertola</familyName></personName><contactDetails><email>drbertola@attglobal.net</email></contactDetails></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af2"><personName><givenNames>Alexandre C.</givenNames><familyName>Pereira</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af2 #af3"><personName><givenNames>Paulo S.L. de</givenNames><familyName>Oliveira</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Chong A.</givenNames><familyName>Kim</familyName></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af2"><personName><givenNames>José Eduardo</givenNames><familyName>Krieger</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="BR" type="organization"><unparsedAffiliation>Genetics Clinic Unit, Instituto da Criança do Hospital das Clínicas, University of São Paulo, São Paulo, Brazil</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="BR" type="organization"><unparsedAffiliation>Laboratório de Genética e Cardiologia Molecular, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="BR" type="organization"><unparsedAffiliation>Disciplina de Informatica Médica, Medical School, University of São Paulo, São Paulo, Brazil</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1"><i>PTPN11</i></keyword><keyword xml:id="kwd2">autosomal dominant disorder</keyword><keyword xml:id="kwd3">Noonan syndrome</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Noonan syndrome (NS) is an autosomal dominant disorder comprising short stature, facial dysmorphism, short and/or webbed neck, heart defects, and cryptorchidism in males. The gene responsible for the disorder (<i>PTPN11</i>) was recently identified, and explains 30–50% of the cases clinically diagnosed as NS. Cardiofaciocutaneous (CFC) syndrome, a similar but distinct entity, is characterized by relative macrocephaly, characteristic facial appearance, ectodermal abnormalities (sparse and friable hair, sparse eyebrows, hyperkeratotic skin), congenital heart defects, and growth and mental retardation. We describe on a young woman who presents clinical features of NS (short stature, triangular facies, with dowslanting palpebral fissures and apparent hypertelorism, webbed neck, pulmonary stenosis, bleeding diathesis, prominent corneal nerves), but with a more prominent ectodermal involvement (sparse and very coarse hair, sparse eyebrows and eyelashes) and developmental delay/mental retardation, which are characteristic of CFC patients. Sequencing of the <i>PTPN11</i> gene showed a T411M substitution, not previously described in patients with NS. The same mutation was found in her mother and older sister, not initially considered to be affected by NS, but with very subtle clinical findings compatible with this diagnosis. Molecular dynamic studies indicate that this new mutation, similar to other previously described mutations, favors a more active protein conformation. However, the main disruptive effect is not directly in the catalytic domain, suggesting that the location of this mutation could make the protein more susceptible to gene–gene or gene–environment interactions. Atypical cases of NS should be screened for mutations in the <i>PTPN11</i> gene and in the case of a positive result, first‐degree relatives should also be tested for the specific mutation. © 2004 Wiley‐Liss, Inc.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Clinical Variability in Noonan Syndrome</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation</title></titleInfo><name type="personal"><namePart type="given">Débora Romeo</namePart><namePart type="family">Bertola</namePart><affiliation>Genetics Clinic Unit, Instituto da Criança do Hospital das Clínicas, University of São Paulo, São Paulo, Brazil</affiliation><affiliation>Av Dr. Éneas Carvalho de Aguiar, 647, Unidade de Genética Clínica do Instituto da Criança—HC‐FMUSP, CEP: 05403‐900, São Paulo, SP, Brazil.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alexandre C.</namePart><namePart type="family">Pereira</namePart><affiliation>Laboratório de Genética e Cardiologia Molecular, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paulo S.L. de</namePart><namePart type="family">Oliveira</namePart><affiliation>Laboratório de Genética e Cardiologia Molecular, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil</affiliation><affiliation>Disciplina de Informatica Médica, Medical School, University of São Paulo, São Paulo, Brazil</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Chong A.</namePart><namePart type="family">Kim</namePart><affiliation>Genetics Clinic Unit, Instituto da Criança do Hospital das Clínicas, University of São Paulo, São Paulo, Brazil</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">José Eduardo</namePart><namePart type="family">Krieger</namePart><affiliation>Laboratório de Genética e Cardiologia Molecular, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil</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">2004-11-01</dateIssued><dateCaptured encoding="w3cdtf">2003-08-13</dateCaptured><dateValid encoding="w3cdtf">2004-04-26</dateValid><copyrightDate encoding="w3cdtf">2004</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="figures">3</extent><extent unit="references">43</extent><extent unit="words">5194</extent></physicalDescription><abstract lang="en">Noonan syndrome (NS) is an autosomal dominant disorder comprising short stature, facial dysmorphism, short and/or webbed neck, heart defects, and cryptorchidism in males. The gene responsible for the disorder (PTPN11) was recently identified, and explains 30–50% of the cases clinically diagnosed as NS. Cardiofaciocutaneous (CFC) syndrome, a similar but distinct entity, is characterized by relative macrocephaly, characteristic facial appearance, ectodermal abnormalities (sparse and friable hair, sparse eyebrows, hyperkeratotic skin), congenital heart defects, and growth and mental retardation. We describe on a young woman who presents clinical features of NS (short stature, triangular facies, with dowslanting palpebral fissures and apparent hypertelorism, webbed neck, pulmonary stenosis, bleeding diathesis, prominent corneal nerves), but with a more prominent ectodermal involvement (sparse and very coarse hair, sparse eyebrows and eyelashes) and developmental delay/mental retardation, which are characteristic of CFC patients. Sequencing of the PTPN11 gene showed a T411M substitution, not previously described in patients with NS. The same mutation was found in her mother and older sister, not initially considered to be affected by NS, but with very subtle clinical findings compatible with this diagnosis. Molecular dynamic studies indicate that this new mutation, similar to other previously described mutations, favors a more active protein conformation. However, the main disruptive effect is not directly in the catalytic domain, suggesting that the location of this mutation could make the protein more susceptible to gene–gene or gene–environment interactions. Atypical cases of NS should be screened for mutations in the PTPN11 gene and in the case of a positive result, first‐degree relatives should also be tested for the specific mutation. © 2004 Wiley‐Liss, Inc.</abstract><subject lang="en"><genre>keywords</genre><topic>PTPN11</topic><topic>autosomal dominant disorder</topic><topic>Noonan syndrome</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><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>2004</date><detail type="volume"><caption>vol.</caption><number>130A</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>378</start><end>383</end><total>6</total></extent></part></relatedItem><identifier type="istex">F396A0B92187C3E38F563C7EBA3D795342A1F68D</identifier><identifier type="DOI">10.1002/ajmg.a.30270</identifier><identifier type="ArticleID">AJMG30270</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2004 Wiley‐Liss, 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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