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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Werner Syndrome" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2021/05/13" /><meta name="citation_author" content="Junko Oshima" /><meta name="citation_author" content="George M Martin" /><meta name="citation_author" content="Fuki M Hisama" /><meta name="citation_pmid" content="20301687" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1514/" /><meta name="citation_keywords" content="Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN" /><meta name="citation_keywords" content="WRN" /><meta name="citation_keywords" content="Werner Syndrome" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Werner Syndrome" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Junko Oshima" /><meta name="DC.Contributor" content="George M Martin" /><meta name="DC.Contributor" content="Fuki M Hisama" /><meta name="DC.Date" content="2021/05/13" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1514/" /><meta name="description" content="Werner syndrome is characterized by the premature appearance of features associated with normal aging and cancer predisposition. Individuals with Werner syndrome develop normally until the end of the first decade. The first sign is the lack of a growth spurt during the early teen years. Early findings (usually observed in the 20s) include loss and graying of hair, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. Myocardial infarction and cancer are the most common causes of death; the mean age of death in individuals with Werner syndrome is 54 years." /><meta name="og:title" content="Werner Syndrome" /><meta name="og:type" content="book" /><meta name="og:description" content="Werner syndrome is characterized by the premature appearance of features associated with normal aging and cancer predisposition. Individuals with Werner syndrome develop normally until the end of the first decade. The first sign is the lack of a growth spurt during the early teen years. Early findings (usually observed in the 20s) include loss and graying of hair, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK1514_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1514_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/weiss-kruszka/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/white-sutton/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK1514_"><span class="title" itemprop="name">Werner Syndrome</span></h1><p class="contrib-group"><span itemprop="author">Junko Oshima</span>, MD, PhD, <span itemprop="author">George M Martin</span>, MD, and <span itemprop="author">Fuki M Hisama</span>, MD.</p><a data-jig="ncbitoggler" href="#__NBK1514_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1514_ai__"><div class="contrib half_rhythm"><span itemprop="author">Junko Oshima</span>, MD, PhD<div class="affiliation small">Department of Pathology<br />University of Washington<br />Seattle, Washington<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.wu@dracip" class="oemail">ude.wu@dracip</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">George M Martin</span>, MD<div class="affiliation small">Department of Pathology and Genome Sciences<br />University of Washington<br />Seattle, Washington<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.wu@nitrammg" class="oemail">ude.wu@nitrammg</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Fuki M Hisama</span>, MD<div class="affiliation small">Division of Medical Genetics<br />Department of Medicine<br />University of Washington<br />Seattle, Washington<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.wu@2hmf" class="oemail">ude.wu@2hmf</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">December 2, 2002</span>; Last Update: <span itemprop="dateModified">May 13, 2021</span>.</p><p><em>Estimated reading time: 21 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="werner.Summary" itemprop="description"><h2 id="_werner_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Werner syndrome is characterized by the premature appearance of features associated with normal aging and cancer predisposition. Individuals with Werner syndrome develop normally until the end of the first decade. The first sign is the lack of a growth spurt during the early teen years. Early findings (usually observed in the 20s) include loss and graying of hair, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. Myocardial infarction and cancer are the most common causes of death; the mean age of death in individuals with Werner syndrome is 54 years.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of Werner syndrome is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with the following cardinal signs: bilateral ocular cataracts, premature graying and/or thinning of scalp hair, characteristic dermatologic pathology, and short stature. Identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>WRN</i> pathogenic variants on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> confirms the diagnosis if clinical features are inconclusive.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Surgical treatment of ocular cataracts using special techniques; cholesterol-lowering drugs if lipid profile is abnormal with statin treatment for those with low-density lipoprotein cholesterol levels >190 mg/dL; lifestyle counseling including tobacco avoidance, regular exercise, and maintenance of healthy weight; treatment of malignancies in a standard fashion; control of type 2 diabetes mellitus; standard treatment of osteoporosis; aggressive treatment of skin ulcers; skin care with trauma avoidance; fertility preservation treatments as needed.</p><p><i>Surveillance:</i> Annual ophthalmologic examination for cataracts; ten-year atherosclerotic cardiovascular disease risk estimation, annual lipid profile, surveillance for cardiovascular risk factors such as hypertension and diabetes mellitus; physical examination including neurologic assessment with attention to signs and symptoms of malignancies common in Werner syndrome; fasting glucose level, hemoglobin A1c, or oral glucose tolerance test annually; monitoring for osteoporosis, and annual skin examination for ulcers and lentiginous melanoma.</p><p><i>Agents/circumstances to avoid:</i> Smoking and obesity, which increase the risk for atherosclerosis. Smoking and alcohol increase the risk of osteoporosis and cataracts. Avoid falls, trauma to the extremities, and excessive sun exposure.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Werner syndrome is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being neither affected nor a carrier. Carrier testing for at-risk relatives and <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk are possible if the pathogenic variants in the family have been identified.</p></div></div><div id="werner.Diagnosis"><h2 id="_werner_Diagnosis_">Diagnosis</h2><div id="werner.Suggestive_Findings"><h3>Suggestive Findings</h3><p>The diagnosis of Werner syndrome <b>should be suspected</b> in individuals who have the following <b>cardinal signs</b> [<a class="bk_pop" href="#werner.REF.oshima.2017.105">Oshima et al 2017</a>]:</p><ul><li class="half_rhythm"><div>Bilateral ocular cataracts (present in 99%) *</div></li><li class="half_rhythm"><div>Premature graying and/or thinning of scalp hair (100%)</div></li><li class="half_rhythm"><div>Characteristic dermatologic pathology (96%)</div></li><li class="half_rhythm"><div>Short stature (95%)</div></li></ul><p>Approximately 91% of affected individuals have all four cardinal signs.</p><p>The clinical diagnosis may be further supported by the presence of the following <b>additional signs</b> and symptoms:</p><ul><li class="half_rhythm"><div>Thin limbs (present in 98%)</div></li><li class="half_rhythm"><div>Pinched facial features (96%)</div></li><li class="half_rhythm"><div>Osteoporosis (91%)</div></li><li class="half_rhythm"><div>Voice change (89%)</div></li><li class="half_rhythm"><div>Hypogonadism (80%)</div></li><li class="half_rhythm"><div>Type 2 diabetes mellitus (71%)</div></li><li class="half_rhythm"><div>Soft tissue calcification (67%)</div></li><li class="half_rhythm"><div>Neoplasm(s) (44%)</div></li><li class="half_rhythm"><div>Skin ulcers, usually of distal legs (40%)</div></li><li class="half_rhythm"><div>Atherosclerosis (30%)</div></li></ul><p>* Note: Percent frequencies are derived from individuals with a diagnosis of Werner syndrome confirmed by molecular testing.</p></div><div id="werner.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The clinical diagnosis of Werner syndrome <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> who has all four cardinal signs and two additional signs (definite) or the first three cardinal signs and two additional signs (probable). Identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>WRN</i> on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> confirms the diagnosis if clinical features are inconclusive (see <a href="/books/NBK1514/table/werner.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobwernerTmoleculargenetictestingused">Table 1</a>).</p><p>Similar diagnostic criteria have been proposed by <a class="bk_pop" href="#werner.REF.takemoto.2013.475">Takemoto et al [2013]</a>.</p><p>
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<b>Molecular genetic testing</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of <i>WRN</i> is performed first and followed by gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> if only one or no <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is found.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>WRN</i> and other genes of interest (see <a href="#werner.Differential_Diagnosis">Differential Diagnosis</a>) may also be considered. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>More comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (when available) including <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a> and <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a> may be considered if single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing (and/or use of a <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a> that includes <i>WRN</i>) fails to confirm a diagnosis in an individual with features of Werner syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation).</div><div class="half_rhythm">For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</div></li></ul><div id="werner.T.molecular_genetic_testing_used" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Werner Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1514/table/werner.T.molecular_genetic_testing_used/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__werner.T.molecular_genetic_testing_used_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_werner.T.molecular_genetic_testing_used_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_werner.T.molecular_genetic_testing_used_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_werner.T.molecular_genetic_testing_used_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_werner.T.molecular_genetic_testing_used_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>WRN</i>
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</td><td headers="hd_h_werner.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_werner.T.molecular_genetic_testing_used_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~97% <sup>4, 5</sup></td></tr><tr><td headers="hd_h_werner.T.molecular_genetic_testing_used_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>6</sup></td><td headers="hd_h_werner.T.molecular_genetic_testing_used_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">6 reported <sup>7</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="werner.TF.1.1"><p class="no_margin">See <a href="/books/NBK1514/#werner.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="werner.TF.1.2"><p class="no_margin">See <a href="#werner.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="werner.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="werner.TF.1.4"><p class="no_margin">Sequence analysis of the <i>WRN</i> <a class="def" href="/books/n/gene/glossary/def-item/coding-region/">coding region</a> detects <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in approximately 97% of affected individuals. The most common <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, c.1105C>T, accounts for 20%-25% of pathogenic variants in the European and Japanese populations [<a class="bk_pop" href="#werner.REF.yokote.2017.7">Yokote et al 2017</a>]. Founder variants have been identified in other populations (see <a href="/books/NBK1514/table/werner.T.notable_wrn_variants/?report=objectonly" target="object" rid-ob="figobwernerTnotablewrnvariants">Table 6</a>).</p></div></dd><dt>5. </dt><dd><div id="werner.TF.1.5"><p class="no_margin">Deep <a class="def" href="/books/n/gene/glossary/def-item/intronic/">intronic</a> pathogenic variants that affect <a class="def" href="/books/n/gene/glossary/def-item/splicing/">splicing</a> [<a class="bk_pop" href="#werner.REF.yokote.2017.7">Yokote et al 2017</a>] would not be detected by routine <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>.</p></div></dd><dt>6. </dt><dd><div id="werner.TF.1.6"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd><dt>7. </dt><dd><div id="werner.TF.1.7"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bk_pop" href="#werner.REF.stenson.2017.665">Stenson et al 2017</a>]. Pathogenic variants that occur in an <a class="def" href="/books/n/gene/glossary/def-item/intron/">intron</a> and create a new <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> as well as multiexon deletions and duplications have also been reported [<a class="bk_pop" href="#werner.REF.yokote.2017.7">Yokote et al 2017</a>].</p></div></dd></dl></div></div></div><p><b>Protein analysis.</b> In certain unusual instances, protein analysis may be useful when both pathogenic <i>WRN</i> alleles cannot be identified by <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>. Because the majority of <i>WRN</i> pathogenic variants are <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> and do not produce WRN protein (or rarely, produce truncated WRN), variants that are not detected by sequencing may be detectable by western blot or immunoblot analysis. Instances where protein analysis may supplement sequence analysis include the following:</p><ul><li class="half_rhythm"><div>When sequencing identifies only one <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> known not to produce WRN. If protein analysis failed to detect any WRN protein, it may be inferred that the second unidentified pathogenic <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> produced no or unstable WRN, thereby providing strong evidence for a diagnosis of Werner syndrome.</div></li><li class="half_rhythm"><div>When compound heterozygosity is identified, where one pathogenic <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> is known to confer WRN absence but a second <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variant is of uncertain clinical significance</div></li><li class="half_rhythm"><div>If protein analysis implicates a <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variant of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> in conferring protein instability, which would suggest that it is a pathogenic <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>. Such instances are rare.</div></li></ul></div></div><div id="werner.Clinical_Characteristics"><h2 id="_werner_Clinical_Characteristics_">Clinical Characteristics</h2><div id="werner.Clinical_Description"><h3>Clinical Description</h3><p>Werner syndrome is characterized by the premature appearance of features associated with normal aging and cancer predisposition. Individuals with Werner syndrome develop normally until the end of the first decade. The first symptom, often recognized retrospectively, is the lack of a growth spurt during the early teen years.</p><p>Symptoms typically start in the 20s. Initial findings include loss and graying of hair, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. Median age of diagnosis ranges from late 30s to 40s [<a class="bk_pop" href="#werner.REF.oshima.2017.105">Oshima et al 2017</a>, <a class="bk_pop" href="#werner.REF.takemoto.2013.475">Takemoto et al 2013</a>].</p><p><b>Cataracts.</b> Median age of onset of cataracts is approximately 31 years [<a class="bk_pop" href="#werner.REF.oshima.2017.105">Oshima et al 2017</a>]. Bilateral cataracts are universal, and progress rapidly in individuals with Werner syndrome. Complications from surgical treatment are common and include (among others) wound dehiscence, peripheral anterior synechiae, epiretinal membrane formation, and cystoid macular edema [<a class="bk_pop" href="#werner.REF.lyons.2019.1371">Lyons et al 2019</a>]. Specific intraoperative and postoperative techniques (phacoemulsification, small incision size, use of viscoelastic to protect corneal endothelium, use of a weak topical steroid to avoid suppression of fibroblast proliferation) have been reviewed [<a class="bk_pop" href="#werner.REF.lyons.2019.1371">Lyons et al 2019</a>] in order to optimize outcome.</p><p><b>Facial features.</b> A characteristic facial appearance, termed "bird-like" because of the pinched appearance at the bridge of the nose, evolves during the third or fourth decade.</p><p><b>Cardiovascular.</b> Affected individuals exhibit several forms of arteriosclerosis; the most serious form, coronary artery atherosclerosis, may lead to myocardial infarction, which, together with cancer, is the most common cause of death. The mean age of death in individuals with Werner syndrome is 54 years [<a class="bk_pop" href="#werner.REF.oshima.2017.105">Oshima et al 2017</a>]. Similarly, the median life span of Japanese individuals with Werner syndrome is 53 years [<a class="bk_pop" href="#werner.REF.goto.2013.13">Goto et al 2013</a>].</p><p><b>Malignancy.</b> The spectrum of cancers in individuals with Werner syndrome is unusual in that it includes a large number of sarcomas and very rare cancer types in typical locations [<a class="bk_pop" href="#werner.REF.lauper.2013.e59709">Lauper et al 2013</a>]. The most common cancers in Japanese individuals (for whom the most data exist) are soft-tissue sarcomas, osteosarcomas, melanomas, and thyroid carcinomas. Acral lentiginous melanomas (most often observed on the feet and nasal mucosa) are particularly prevalent compared to levels observed in the general population [<a class="bk_pop" href="#werner.REF.lauper.2013.e59709">Lauper et al 2013</a>]. Common types of carcinomas have also been observed.</p><p><b>Osteoporosis.</b> The osteoporosis of individuals with Werner syndrome is unusual in that it preferentially affects the long bones [<a class="bk_pop" href="#werner.REF.mori.2021.146">Mori et al 2021</a>]. In contrast, osteoporosis during normative aging preferentially involves the vertebral bodies, particularly in women. Characteristic osteolytic lesions of the distal phalanges of the fingers are observed on radiograph.</p><p><b>Skin.</b> Deep, chronic ulcers around the ankles (Achilles tendon, medial malleolus, lateral malleolus) are highly characteristic [<a class="bk_pop" href="#werner.REF.kubota.2021.153">Kubota et al 2021</a>].</p><p><b>Neurologic.</b> Controversy exists concerning the degree to which the brain is involved. While individuals with Werner syndrome may have cerebrovascular disease resulting in stroke, they do not appear to be unusually susceptible to Alzheimer disease. Cognitive changes are not typically observed. Diffuse changes observed on brain MRI in some individuals warrant further investigation in research studies [<a class="bk_pop" href="#werner.REF.de_stefano.2003.1169">De Stefano et al 2003</a>].</p><p><b>Fertility.</b> Fertility appears to decline soon after sexual maturity. This decline in fertility is associated with testicular atrophy and probable accelerated rate of loss of primordial follicles in the ovaries, although data are sparse. Early menopause is common in women, as are multiple miscarriages, but successful pregnancies have also been reported. Men have fathered children, usually at younger ages than in the general population.</p></div><div id="werner.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>The chronologic order of the onset of signs and symptoms is similar in all individuals with Werner syndrome regardless of the specific <i>WRN</i> pathogenic variants.</p><p>The specific cell type in which cancer develops may depend on the type of <i>WRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> present. In individuals of Japanese descent, papillary thyroid carcinoma has been associated with an N-terminal variant, whereas follicular thyroid carcinoma is more frequently observed with a C-terminal variant [<a class="bk_pop" href="#werner.REF.ishikawa.1999.1345">Ishikawa et al 1999</a>]. This finding clearly contradicts the original assumption that all identified <i>WRN</i> pathogenic variants result in truncation of the nuclear localization signal of WRN protein and thereby act as <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> variants.</p><p>The <a href="/books/NBK1514/table/werner.T.notable_wrn_variants/?report=objectonly" target="object" rid-ob="figobwernerTnotablewrnvariants">p.Arg834Cys</a> <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> is common in Latino populations, and results in reduced helicase and exonuclease activity in vitro, but multiple Mexican individuals <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> for the allele have been reported to have no clinical features of Werner syndrome [<a class="bk_pop" href="#werner.REF.kamathloeb.2017.44081">Kamath-Loeb et al 2017</a>].</p></div><div id="werner.Nomenclature"><h3>Nomenclature</h3><p>An older term for Werner syndrome was "progeria of the adult" (to distinguish it from the <a href="/books/n/gene/hgps/">Hutchinson-Gilford progeria syndrome,</a> which was often referred to as progeria of childhood).</p></div><div id="werner.Prevalence"><h3>Prevalence</h3><p>The prevalence of Werner syndrome varies with the level of <a class="def" href="/books/n/gene/glossary/def-item/consanguinity/">consanguinity</a> in populations.</p><p>Apparent <i>WRN</i> founder variants contribute to higher prevalence in some populations. In the Japanese, the frequency ranges from about 1:20,000 to 1:40,000, based on the frequencies of detectable <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic variants [<a class="bk_pop" href="#werner.REF.yokote.2017.7">Yokote et al 2017</a>]. This is most likely the result of a <a class="def" href="/books/n/gene/glossary/def-item/founder-variant/">founder variant</a> in the Japanese population. Similarly, in the Sardinian population, the frequency is estimated at 1:50,000 [<a class="bk_pop" href="#werner.REF.yokote.2017.7">Yokote et al 2017</a>].</p><p>Based on the population <a class="def" href="/books/n/gene/glossary/def-item/allele-frequency/">allele frequency</a> of the most common <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, <a href="/books/NBK1514/table/werner.T.notable_wrn_variants/?report=objectonly" target="object" rid-ob="figobwernerTnotablewrnvariants">c.1105C>T</a>, which accounts for approximately 20% of pathogenic alleles, the prevalence of Werner syndrome is estimated at 1:380,000-1:1,000,000.</p></div></div><div id="werner.Genetically_Related_Allelic_Disor"><h2 id="_werner_Genetically_Related_Allelic_Disor_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> pathogenic variants in <i>WRN</i>.</p></div><div id="werner.Differential_Diagnosis"><h2 id="_werner_Differential_Diagnosis_">Differential Diagnosis</h2><p>The differential diagnosis depends on the presenting symptoms and age of onset.</p><div id="werner.T.genetic_disorders_in_the_differ" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Genetic Disorders in the Differential Diagnosis of Werner Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1514/table/werner.T.genetic_disorders_in_the_differ/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__werner.T.genetic_disorders_in_the_differ_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Presenting Symptoms</th><th id="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Other Features / Comments</th></tr></thead><tbody><tr><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_1" rowspan="5" scope="row" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">Progeroid features</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_2" rowspan="3" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">
|
||
<i>LMNA</i>
|
||
</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">Atypical Werner syndrome <sup>1</sup></td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_4" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_5" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">Usually earlier onset (early 20s or earlier) & faster rate of progression of symptoms than in typical Werner syndrome</td></tr><tr><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_3" colspan="1" scope="row" rowspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;"><a href="/books/n/gene/hgps/">Hutchinson-Gilford progeria syndrome</a> (HGPS, progeria of childhood) <sup>2</sup></td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_4" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_5" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">Like Werner syndrome, affects multiple organs w/presentations characterized as accelerated aging. Typically healthy at birth; profound FTT occurs in 1st yr. Death (usually from complications of cardiac or cerebrovascular disease) generally by age 6-20 yrs</td></tr><tr><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_3" colspan="1" scope="row" rowspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">Mandibuloacral dysplasia w/type A lipodystrophy (OMIM <a href="https://omim.org/entry/248370" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">248370</a>)</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_4" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_5" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">Characterized by growth deficiency, mandibular hypoplasia, progressive osteolysis of distal phalanges & clavicles, & acral lipodystrophy w/normal fat in neck & trunk</td></tr><tr><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_2" colspan="1" scope="row" rowspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">
|
||
<i>POLD1</i>
|
||
</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">Mandibular hypoplasia, deafness, progeroid features, & lipodystrophy (MDPL) syndrome (OMIM <a href="https://omim.org/entry/615381" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615381</a>)</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_4" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_5" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">Unlike Werner syndrome, ocular cataracts are not a feature of MDPL syndrome & risk of malignancy does not appear increased.</td></tr><tr><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_2" colspan="1" scope="row" rowspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">
|
||
<i>ZMPSTE24</i>
|
||
</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">Mandibuloacral dysplasia w/type B lipodystrophy (OMIM <a href="https://omim.org/entry/608612" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">608612</a>)</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_4" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_5" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">Onset at birth or early childhood of mandibular hypoplasia w/prominent eyes, atrophic skin, acroosteolysis, & lipodystrophy</td></tr><tr><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_1" rowspan="2" scope="row" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">Young adult-onset cataracts</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_2" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">
|
||
<i>CNBP</i>
|
||
</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;"><a href="/books/n/gene/myotonic-d2/">Myotonic dystrophy type 2</a> (DM2)</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_4" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_5" rowspan="2" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">May be considered w/young-adult onset cataracts, & adults may show muscle wasting, but other manifestations (e.g., myotonia or cardiac conduction abnormalities) are quite different & onset is usually in adulthood.</td></tr><tr><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_2" colspan="1" scope="row" rowspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">
|
||
<i>DMPK</i>
|
||
</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/myotonic-d/">Myotonic dystrophy type 1</a>
|
||
</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_4" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">AD</td></tr><tr><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_1" rowspan="3" scope="row" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">Cancer</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_2" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">
|
||
<i>BLM</i>
|
||
</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/bloom/">Bloom syndrome</a>
|
||
</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_4" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_5" rowspan="2" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">May be considered if cancer is presenting symptom, but RTS & Bloom syndrome are childhood-onset disorders. Also, Werner syndrome cells do not exhibit ↑ <a class="def" href="/books/n/gene/glossary/def-item/sister-chromatid-exchange/">sister chromatid exchange</a> typical of Bloom syndrome.</td></tr><tr><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_2" colspan="1" scope="row" rowspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">
|
||
<i>RECQL4</i>
|
||
</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;"><a href="/books/n/gene/rts/">Rothmund-Thomson syndrome</a> (RTS)</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_4" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">AR</td></tr><tr><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_2" colspan="1" scope="row" rowspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">
|
||
<i>TP53</i>
|
||
</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;"><a href="/books/n/gene/li-fraumeni/">Li-Fraumeni syndrome</a> (LFS)</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_4" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_5" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">May present w/multiple cancers, incl non-epithelial cancers similar to those in Werner syndrome, but juvenile-onset cataracts & other manifestations of Werner syndrome are not part of LFS.</td></tr><tr><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Progeria-like facies & lipodystrophy</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PIK3R1</i>
|
||
</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/short/">SHORT syndrome</a>
|
||
</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May incl progeria-like facies & lipodystrophy, type 2 diabetes mellitus, cataracts, & glaucoma</td></tr><tr><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Premature graying in adults</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TFAP2A</i>
|
||
</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/bofs/">Branchiooculofacial syndrome</a>
|
||
</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_werner.T.genetic_disorders_in_the_differ_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eye findings typically incl strabismus, coloboma, & microphthalmia; <a class="def" href="/books/n/gene/glossary/def-item/dysmorphic/">dysmorphic</a> facial features are also present.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; FTT = failure to thrive; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; SHORT = <i>s</i>hort stature, <i>h</i>yperextensibility, hernia, <i>o</i>cular depression, <i>R</i>ieger anomaly, & <i>t</i>eething delay</p></div></dd><dt>1. </dt><dd><div id="werner.TF.2.1"><p class="no_margin">A small subset of persons in the Werner Syndrome Registry have normal WRN protein and some signs and symptoms that sufficiently overlap with Werner syndrome. Among this group, approximately 15% had novel <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants in <i>LMNA</i> [<a class="bk_pop" href="#werner.REF.oshima.2014.239">Oshima & Hisama 2014</a>].</p></div></dd><dt>2. </dt><dd><div id="werner.TF.2.2"><p class="no_margin">Classic Hutchinson-Gilford progeria syndrome is defined by the presence of the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> c.1824C>T.</p></div></dd></dl></div></div></div><p><b>Early-onset type 2 diabetes</b> with secondary complications of vascular disease and skin complications could mimic some features of Werner syndrome.</p><p><b>Isolated</b>
|
||
<b>cataracts.</b>
|
||
Isolated <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a>, infantile, or juvenile cataracts are not likely to be a feature of Werner syndrome. (Although bilateral ocular cataracts – more commonly posterior subcapsular rather than nuclear cataracts – are one of the most commonly observed features of Werner syndrome, the age of onset is typically in the second decade, when graying of hair and skin findings would likely be present.)</p></div><div id="werner.Management"><h2 id="_werner_Management_">Management</h2><div id="werner.Evaluations_Following_Initial_Dia"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with Werner syndrome, the evaluations summarized in <a href="/books/NBK1514/table/werner.T.recommended_evaluations_followi/?report=objectonly" target="object" rid-ob="figobwernerTrecommendedevaluationsfollowi">Table 3</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="werner.T.recommended_evaluations_followi" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Werner Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1514/table/werner.T.recommended_evaluations_followi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__werner.T.recommended_evaluations_followi_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_werner.T.recommended_evaluations_followi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_werner.T.recommended_evaluations_followi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_werner.T.recommended_evaluations_followi_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Eyes</b>
|
||
</td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic eval incl slit lamp exam for cataracts; eval for glaucoma & diabetic retinopathy</td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_3" rowspan="4" colspan="1" style="text-align:left;vertical-align:middle;">At diagnosis</td></tr><tr><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiovascular</b>
|
||
</td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Use of a 10-yr risk calculator & assessment of risk factors</div></li><li class="half_rhythm"><div>Lipid profile</div></li><li class="half_rhythm"><div>Blood pressure</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Malignancy</b>
|
||
</td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical exam for cancers common in Werner syndrome (e.g., thyroid nodules, skin tumors)</td></tr><tr><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Endocrine</b>
|
||
</td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Screening for type 2 diabetes mellitus by standard clinical assays incl fasting glucose level, hemoglobin A1c, or oral glucose tolerance test</div></li><li class="half_rhythm"><div>Ask about menstrual cycle (women) or sexual dysfunction (men) to screen for hypogonadism.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Skeletal</b>
|
||
</td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Bone mineral density screening</div></li><li class="half_rhythm"><div>Encourage adequate intake of calcium, vitamin D.</div></li><li class="half_rhythm"><div>Counsel on fall prevention & weight-bearing exercise.</div></li></ul>
|
||
</td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Beginning at age 40 yrs</td></tr><tr><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Integument</b>
|
||
</td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Skin exam for common findings, esp calluses or early ulcerations of elbows & lower legs; special attn to nail beds & soles of feet for lentiginous melanoma</td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At diagnosis</td></tr><tr><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Head MRI if neurologic symptoms incl new-onset seizures, focal neurologic signs such as weakness or visual field defect, or symptoms such as diploplia or headache</td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">These signs/symptoms can be indicative of meningioma, a common neoplasm in Werner syndrome.</td></tr><tr><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic counseling</b>
|
||
</td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & families re nature, MOI, & implications of Werner syndrome to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Psychosocial</b>
|
||
</td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment of coping & psychological fitness in light of prognosis</td><td headers="hd_h_werner.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At diagnosis</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a></p></div></dd><dt>1. </dt><dd><div id="werner.TF.3.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="werner.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div id="werner.T.treatment_of_manifestations_in" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Werner Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1514/table/werner.T.treatment_of_manifestations_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__werner.T.treatment_of_manifestations_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/<br />Concern</th><th id="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cataracts</b>
|
||
</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Surgical treatment of ocular cataracts</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cystic macular edema is a postsurgical complication [<a class="bk_pop" href="#werner.REF.lyons.2019.1371">Lyons et al 2019</a>].</td></tr><tr><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Atherosclerosis</b>
|
||
</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Use of cholesterol-lowering drugs if lipid profile is abnormal w/statin treatment for those w/LDL cholesterol levels >190 mg/dL</div></li><li class="half_rhythm"><div>Primary prevention per current guidelines [<a class="bk_pop" href="#werner.REF.arnett.2019.e596">Arnett et al 2019</a>]</div></li><li class="half_rhythm"><div>Evaluate stable angina w/cardiac stress testing per current guidelines.</div></li></ul>
|
||
</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In persons w/Werner syndrome, >80%-100% achieve target levels on statin therapy [<a class="bk_pop" href="#werner.REF.tsukamoto.2021.133">Tsukamoto et al 2021</a>].</td></tr><tr><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Malignancy</b>
|
||
</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment of malignancies</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Type 2 diabetes</b>
|
||
<br />
|
||
<b>mellitus</b>
|
||
</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Control of type 2 diabetes mellitus; favorable results reported w/use of thiazolidine, metformin, & sitagliptin</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a class="bk_pop" href="#werner.REF.watanabe.2013.e119">Watanabe et al [2013]</a>, <a class="bk_pop" href="#werner.REF.takemoto.2021.142">Takemoto et al [2021]</a></td></tr><tr><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Osteoporosis</b>
|
||
</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treat osteoporosis per current guidelines [<a class="bk_pop" href="#werner.REF.cosman.2014.2359">Cosman et al 2014</a>]. Options incl: bisphosphonates, teriparatide. In women: calcitonin, estrogen/hormone therapy.</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#werner.REF.cosman.2014.2359">Cosman et al [2014]</a>
|
||
</td></tr><tr><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Skin ulcers</b>
|
||
</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Aggressive treatment of skin ulcers w/debridement, topical medication to promote moist environment & wound healing, negative pressure wound therapy & skin grafting or flap surgery</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#werner.REF.kubota.2021.153">Kubota et al [2021]</a>
|
||
</td></tr><tr><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Bosentan</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a class="bk_pop" href="#werner.REF.matuccicerinic.2011.32">Matucci-Cerinic et al [2011]</a>
|
||
</td></tr><tr><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Reduced fertility /</b>
|
||
<br />
|
||
<b>Infertility</b>
|
||
</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fertility preservation may be achieved w/oocyte cryopreservation, sperm banking, or embryo banking.</td><td headers="hd_h_werner.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Affected persons may benefit from consultation w/reproductive endocrinology infertility specialist.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">LDL = low-density lipoprotein</p></div></dd></dl></div></div></div></div><div id="werner.Surveillance"><h3>Surveillance</h3><div id="werner.T.recommended_surveillance_for_in" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Werner Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1514/table/werner.T.recommended_surveillance_for_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__werner.T.recommended_surveillance_for_in_lrgtbl__"><table><thead><tr><th id="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cataracts</b>
|
||
</td><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic exam</td><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_3" rowspan="5" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Atherosclerosis</b>
|
||
</td><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Use of a 10-yr risk calculator</div></li><li class="half_rhythm"><div>Lipid profile</div></li><li class="half_rhythm"><div>Blood pressure</div></li><li class="half_rhythm"><div>Lifestyle counseling: diet rich in fruits & vegetables, tobacco avoidance, regular exercise, healthy weight</div></li><li class="half_rhythm"><div>Std clinical assessment for atherosclerosis risk, signs/symptoms of angina, & peripheral or cerebrovascular disease</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Malignancy</b>
|
||
</td><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Physical exam for malignancies common in Werner syndrome</div></li><li class="half_rhythm"><div>Incl neurologic assessment for signs/symptoms of intracranial tumors.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Type 2 diabetes</b>
|
||
<br />
|
||
<b>mellitus</b>
|
||
</td><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fasting glucose level, hemoglobin A1c, or oral glucose tolerance test</td></tr><tr><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hypogonadism</b>
|
||
</td><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ask about menstrual cycle (women) or sexual dysfunction (men).</td></tr><tr><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Skeletal</b>
|
||
</td><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bone mineral density by dual-energy x-ray absorptiometry</td><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency depends on initial Z score.</td></tr><tr><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Integument</b>
|
||
</td><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Prevention of calluses & ulcers w/orthotics, changing limb position, & padding to avoid pressure sores; eval of ulcers for any assoc malignancy</td><td headers="hd_h_werner.T.recommended_surveillance_for_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr></tbody></table></div></div></div><div id="werner.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Smoking and obesity increase the risk of atherosclerosis.</p><p>Smoking and alcohol ingestion increase the risk of osteoporosis and cataracts.</p><p>Falls resulting in fracture can be prevented or reduced by adding grab bars in the bathroom, eliminating slippery surfaces and tripping hazards, and providing adequate lighting.</p><p>Avoid trauma to the extremities and prolonged pressure to the elbows, feet, and ankles, where ulcers commonly form.</p><p>Avoidance of excessive sun exposure, use of sunscreen, protective clothing, and UV blocking sunglasses may reduce the risk of skin cancer (including melanoma) and cataracts.</p></div><div id="werner.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to evaluate apparently asymptomatic older and younger sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>/at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include:</p><ul><li class="half_rhythm"><div>Molecular genetic testing if the pathogenic variants in the family are known;</div></li><li class="half_rhythm"><div>Clinical examination including growth assessment, skin examination, and ophthalmology evaluation including slit lamp examination if the pathogenic variants in the family are not known.</div></li></ul><p>See <a href="#werner.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="werner.Pregnancy_Management"><h3>Pregnancy Management</h3><p>In one study of individuals with Werner syndrome, signs of hypogonadism were reported in 80%; however, approximately half of those had children and showed signs of hypogonadism after age 30 years [<a class="bk_pop" href="#werner.REF.goto.1997.239">Goto 1997</a>]. Reports in the medical literature of pregnancy in individuals with Werner syndrome are rare; however, many of the women in the <a href="http://www.pathology.washington.edu/research/werner/registry/registry.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">International Registry of Werner Syndrome</a> have had offspring. Preterm delivery has been reported in several cases, and has been attributed to cervical incompetence [<a class="bk_pop" href="#werner.REF.so_ekpastuszka.2011.201">Sołek-Pastuszka et al 2011</a>]. Preeclampsia is another reported obstetric complication.</p><p>The use of assisted reproductive technologies such as in vitro fertilization and egg donation has not been reported in women with Werner syndrome.</p></div><div id="werner.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="werner.Genetic_Counseling"><h2 id="_werner_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="werner.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Werner syndrome is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div><div id="werner.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one <i>WRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> based on family history).</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> to confirm that both parents are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>WRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and to allow reliable <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>One of the pathogenic variants identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> occurred as a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> event in the proband or as a <a class="def" href="/books/n/gene/glossary/def-item/postzygotic/">postzygotic</a> <i>de novo</i> event in a mosaic parent [<a class="bk_pop" href="#werner.REF.j_nsson.2017.519">Jónsson et al 2017</a>].</div></li><li class="half_rhythm"><div>Uniparental isodisomy for the parental <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> with the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> resulted in homozygosity for the pathogenic variant in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li></ul></li><li class="half_rhythm"><div>Although systematic clinical studies have not been reported, heterozygotes (carriers) are asymptomatic and do not appear to be at increased risk of developing the disorder.</div></li></ul><p>
|
||
<b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>If both parents are known to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>WRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier.</div></li><li class="half_rhythm"><div>Although systematic clinical studies have not been reported, heterozygotes (carriers) are asymptomatic and do not appear to be at increased risk of developing the disorder.</div></li></ul><p>
|
||
<b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>The offspring of an individual with Werner syndrome are obligate heterozygotes (carriers) for a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>WRN</i>.</div></li><li class="half_rhythm"><div>Due to the very low prevalence in the US population, the risk for Werner syndrome in the offspring of an affected individual is negligible unless the affected individual and his/her reproductive partner are <a class="def" href="/books/n/gene/glossary/def-item/consanguineous/">consanguineous</a>.</div></li><li class="half_rhythm"><div>In Japan, where heterozygotes may be as common as one in 150, the risk for Werner syndrome in an offspring is still less than 1/500.</div></li></ul><p><b>Other family members.</b> Each sib of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents is at a 50% risk of being a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> of a <i>WRN</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div><div id="werner.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>WRN</i> pathogenic variants in the family.</p></div><div id="werner.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#werner.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic alteration/s are unknown).</p></div><div id="werner.Prenatal_Testing_and_Preimplantat"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>WRN</i> pathogenic variants have been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="werner.Resources"><h2 id="_werner_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>MedlinePlus</b>
|
||
</div><div>
|
||
<a href="https://medlineplus.gov/genetics/condition/werner-syndrome/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Werner syndrome</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>National Organization for Rare Disorders (NORD)</b>
|
||
</div><div>
|
||
<a href="http://rarediseases.org/rare-diseases/werner-syndrome/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Werner Syndrome</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>NCBI Genes and Disease</b>
|
||
</div><div>
|
||
<a href="/books/NBK22252/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Werner syndrome</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>International Registry of Werner Syndrome</b>
|
||
</div><div>University of Washington School of Medicine, Department of Pathology</div><div>Box 357470</div><div>Seattle WA 98195-7470</div><div><b>Phone:</b> 206-543-5088</div><div><b>Fax:</b> 206-685-8356</div><div><b>Email:</b> kshih@u.washington.edu</div><div>
|
||
<a href="http://www.pathology.washington.edu/research/werner/registry/registry.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">International Registry of Werner Syndrome</a>
|
||
</div></li></ul>
|
||
</div><div id="werner.Molecular_Genetics"><h2 id="_werner_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="werner.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Werner Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1514/table/werner.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__werner.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_werner.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_werner.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_werner.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_werner.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_werner.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_werner.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_werner.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/7486" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>WRN</i>
|
||
</a>
|
||
</td><td headers="hd_b_werner.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=7486" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">8p12</a>
|
||
</td><td headers="hd_b_werner.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q14191" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN</a>
|
||
</td><td headers="hd_b_werner.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.pathology.washington.edu/research/werner/database/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Werner Syndrome Mutational Database</a>
|
||
<br />
|
||
<a href="http://databases.lovd.nl/shared/genes/WRN" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">WRN database</a>
|
||
</td><td headers="hd_b_werner.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=WRN" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">WRN</a>
|
||
</td><td headers="hd_b_werner.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=WRN[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">WRN</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="werner.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="werner.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Werner Syndrome (<a href="/omim/277700,604611" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1514/table/werner.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__werner.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/277700" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">277700</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">WERNER SYNDROME; WRN</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/604611" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">604611</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">RECQ PROTEIN-LIKE 2; RECQL2</td></tr></tbody></table></div></div><div id="werner.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>WRN</i> encodes a multifunctional nuclear protein that is a member of the RecQ family of DNA helicases [<a class="bk_pop" href="#werner.REF.yu.1996.258">Yu et al 1996</a>]. DNA-type helicases are ATP-dependent 3'→ 5' helicases that are necessary to maintain <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> integrity in cells. The N-terminal region of the protein encoded by <i>WRN</i> has exonuclease activity as well.</p><p>Studies suggest that WRN protein is involved in DNA repair, <a class="def" href="/books/n/gene/glossary/def-item/recombination/">recombination</a>, replication, and transcription as well as combined functions such as DNA repair during replication. WRN protein can potentially unwind or digest aberrant DNA structures accidentally generated during various DNA metabolic processes and can also regulate DNA recombination and repair processes by unwinding or digesting intermediate DNA structures. WRN protein is also involved in the maintenance of telomeres. These findings are consistent with the notion that WRN plays a role in maintenance of <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> stability [<a class="bk_pop" href="#werner.REF.croteau.2014.519">Croteau et al 2014</a>].</p><p>More than 90 different <i>WRN</i> pathogenic variants have been identified. The majority of pathogenic variants are stop codons, insertions, or deletions that result in a frameshift, or a splice donor or acceptor site variant that results in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> skipping. Several <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants that abolish helicase activity or confer protein instability have been reported. Pathogenic variants that occur in an <a class="def" href="/books/n/gene/glossary/def-item/intron/">intron</a> and result in creation of a new exon as well as multiexon deletions and duplications have also been reported [<a class="bk_pop" href="#werner.REF.yokote.2017.7">Yokote et al 2017</a>].</p><p><b>Mechanism of disease causation.</b> Loss of function</p><div id="werner.T.notable_wrn_variants" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Notable <i>WRN</i> Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1514/table/werner.T.notable_wrn_variants/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__werner.T.notable_wrn_variants_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_werner.T.notable_wrn_variants_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference<br />Sequences</th><th id="hd_h_werner.T.notable_wrn_variants_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_werner.T.notable_wrn_variants_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_werner.T.notable_wrn_variants_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_1" rowspan="7" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000553.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000553<wbr style="display:inline-block"></wbr>.6</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000544.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000544<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.2500C>T</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg834Cys</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variant common in Latino population (<a class="def" href="/books/n/gene/glossary/def-item/heterozygote/">heterozygote</a> frequency of 0.02); significantly reduces helicase & exonuclease activity in vitro. Homozygotes do not exhibit a Werner syndrome <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> [<a class="bk_pop" href="#werner.REF.kamathloeb.2017.44081">Kamath-Loeb et al 2017</a>].</td></tr><tr><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1105C>T</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg369Ter</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Most common <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> worldwide; accounts for 20%-25% of pathogenic variants in the European & Japanese populations [<a class="bk_pop" href="#werner.REF.yokote.2017.7">Yokote et al 2017</a>]</td></tr><tr><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2089-3024A>G</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 1.</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">A <a class="def" href="/books/n/gene/glossary/def-item/founder-variant/">founder variant</a> in the Sardinian population [<a class="bk_pop" href="#werner.REF.yokote.2017.7">Yokote et al 2017</a>]</td></tr><tr><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2179dupT</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Cys727LeufsTer5</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Potential <a class="def" href="/books/n/gene/glossary/def-item/founder-variant/">founder variant</a> in the Moroccan population [<a class="bk_pop" href="#werner.REF.yokote.2017.7">Yokote et al 2017</a>]</td></tr><tr><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.3139-1G>C</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 2.</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Founder variant in the Japanese population; accounts for ~60% of variants in affected persons in this group [<a class="bk_pop" href="#werner.REF.yokote.2017.7">Yokote et al 2017</a>]</td></tr><tr><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.3460-2A>C</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 3.</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Potential <a class="def" href="/books/n/gene/glossary/def-item/founder-variant/">founder variant</a> in the Turkish population [<a class="bk_pop" href="#werner.REF.yokote.2017.7">Yokote et al 2017</a>]</td></tr><tr><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.3590delA</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asn1197ThrfsTer2</td><td headers="hd_h_werner.T.notable_wrn_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Potential <a class="def" href="/books/n/gene/glossary/def-item/founder-variant/">founder variant</a> in the Dutch population [<a class="bk_pop" href="#werner.REF.yokote.2017.7">Yokote et al 2017</a>]</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd><dt>1. </dt><dd><div id="werner.TF.6.1"><p class="no_margin">Creates a new <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> between exons 18 and 19 that introduces a stop codon and alters the length of the protein [<a class="bk_pop" href="#werner.REF.yokote.2017.7">Yokote et al 2017</a>]</p></div></dd><dt>2. </dt><dd><div id="werner.TF.6.2"><p class="no_margin">Results in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 26 skipping</p></div></dd><dt>3. </dt><dd><div id="werner.TF.6.3"><p class="no_margin">Results in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 30 <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a></p></div></dd></dl></div></div></div></div></div><div id="werner.Chapter_Notes"><h2 id="_werner_Chapter_Notes_">Chapter Notes</h2><div id="werner.Author_Notes"><h3>Author Notes</h3><p><a href="http://www.pathology.washington.edu/research/werner/registry/registry.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">International Registry of Werner Syndrome</a><br />Phone: 206-543-5088 <br />Fax: 206-685-6356</p></div><div id="werner.Author_History"><h3>Author History</h3><p>Nancy Hanson, MS, CGC; University of Washington (2002-2011)<br />Fuki M Hisama, MD (2011-present)<br />Dru F Leistritz, MS, CGC; University of Washington (2002-2011)<br />George M Martin, MD (2002-present)<br />Junko Oshima, MD, PhD (2002-present)</p></div><div id="werner.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>13 May 2021 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>29 September 2016 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>27 March 2014 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>13 December 2012 (cd) Revision: <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> available clinically</div></li><li class="half_rhythm"><div>1 November 2012 (cd) Revision: <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> available clinically</div></li><li class="half_rhythm"><div>9 February 2012 (cd) Revision: protein analysis clinically available</div></li><li class="half_rhythm"><div>29 December 2011 (cd) Revision: <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> and <a class="def" href="/books/n/gene/glossary/def-item/carrier-testing/">carrier testing</a> available clinically</div></li><li class="half_rhythm"><div>17 November 2011 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>8 March 2007 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>13 January 2005 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>16 March 2004 (nh) Revision: Normal allelic variants</div></li><li class="half_rhythm"><div>2 December 2002 (me) Review posted live</div></li><li class="half_rhythm"><div>30 July 2002 (nh) Original submission</div></li></ul></div></div><div id="werner.References"><h2 id="_werner_References_">References</h2><div id="werner.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="werner.REF.arnett.2019.e596">Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Himmelfarb CD, Khera A, Lloyd-Jones D, McEvoy JW, Michos ED, Miedema MD, Munoz D, Smith SC Jr, Virani SS, Williams KA, Yeboah J, Ziaeian B. ACC/AHA guideline on the primary prevention of cardiovascular disease (2019). <span><span class="ref-journal">Circulation. </span>2019;<span class="ref-vol">140</span>:e596–e646.</span> [<a href="/pmc/articles/PMC7734661/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7734661</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30879355" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30879355</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.cosman.2014.2359">Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R. Clinician's guide to prevention and treatment of osteoporosis. <span><span class="ref-journal">Osteoporos Int. </span>2014;<span class="ref-vol">25</span>:2359–81.</span> [<a href="/pmc/articles/PMC4176573/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4176573</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25182228" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25182228</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.croteau.2014.519">Croteau DL, Popuri V, Opresko PL, Bohr VA. Human RecQ helicases in DNA repair, recombination, and replication. <span><span class="ref-journal">Annu Rev Biochem. </span>2014;<span class="ref-vol">83</span>:519–52.</span> [<a href="/pmc/articles/PMC4586249/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4586249</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24606147" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24606147</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.de_stefano.2003.1169">De Stefano N, Dotti MT, Battisti C, Sicurelli F, Stromillo ML, Mortilla M, Federico A. MR evidence of structural and metabolic changes in brains of patients with Werner's syndrome. <span><span class="ref-journal">J Neurol. </span>2003;<span class="ref-vol">250</span>:1169–73.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14586596" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14586596</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.goto.1997.239">Goto M. Hierarchical deterioration of body systems in Werner's syndrome: implications for normal ageing. <span><span class="ref-journal">Mech Ageing Dev. </span>1997;<span class="ref-vol">98</span>:239–54.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9352493" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9352493</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.goto.2013.13">Goto M, Ishikawa Y, Sugimoto M, Furuichi Y. Werner syndrome: a changing pattern of clinical manifestations in Japan (1917~2008). <span><span class="ref-journal">Biosci Trends. </span>2013;<span class="ref-vol">7</span>:13–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23524889" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23524889</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.ishikawa.1999.1345">Ishikawa Y, Sugano H, Matsumoto T, Furuichi Y, Miller RW, Goto M. Unusual features of thyroid carcinomas in Japanese patients with Werner syndrome and possible genotype-phenotype relations to cell type and race. <span><span class="ref-journal">Cancer. </span>1999;<span class="ref-vol">85</span>:1345–52.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10189141" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10189141</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.j_nsson.2017.519">Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. <span><span class="ref-journal">Nature. </span>2017;<span class="ref-vol">549</span>:519–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28959963" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28959963</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.kamathloeb.2017.44081">Kamath-Loeb AS, Zavala-van Rankin DG, Flores-Morales J, Emond MJ, Sidorova JM, Carnevale A, del Carmen Cardenas-Cortes M, Norwood TH, Monnat RJ, Loeb LA, Mercado-Celis GE. Homozygosity for the WRN helicase-inactivating variant, R834C, does not confer a Werner syndrome clinical phenotype. <span><span class="ref-journal">Scientific Reports. </span>2017;<span class="ref-vol">7</span>:44081.</span> [<a href="/pmc/articles/PMC5343477/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5343477</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28276523" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28276523</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.kubota.2021.153">Kubota Y, Takemoto M, Taniguchi T, Motegi S, Taniguchi A, Nakagami H, Maezawa Y, Koshizaka M, Kato H, Mori S, Tsukamoto K, Kuzuya M, Yokote K. Management guideline for Werner syndrome 2020.6. Skin ulcers associated with Werner syndrome: prevention and non-surgical and surgical treatment. <span><span class="ref-journal">Geriatr Gerontol Int. </span>2021;<span class="ref-vol">21</span>:153–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/33225552" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33225552</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.lauper.2013.e59709">Lauper JM, Krause A, Vaughan TL, Monnat RJ Jr. Spectrum and risk of neoplasia in Werner syndrome: a systematic review. <span><span class="ref-journal">PLoS One. </span>2013;<span class="ref-vol">8</span>:e59709. </span> [<a href="/pmc/articles/PMC3613408/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3613408</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23573208" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23573208</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.lyons.2019.1371">Lyons C, Gallagher D, McSwiney T, McElnea E, Kinsella F. The ophthalmic diagnosis and management of four siblings with Werner syndrome. <span><span class="ref-journal">Int Ophthal. </span>2019;<span class="ref-vol">39</span>:1371–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/29705892" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29705892</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.matuccicerinic.2011.32">Matucci-Cerinic M, Denton CP, Furst DE, Mayes MD, Hsu VM, Carpentier P, Wigley FM, Black CM, Fessler BJ, Merkel PA, Pope JE, Sweiss NJ, Doyle MK, Hellmich B, Medsger TA Jr, Morganti A, Kramer F, Korn JH, Seibold JR. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. <span><span class="ref-journal">Ann Rheum Dis. </span>2011;<span class="ref-vol">70</span>:32–8.</span> [<a href="/pmc/articles/PMC3002766/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3002766</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20805294" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20805294</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.mori.2021.146">Mori S, Takemoto M, Kubota Y, Taniguchi T, Motegi SI, Taniguchi A, Nakagami H, Maezawa Y, Koshizaka M, Kato H, Tsukamoto K, Kuzuya M, Yokote K. Management guideline for Werner syndrome 2020. 4. Osteoporosis associated with Werner syndrome. <span><span class="ref-journal">Geriatr Gerontol Int. </span>2021;<span class="ref-vol">21</span>:146–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/33155383" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33155383</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.oshima.2014.239">Oshima J, Hisama FM. Search and insights into novel genetic alterations leading to classical and atypical Werner syndrome. <span><span class="ref-journal">Gerontology. </span>2014;<span class="ref-vol">60</span>:239–46.</span> [<a href="/pmc/articles/PMC3997596/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3997596</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24401204" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24401204</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.oshima.2017.105">Oshima J, Sidorova JM, Monnat RJ Jr. Werner syndrome: clinical features, pathogenesis and potential therapeutic interventions. <span><span class="ref-journal">Ageing Res Rev. </span>2017;<span class="ref-vol">33</span>:105–114.</span> [<a href="/pmc/articles/PMC5025328/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5025328</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26993153" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26993153</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.so_ekpastuszka.2011.201">Sołek-Pastuszka J, Zagrodnik-Ułan E, Płonka T, Wylot M, Biernawska J, Bohatyrewicz R, Kos W, Zukowski M, Celewicz Z. Pregnancy complicated by Werner syndrome. <span><span class="ref-journal">Acta Obstet Gynecol Scand. </span>2011;<span class="ref-vol">90</span>:201–2.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21241272" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21241272</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.stenson.2017.665">Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. <span><span class="ref-journal">Hum Genet. </span>2017;<span class="ref-vol">136</span>:665–77.</span> [<a href="/pmc/articles/PMC5429360/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5429360</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28349240" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28349240</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.takemoto.2021.142">Takemoto M, Kubota Y, Taniguchi T, Motegi S, Tanoguchi A, Nakagami H, Maezawa Y, Koshizaka M, Kato H, Tsukamoto K, Mori S, Kuzuya M, Yokote K. Management guideline for Werner syndrome 2020.3. diabetes associated with Werner syndrome. <span><span class="ref-journal">Geriatr Gerontol Int. </span>2021;<span class="ref-vol">21</span>:142–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/33169495" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33169495</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.takemoto.2013.475">Takemoto M, Mori S, Kuzuya M, Yoshimoto S, Shimamoto A, Igarashi M, Tanaka Y, Miki T, Yokote K. Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey. <span><span class="ref-journal">Geriatr Gerontol Int. </span>2013;<span class="ref-vol">13</span>:475–81.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22817610" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22817610</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.tsukamoto.2021.133">Tsukamoto K, Takemoto M, Taniguchi T, Motegi S, Taniguchi A, Nakagami H, Maezawa Y, Koshizaka M, Kato H, Mori S, Kuzuya M, Yokote K. Management guideline for Werner syndrome 2020.1. dyslipidemia and fatty liver associated with Werner syndrome. <span><span class="ref-journal">Geriatr Gerontol Int. </span>2021;<span class="ref-vol">21</span>:133–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/33258561" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33258561</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.watanabe.2013.e119">Watanabe K, Kobayashi K, Takemoto M, Ishibashi R, Yamaga M, Kawamura H, Fujimoto M, Ishikawa T, Onishi S, Okabe E, He P, Yokote K. Sitagliptin improves postprandial hyperglycemia by inhibiting glucagon secretion in Werner syndrome with diabetes. <span><span class="ref-journal">Diabetes Care. </span>2013;<span class="ref-vol">36</span>:e119. </span> [<a href="/pmc/articles/PMC3714499/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3714499</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23881973" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23881973</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.yokote.2017.7">Yokote K, Chanprasert S, Lee L, Eirich K, Takemoto M, Watanabe A, Koizumi N, Lessel D, Mori T, Hisama FM, Ladd PD, Angle B, Baris H, Cefle K, Palanduz S, Ozturk S, Chateau A, Deguchi K, Easwar TKM, Federico A, Fox A, Grebe TA, Hay B, Nampoothiri S, Seitner K, Streeten E, Pina-Aguilar RE, Poke G, Poot M, Posmyk R, Martin GM, Kubisch C, Schindler D, Oshima J. WRN mutation update: mutation spectrum, patient registries, and translational prospects. <span><span class="ref-journal">Hum Mutat. </span>2017;<span class="ref-vol">38</span>:7–15.</span> [<a href="/pmc/articles/PMC5237432/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5237432</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27667302" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27667302</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="werner.REF.yu.1996.258">Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J, Schellenberg GD. Positional cloning of the Werner's syndrome gene. <span><span class="ref-journal">Science. </span>1996;<span class="ref-vol">272</span>:258–62.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8602509" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8602509</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK1514/?report=reader">PubReader</a></li><li><a href="/books/NBK1514/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK1514" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK1514" style="display:none" title="Cite this Page"><div class="bk_tt">Oshima J, Martin GM, Hisama FM. Werner Syndrome. 2002 Dec 2 [Updated 2021 May 13]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK1514/pdf/Bookshelf_NBK1514.pdf">PDF version of this page</a> (483K)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this GeneReview</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#werner.Summary" ref="log$=inpage&link_id=inpage">Summary</a></li><li><a href="#werner.Diagnosis" ref="log$=inpage&link_id=inpage">Diagnosis</a></li><li><a href="#werner.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#werner.Genetically_Related_Allelic_Disor" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#werner.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#werner.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#werner.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#werner.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#werner.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#werner.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li><li><a href="#werner.References" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/ca/84/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download GeneReviews data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>GeneReviews Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/gene/advanced/"><i>GeneReviews</i> Advanced Search</a></li><li><a href="/books/n/gene/glossary/"><i>GeneReviews</i> Glossary</a></li><li><a href="/books/n/gene/resource_mats/">Resource Materials</a> <span class="bk_hlight1">NEW FEATURE</span></li><li><a href="/books/n/gene/updates/">New in <i>GeneReviews</i></a></li><li><a href="/books/n/gene/authors/">Author List</a></li><li><a href="/books/n/gene/prospective_authors/">For Current/Prospective Authors</a></li><li><a href="/books/n/gene/GRpersonnel/"><i>GeneReviews</i> Personnel</a></li><li><a href="/books/n/gene/howto_linkin/">Download/Link to <i>GeneReviews</i></a></li><li><a href="/books/n/gene/contact_us/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Tests in GTR by Gene</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
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