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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="SALL4-Related Disorders" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2022/03/17" /><meta name="citation_author" content="Jürgen Kohlhase" /><meta name="citation_pmid" content="20301547" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1373/" /><meta name="citation_keywords" content="Duane-Radial Ray Syndrome (DRRS) / Okihiro Syndrome" /><meta name="citation_keywords" content="Acro-Renal-Ocular Syndrome (AROS)" /><meta name="citation_keywords" content="SALL4-Related Holt-Oram Syndrome (HOS)" /><meta name="citation_keywords" content="Sal-like protein 4" /><meta name="citation_keywords" content="SALL4" /><meta name="citation_keywords" content="SALL4-Related Disorders" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="SALL4-Related Disorders" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Jürgen Kohlhase" /><meta name="DC.Date" content="2022/03/17" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1373/" /><meta name="description" content="SALL4-related disorders include Duane-radial ray syndrome (DRRS, Okihiro syndrome), acro-renal-ocular syndrome (AROS), and SALL4-related Holt-Oram syndrome (HOS) – three phenotypes previously thought to be distinct entities." /><meta name="og:title" content="SALL4-Related Disorders" /><meta name="og:type" content="book" /><meta name="og:description" content="SALL4-related disorders include Duane-radial ray syndrome (DRRS, Okihiro syndrome), acro-renal-ocular syndrome (AROS), and SALL4-related Holt-Oram syndrome (HOS) – three phenotypes previously thought to be distinct entities." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK1373/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/gene/drrs/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK1373/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script><meta name="book-collection" content="NONE" />
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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="#__NBK1373_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1373_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/tbs/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/samd9l-ap/" 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="_NBK1373_"><span class="title" itemprop="name"><i>SALL4</i>-Related Disorders</span></h1><p class="contrib-group"><span itemprop="author">Jürgen Kohlhase</span>, MD.</p><a data-jig="ncbitoggler" href="#__NBK1373_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1373_ai__"><div class="contrib half_rhythm"><span itemprop="author">Jürgen Kohlhase</span>, MD<div class="affiliation small">SYNLAB Center for Human Genetics
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Freiburg, Germany<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.balnys@esahlhok.negreuj" class="oemail">moc.balnys@esahlhok.negreuj</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">August 16, 2004</span>; Last Update: <span itemprop="dateModified">March 17, 2022</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="drrs.Summary" itemprop="description"><h2 id="_drrs_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>SALL4</i>-related disorders include Duane-radial ray syndrome (DRRS, Okihiro syndrome), acro-renal-ocular syndrome (AROS), and <i>SALL4</i>-related Holt-Oram syndrome (HOS) – three phenotypes previously thought to be distinct entities.</p><ul><li class="half_rhythm"><div>DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly).</div></li><li class="half_rhythm"><div>AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly.</div></li><li class="half_rhythm"><div>Rarely, pathogenic variants in <i>SALL4</i> may cause clinically typical HOS (i.e., radial ray malformations and cardiac malformations without additional features).</div></li></ul></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of a <i>SALL4</i>-related disorder is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with suggestive findings and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>SALL4</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Surgery as needed for strabismus from Duane anomaly, malformations of the forearms, and <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart defects; management of renal anomalies per nephrologist and/or urologist; antiarrhythmic medications or pacemaker for those with conduction defects or heart block; cardiologist can assist in determining the need for anticoagulants and antibiotic prophylaxis for bacterial endocarditis; hearing aids as needed; consideration of growth hormone therapy for children with growth deficiency; treatment of pituitary hypoplasia per endocrinologist.</p><p><i>Surveillance:</i> Ophthalmologic exam with frequency as recommended by ophthalmologist; monitor renal function in those with renal anomalies, even if renal function is normal initially; periodic renal ultrasound evaluation if renal position anomalies could cause obstruction; periodic echocardiographic surveillance may be recommended for individuals with certain <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart defects; in those at risk for conduction defects, EKG at least annually with consideration of annual Holter monitor in those with known conduction defects; at least annual blood counts in those with a history of thrombocytopenia and leukocytosis; audiologic evaluation as needed; assessment of growth and for signs and symptoms of pituitary hypoplasia at each visit.</p><p><i>Agents/circumstances to avoid:</i> Drugs affecting the kidney if renal function is impaired, or the inner ear if hearing is impaired; certain medications may be contraindicated in those with arrhythmias.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>SALL4</i>-related disorders are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner. The proportion of cases caused by a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is approximately 40%-50%. Each child of an individual with a <i>SALL4</i>-related disorder has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant has been identified in an affected family member.</p></div></div><div id="drrs.GeneReview_Scope"><h2 id="_drrs_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><div id="drrs.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1373/table/drrs.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__drrs.Tc_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_drrs.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>SALL4</i>-Related Disorders: Included Phenotypes</th></tr></thead><tbody><tr><td headers="hd_h_drrs.Tc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Duane-radial ray syndrome (DRRS) / Okihiro syndrome</div></li><li class="half_rhythm"><div>Acro-renal-ocular syndrome (AROS)</div></li><li class="half_rhythm"><div><i>SALL4</i>-related Holt-Oram syndrome (HOS)</div></li></ul>
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</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">For synonyms and outdated names see <a href="#drrs.Nomenclature">Nomenclature</a>.</p></div></dd></dl></div></div></div></div><div id="drrs.Diagnosis"><h2 id="_drrs_Diagnosis_">Diagnosis</h2><div id="drrs.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>SALL4</i>-related disorders include a spectrum of phenotypes: Duane-radial ray syndrome (DRRS), or Okihiro syndrome; acro-renal-ocular syndrome (AROS); and <i>SALL4</i>-related Holt-Oram syndrome (HOS). A <i>SALL4</i>-related disorder <b>should be suspected</b> in individuals with clinical features of DRRS, AROS, or HOS.</p><p>
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<b>DRRS clinical features</b>
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</p><ul><li class="half_rhythm"><div><b>Duane anomaly.</b> Uni- or bilateral limitation of abduction of the eye associated with retraction of the globe and narrowing of the palpebral fissure on adduction. The abducens nucleus and nerve (cranial nerve VI) are absent and the lateral rectus muscle is innervated by a branch of the oculomotor nerve (cranial nerve III), which explains the aberrant ocular movements (see <a href="/books/n/gene/duane/">Duane Syndrome</a>).</div></li><li class="half_rhythm"><div><b>Radial ray malformation.</b> Thenar hypoplasia and/or hypoplasia or aplasia of the thumbs; hypoplasia or aplasia of the radii; shortening and radial deviation of the forearms; triphalangeal thumbs; and duplication of the thumb (preaxial polydactyly)</div></li><li class="half_rhythm"><div><b>Other features</b> are variably present; see <a href="#drrs.Clinical_Characteristics">Clinical Characteristics</a>.</div></li></ul><p><b>AROS</b>
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<b>clinical features</b></p><ul><li class="half_rhythm"><div>Radial ray malformations</div></li><li class="half_rhythm"><div>Renal abnormalities: mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, and bladder diverticula</div></li><li class="half_rhythm"><div>Ocular abnormalities: ocular coloboma and Duane anomaly</div></li></ul><p><b><i>SALL4</i>-related HOS</b>
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<b>clinical features</b></p><ul><li class="half_rhythm"><div class="half_rhythm">Upper-extremity malformations: radial, thenar, and/or carpal bones, including preaxial polydactyly</div></li><li class="half_rhythm"><div class="half_rhythm">Congenital heart malformations: ventricular septal defects, atrial septal defects, and tetralogy of Fallot</div></li><li class="half_rhythm"><div class="half_rhythm">Cardiac conduction defects (less common than in <i>TBX5</i>-related HOS)</div><div class="half_rhythm">Note: HOS is a heterogeneous <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> in which 70% of affected individuals have pathogenic variants in <i>TBX5</i>; see <a href="#drrs.Differential_Diagnosis">Differential Diagnosis</a> and <a href="/books/n/gene/hos/">Holt-Oram Syndrome</a> for further clinical information on this condition.</div></li></ul></div><div id="drrs.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of a <i>SALL4</i>-related disorder <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with <a href="#drrs.Suggestive_Findings">suggestive findings</a> and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>SALL4</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK1373/table/drrs.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobdrrsTmoleculargenetictestingusedin">Table 1</a>).</p><p>Note: Identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>SALL4</i> variant of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> does not establish or rule out the diagnosis of this disorder.</p><p>Molecular genetic testing approaches can include single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing (see <a href="#drrs.Option_1">Option 1</a>) or use of a <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a> (see <a href="#drrs.Option_2">Option 2</a>) depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p><div id="drrs.Option_1"><h4>Option 1</h4><p>When the phenotypic findings suggest the diagnosis of a <i>SALL4</i>-related disorder, consider <b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b>:</p><ul><li class="half_rhythm"><div>Sequence analysis of <i>SALL4</i> is performed first to detect 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. Note: Depending on the sequencing method used, single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a>, multiexon, or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications may not be detected.</div></li><li class="half_rhythm"><div>If no variant is detected by the sequencing method used, the next step is to perform <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> to detect <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> and whole-gene deletions or duplications.</div></li></ul></div><div id="drrs.Option_2"><h4>Option 2</h4><p>When the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> falls outside of the typical spectrum of <i>SALL4</i>-related disorders, consider a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>SALL4</i> and other genes of interest (see <a href="#drrs.Differential_Diagnosis">Differential Diagnosis</a>) to identify the genetic cause of the condition 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 phenotype. 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>. (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.</p><p>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>.</p><div id="drrs.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>SALL4</i>-Related Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1373/table/drrs.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__drrs.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_drrs.T.molecular_genetic_testing_used_in_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_drrs.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_drrs.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>2, 3</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_drrs.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SALL4</i>
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</td><td headers="hd_h_drrs.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>4</sup></td><td headers="hd_h_drrs.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">85%-90% <sup>5</sup></td></tr><tr><td headers="hd_h_drrs.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Deletion/<a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> analysis <sup>6</sup></td><td headers="hd_h_drrs.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10%-15% <sup>7</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="drrs.TF.1.1"><p class="no_margin">See <a href="/books/NBK1373/#drrs.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="drrs.TF.1.2"><p class="no_margin">See <a href="#drrs.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="drrs.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>5. </dt><dd><div id="drrs.TF.1.4"><p class="no_margin"><a class="bk_pop" href="#drrs.REF.albaradie.2002.1195">Al-Baradie et al [2002]</a>, <a class="bk_pop" href="#drrs.REF.kohlhase.2002.2979">Kohlhase et al [2002]</a>, <a class="bk_pop" href="#drrs.REF.kohlhase.2003.473">Kohlhase et al [2003]</a>, <a class="bk_pop" href="#drrs.REF.borozdin.2004b.e102">Borozdin et al [2004b]</a>, <a class="bk_pop" href="#drrs.REF.kohlhase.2005.176">Kohlhase et al [2005]</a></p></div></dd><dt>6. </dt><dd><div id="drrs.TF.1.5"><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 range of techniques such as <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="drrs.TF.1.6"><p class="no_margin"><a class="bk_pop" href="#drrs.REF.borozdin.2004a.e113">Borozdin et al [2004a]</a>, <a class="bk_pop" href="#drrs.REF.borozdin.2007.830">Borozdin et al [2007]</a></p></div></dd></dl></div></div></div></div></div></div><div id="drrs.Clinical_Characteristics"><h2 id="_drrs_Clinical_Characteristics_">Clinical Characteristics</h2><div id="drrs.Clinical_Description"><h3>Clinical Description</h3><p><i>SALL4</i>-related disorders include Duane-radial ray syndrome (DRRS, Okihiro syndrome), acro-renal-ocular syndrome (AROS), and <i>SALL4</i>-related Holt-Oram syndrome (HOS) – three phenotypes previously thought to be distinct entities [<a class="bk_pop" href="#drrs.REF.albaradie.2002.1195">Al-Baradie et al 2002</a>, <a class="bk_pop" href="#drrs.REF.kohlhase.2002.2979">Kohlhase et al 2002</a>, <a class="bk_pop" href="#drrs.REF.kohlhase.2003.473">Kohlhase et al 2003</a>, <a class="bk_pop" href="#drrs.REF.borozdin.2004a.e113">Borozdin et al 2004a</a>, <a class="bk_pop" href="#drrs.REF.borozdin.2004b.e102">Borozdin et al 2004b</a>, <a class="bk_pop" href="#drrs.REF.kohlhase.2005.176">Kohlhase et al 2005</a>, <a class="bk_pop" href="#drrs.REF.borozdin.2007.830">Borozdin et al 2007</a>].</p><ul><li class="half_rhythm"><div>DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly).</div></li><li class="half_rhythm"><div>AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly.</div></li><li class="half_rhythm"><div>Rarely, pathogenic variants in <i>SALL4</i> may cause clinically typical HOS (i.e., radial ray malformations and cardiac malformations without additional features).</div></li></ul><p>Of 69 affected individuals from 23 families with a <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, 13% show the triad of Duane anomaly, radial ray malformation, and sensorineural hearing loss originally described for Okihiro syndrome; 45% have Duane anomaly and radial defects; and 21% have radial defects only. To date, more than 100 individuals with a pathogenic variant in <i>SALL4</i> have been identified [<a class="bk_pop" href="#drrs.REF.albaradie.2002.1195">Al-Baradie et al 2002</a>, <a class="bk_pop" href="#drrs.REF.kohlhase.2002.2979">Kohlhase et al 2002</a>, <a class="bk_pop" href="#drrs.REF.kohlhase.2003.473">Kohlhase et al 2003</a>, <a class="bk_pop" href="#drrs.REF.borozdin.2004a.e113">Borozdin et al 2004a</a>, <a class="bk_pop" href="#drrs.REF.borozdin.2004b.e102">Borozdin et al 2004b</a>, <a class="bk_pop" href="#drrs.REF.kohlhase.2005.176">Kohlhase et al 2005</a>, <a class="bk_pop" href="#drrs.REF.borozdin.2007.830">Borozdin et al 2007</a>, <a class="bk_pop" href="#drrs.REF.vanlerberghe.2019.360">Vanlerberghe et al 2019</a>, <a class="bk_pop" href="#drrs.REF.van_de_putte.2020.310">van de Putte et al 2020</a>, and others]. The following description of the phenotypic features associated with this condition is based on these reports.</p><div id="drrs.T.sall4related_disorders_frequency" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p><i>SALL4</i>-Related Disorders: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1373/table/drrs.T.sall4related_disorders_frequency/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__drrs.T.sall4related_disorders_frequency_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons w/Feature</th><th id="hd_h_drrs.T.sall4related_disorders_frequency_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_drrs.T.sall4related_disorders_frequency_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Duane anomaly</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">65%</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Other ocular anomalies rarely reported</td></tr><tr><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Radial ray anomaly</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>90%</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Renal abnormality</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">38%</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Congenital heart anomaly</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15%</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiac conduction defect</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing loss</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">16%</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Choanal atresia</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5%</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Short stature</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7%</td><td headers="hd_h_drrs.T.sall4related_disorders_frequency_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">J Kohlhase, unpublished data</p></div></dd></dl></div></div></div><p><b>Ocular.</b> Duane anomaly is the most common ocular finding. Other ocular anomalies include iris, retinal, and choroidal colobomata, cataract, optic disc hypoplasia, and microphthalmia (structural eye anomalies are rare).</p><p><b>Musculoskeletal.</b> Radial ray anomalies can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs; hypoplasia or aplasia of the radii; shortening and radial deviation of the forearms; triphalangeal thumbs; and duplication of the thumb (preaxial polydactyly). Other reported upper-extremity anomalies include concomitant shortening of ulnae, syndactyly, radial clubhand, carpal bone anomalies, shortened humeri, and hypoplasia of deltoid muscles. Lower-extremity anomalies include talipes, clubfoot, tibial hemimelia, and syndactyly of toes. Fused vertebrae have also been reported.</p><p><b>Renal anomalies</b> include mild malrotation, ectopia, crossed renal ectopia, horseshoe kidney, renal hypoplasia, renal agenesis, vesicoureteral reflux, and bladder diverticula.</p><p><b>Cardiac.</b> Congenital heart malformations include ventricular septal defect, atrial septal defect, and tetralogy of Fallot. Cardiac conduction defects are also reported but are less common than in <a href="/books/n/gene/hos/"><i>TBX5</i>-related HOS</a>.</p><p><b>Ears/hearing.</b> Sensorineural and/or conductive deafness can occur. Ear anomalies include abnormal pinnae, slit-like opening of auditory canals, and small ears.</p><p><b>Gastrointestinal features</b> can include anal stenosis and imperforate anus.</p><p><b>Characteristic facial features</b> reported in some individuals include epicanthal folds, widely spaced eyes, depressed nasal bridge, and hemifacial microsomia.</p><p><b>Pituitary.</b> Growth hormone deficiency, postnatal growth deficiency, pituitary hypoplasia</p><p><b>Development and cognition</b> are normal.</p><p>
|
||
<b>Other</b>
|
||
</p><ul><li class="half_rhythm"><div><b>Central nervous system.</b> Neural tube defects (rare); meningomyelocele has been observed in two affected individuals [J Kohlhase, unpublished data].</div></li><li class="half_rhythm"><div><b>Mild thrombocytopenia and leukocytosis</b> were reported in some affected individuals with one <i>SALL4</i> pathogenic <a class="def" href="/books/n/gene/glossary/def-item/frameshift-variant/">frameshift variant</a> from one family. See IVIC syndrome (OMIM <a href="https://omim.org/entry/147750" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">147750</a>).</div></li><li class="half_rhythm"><div><b>Isolated ventricular septal defects (VSD).</b> Two <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants have been reported to be associated with <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> VSD [<a class="bk_pop" href="#drrs.REF.wang.2010.224">Wang et al 2010</a>]. However, since neither of these missense variants affects amino acids with known functional domains, it is unclear if this <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> is clearly associated with pathogenic variants in <i>SALL4</i>.</div></li></ul></div><div id="drrs.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>Most <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> variants are <a class="def" href="/books/n/gene/glossary/def-item/private/">private</a> or have been observed in no more than three independent families. The <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of larger deletions (not extending into other genes) is not significantly different from that caused by almost all truncating single-nucleotide variants, and these are expected to result in <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>-mediated <a class="def" href="/books/n/gene/glossary/def-item/mrna/">mRNA</a> decay.</p><p>The only clearly pathogenic <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variant identified to date in an individual with malformations (<a href="/books/NBK1373/table/drrs.T.notable_sall4_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobdrrsTnotablesall4pathogenicvariants">c.2663A>G</a>, p.His888Arg) affects an essential coordinating amino acid and is associated with central midline defects (single upper incisor, pituitary hypoplasia, widely spaced eyes). It is predicted to result in an increase of DNA binding capacity [<a class="bk_pop" href="#drrs.REF.miertus.2006.154">Miertus et al 2006</a>].</p><p>The only truncating <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> predicted to escape <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>-mediated <a class="def" href="/books/n/gene/glossary/def-item/mrna/">mRNA</a> decay is associated with extensive clinical variability and severe hemifacial microsomia in one affected member of the reported family [<a class="bk_pop" href="#drrs.REF.terhal.2006.222">Terhal et al 2006</a>].</p><p>Some pathogenic <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants have been reported to result in a gain of function, and those variants have been reported to cause premature ovarian failure alone, without developmental disorder (see <a href="#drrs.Genetically_Related_Allelic_Disorde">Genetically Related Disorders</a>) [<a class="bk_pop" href="#drrs.REF.wang.2019.83">Wang et al 2019</a>].</p></div><div id="drrs.Penetrance"><h3>Penetrance</h3><p>Penetrance is approximately 95% but may be lower for certain pathogenic variants.</p><p><b>In two reported families.</b> An individual known (on the basis of <a class="def" href="/books/n/gene/glossary/def-item/pedigree/">pedigree</a> position) to have the <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is unaffected; an individual with a proven <i>SALL4</i> pathogenic variant shows no signs of a <i>SALL4</i>-related disorder [<a class="bk_pop" href="#drrs.REF.hayes.1985.273">Hayes et al 1985</a>, <a class="bk_pop" href="#drrs.REF.kohlhase.2002.2979">Kohlhase et al 2002</a>]. In the latter family, however, the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> was mild in all individuals with the pathogenic variant (i.e., presenting with only thenar hypoplasia and Duane anomaly).</p><p>Of 69 family members known in 2004 to have a <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, only one (1.4%) was clinically unaffected [J Kohlhase, personal observation]. No further case of non-<a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> is known to the author.</p></div><div id="drrs.Nomenclature"><h3>Nomenclature</h3><p>One of the earliest reports of Duane anomaly occurring together with radial ray defects is that of <a class="bk_pop" href="#drrs.REF.ferrell.1966.630">Ferrell et al [1966]</a> (earlier reports are cited in <a href="https://omim.org/entry/607323" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>). Further families were reported by <a class="bk_pop" href="#drrs.REF.temtamy.1975.344">Temtamy et al [1975]</a> and <a class="bk_pop" href="#drrs.REF.okihiro.1977.174">Okihiro et al [1977]</a>. <a class="bk_pop" href="#drrs.REF.temtamy.1978">Temtamy & McKusick [1978]</a> named the syndrome Duane/radial dysplasia syndrome (DR syndrome, later modified to Duane-radial ray syndrome [DRRS]). The term "Okihiro syndrome" was first used by <a class="bk_pop" href="#drrs.REF.hayes.1985.273">Hayes et al [1985]</a>.</p><p>The term "acro-renal-ocular syndrome" was used in 1984 to describe a family with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> inheritance of thumb abnormalities, renal malformations, and ocular coloboma, ptosis, and Duane anomaly [<a class="bk_pop" href="#drrs.REF.halal.1984.753">Halal et al 1984</a>].</p><p>Holt-Oram syndrome has also been referred to as heart-hand syndrome, a nonspecific designation that could apply to any number of conditions with involvement of these structures.</p></div><div id="drrs.Prevalence"><h3>Prevalence</h3><p>The prevalence is unknown, partly because in many countries <i>SALL4</i>-related disorders have not been and are still not differentiated from HOS caused by pathogenic variants in <i>TBX5</i>, or from other heart-hand syndromes.</p></div></div><div id="drrs.Genetically_Related_Allelic_Disorde"><h2 id="_drrs_Genetically_Related_Allelic_Disorde_">Genetically Related (Allelic) Disorders</h2><p><b>Premature ovarian failure.</b> Three <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants have been reported to be associated with premature ovarian failure (POI) (see <a href="/books/NBK1373/table/drrs.T.notable_sall4_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobdrrsTnotablesall4pathogenicvariants">Table 7</a>) [<a class="bk_pop" href="#drrs.REF.wang.2019.83">Wang et al 2019</a>]. All three variants result in increased SALL4 protein expression and increased activation of the downstream <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> <i>POU5F1</i>, suggesting that these variants act as <a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a> variants. None of these variants were detected in individuals with <i>SALL4</i>-related disorders, and individuals with <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> variants have not been reported to have decreased fertility or POI. Therefore, while <i>SALL4</i> loss-of-function variants lead to Duane-radial ray syndrome (DRRS, Okihiro syndrome), acro-renal-ocular syndrome, and <i>SALL4</i>-related Holt-Oram syndrome, <i>SALL4</i> gain-of-function variants are not associated with those phenotypes but interfere with ovarian function.</p><p>Persons with DRRS and developmental delay are likely to have a larger <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> including <i>SALL4</i> and neighboring genes [<a class="bk_pop" href="#drrs.REF.borozdin.2007.830">Borozdin et al 2007</a>].</p></div><div id="drrs.Differential_Diagnosis"><h2 id="_drrs_Differential_Diagnosis_">Differential Diagnosis</h2><div id="drrs.T.genes_of_interest_in_the_differen" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of <i>SALL4</i>-Related Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1373/table/drrs.T.genes_of_interest_in_the_differen/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__drrs.T.genes_of_interest_in_the_differen_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s) <sup>1</sup></th><th id="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Overlapping Clinical Features</th><th id="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment / Distinguishing Features</th></tr></thead><tbody><tr><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>TBX5</i>
|
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</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>TBX5</i>-related <a href="/books/n/gene/hos/">Holt-Oram syndrome</a> (<i>TBX5</i>-HOS)</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Upper-limb malformations (radial, thenar, or carpal bones); CHD (ostium secundum ASD, VSD, esp those occurring in muscular trabeculated septum, & cardiac conduction defects)</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Preaxial polydactyly is almost exclusively assoc w/<i>SALL4</i>-RD. In <i>TBX5</i>-HOS ASD may be more common than VSD, whereas the opposite may apply for <i>SALL4</i>-RD. Cardiac conduction defects are observed less commonly in <i>SALL4-RD</i> than in <i>TBX5</i>-HOS. Persons w/typical radial ray malformations & renal or urogenital malformation (esp position anomalies of kidneys) but w/o Duane anomaly are more likely to have <i>SALL4</i>-RD than <i>TBX5-</i>HOS.</td></tr><tr><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SALL1</i>
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</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/tbs/">Townes-Brocks syndrome</a> (TBS)</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dysplastic ears, imperforate anus, & triphalangeal thumbs / preaxial polydactyly</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Radial aplasia has not been observed in TBS.</td></tr><tr><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>RBM8A</i>
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||
</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/tar/">Thrombocytopenia absent radius (TAR) syndrome</a>
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</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bilateral absence of radii; other skeletal, cardiac, & GI anomalies</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In TAR syndrome: thumbs are never absent but may appear malformed; thrombocytopenia is generally transient.</td></tr><tr><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>BRCA1</i>
|
||
<br />
|
||
<i>BRCA2</i>
|
||
<br />
|
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<i>BRIP1</i>
|
||
<br />
|
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<i>ERCC4</i>
|
||
<br />
|
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<i>FAAP100</i>
|
||
<br />
|
||
<i>FANCA</i>
|
||
<br />
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<i>FANCB</i>
|
||
<br />
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<i>FANCC</i>
|
||
<br />
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<i>FANCD2</i>
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||
<br />
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<i>FANCE</i>
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<br />
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<i>FANCF</i>
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<br />
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<i>FANCG</i>
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<br />
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<i>FANCI</i>
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<br />
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<i>FANCL</i>
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<br />
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<i>FANCM</i>
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||
<br />
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<i>MAD2L2</i>
|
||
<br />
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<i>PALB2</i>
|
||
<br />
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||
<i>RAD51</i>
|
||
<br />
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||
<i>RAD51C</i>
|
||
<br />
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||
<i>RFWD3</i>
|
||
<br />
|
||
<i>SLX4</i>
|
||
<br />
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<i>UBE2T</i>
|
||
<br />
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<i>XRCC2</i>
|
||
</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/fa/">Fanconi anemia</a> (FA)</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />AD<br />XL <sup>2</sup></td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Radial ray malformations; other skeletal, cardiac, & GI anomalies</td><td headers="hd_h_drrs.T.genes_of_interest_in_the_differen_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In FA: progressive bone marrow failure, cancer susceptibility, DD/ID<br />In <i>SALL4</i>-RD: Duane anomaly</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>; ASD = atrial septal defect; CHD = <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart defect; DD = developmental delay; ID = intellectual delay; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; <i>SALL4</i>-RD = <i>SALL4</i>-related disorders; VSD = ventricular septal defect; XL = <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a></p></div></dd><dt>1. </dt><dd><div id="drrs.TF.3.1"><p class="no_margin">Genes are ordered by relevance to the differential diagnosis of <i>SALL4</i>-related disorders.</p></div></dd><dt>2. </dt><dd><div id="drrs.TF.3.2"><p class="no_margin">Fanconi anemia (FA) can be inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner, an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner (<i>RAD51</i>-related FA), or an <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> manner (<i>FANCB</i>-related FA).</p></div></dd></dl></div></div></div><p>
|
||
<b>Disorders of unknown cause associated with Duane anomaly</b>
|
||
</p><ul><li class="half_rhythm"><div><b>Arthrogryposis-ophthalmoplegia syndrome.</b> In this syndrome, Duane anomaly is associated with deafness, muscle wasting, and contractures, but not typical radial limb malformations. A <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> was not identified in one of the few families reported [<a class="bk_pop" href="#drrs.REF.mccann.2005.123">McCann et al 2005</a>].</div></li><li class="half_rhythm"><div><b>Wildervanck syndrome</b> (OMIM <a href="https://omim.org/entry/314600" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">314600</a>) consists of <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> perceptive deafness, Klippel-Feil anomaly, and Duane anomaly. The disorder affects females almost exclusively. <i>SALL4</i> pathogenic variants have not been detected in some persons who meet the diagnostic criteria for Wildervanck syndrome [J Kohlhase, unpublished data].</div></li></ul><p><b>Thalidomide embryopathy.</b> Thalidomide is currently prescribed to treat conditions such as multiple myeloma, HIV, and leprosy. Fetal abnormalities related to thalidomide administration during pregnancy include amelia, phocomelia, radial hypoplasia, external ear abnormalities, facial palsy, eye abnormalities (anophthalmos, microphthalmos, Duane anomaly, cranial nerve misrouting resulting in "crocodile tears"), and <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart defects. Alimentary tract, urinary tract, and genital malformations also occur. If an individual with a diagnosis of thalidomide embryopathy has a child with radial ray malformations similar to those seen in Holt-Oram syndrome and <i>SALL4</i>-related disorders and additional malformations (e.g., Duane anomaly, kidney defects), a <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is more likely to be found than a <i>TBX5</i> pathogenic variant [<a class="bk_pop" href="#drrs.REF.kohlhase.2003.473">Kohlhase et al 2003</a>].</p></div><div id="drrs.Management"><h2 id="_drrs_Management_">Management</h2><p>No clinical practice guidelines for <i>SALL4</i>-related disorders have been published.</p><div id="drrs.Evaluations_Following_Initial_Diagn"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with a <i>SALL4</i>-related disorder, the evaluations summarized in <a href="/books/NBK1373/table/drrs.T.recommended_evaluations_following/?report=objectonly" target="object" rid-ob="figobdrrsTrecommendedevaluationsfollowing">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="drrs.T.recommended_evaluations_following" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with <i>SALL4</i>-Related Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1373/table/drrs.T.recommended_evaluations_following/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__drrs.T.recommended_evaluations_following_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_drrs.T.recommended_evaluations_following_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_drrs.T.recommended_evaluations_following_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_drrs.T.recommended_evaluations_following_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_drrs.T.recommended_evaluations_following_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_drrs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Complete eye exam by ophthalmologist w/special attn to extraocular movements & structural eye defects</td><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal</b>
|
||
</td><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Clinical assessment for upper- & lower-extremity anomalies</div></li><li class="half_rhythm"><div>X-rays if needed by orthopedist</div></li></ul>
|
||
</td><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to orthopedist as needed</td></tr><tr><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Renal</b>
|
||
</td><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Renal ultrasound exam</div></li><li class="half_rhythm"><div>Assess renal function w/serum electrolyte concentrations, BUN, & creatinine.</div></li></ul>
|
||
</td><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiac</b>
|
||
</td><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Eval by cardiologist</div></li><li class="half_rhythm"><div>Echocardiogram</div></li><li class="half_rhythm"><div>EKG</div></li></ul>
|
||
</td><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If cardiac conduction defect is suspected, a more extensive eval may be needed esp when structural heart defects are present.</td></tr><tr><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hearing</b>
|
||
</td><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="/books/n/gene/deafness-overview/">Hereditary Hearing Loss and Deafness Overview</a>.</td><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Anal stenosis /</b>
|
||
<br />
|
||
<b>Imperforate anus</b>
|
||
</td><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to surgeon for anal anomalies if present</td><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.recommended_evaluations_following_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_drrs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assess for growth deficiency &/or growth hormone deficiency.</div></li><li class="half_rhythm"><div>Assess for signs/symptoms of pituitary hypoplasia.</div></li></ul>
|
||
</td><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to endocrinologist as needed</td></tr><tr><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cytopenias</b>
|
||
</td><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CBC to evaluate for thrombocytopenia &/or leukocytosis</td><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to hematologist if needed</td></tr><tr><td headers="hd_h_drrs.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic</b>
|
||
<br />
|
||
<b>counseling</b>
|
||
</td><td headers="hd_h_drrs.T.recommended_evaluations_following_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_drrs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & their families re nature, MOI, & implications of <i>SALL4</i>-related disorders to facilitate medical & personal decision making</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">BUN = blood urea nitrogen; CBC = complete blood count; 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="drrs.TF.4.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="drrs.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div id="drrs.T.treatment_of_manifestations_in_in" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with <i>SALL4</i>-Related Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1373/table/drrs.T.treatment_of_manifestations_in_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__drrs.T.treatment_of_manifestations_in_in_lrgtbl__"><table><thead><tr><th id="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_drrs.T.treatment_of_manifestations_in_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_drrs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Duane anomaly</b>
|
||
</td><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe strabismus may require eye surgery.</td><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Radial ray malformations</b>
|
||
</td><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe malformations of forearms may require surgery, e.g., surgery to correct aplasia of thumb by constructing functional thumb (pollicization)</td><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Renal anomalies</b>
|
||
</td><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mgmt per nephrologist &/or urologist</td><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiac anomalies &/or conduction defects</b>
|
||
</td><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cardiac surgery, if required for <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart defect, is standard.</div></li><li class="half_rhythm"><div>Cardiologist can assist in determining need for antiarrhythmic medications & surgery.</div></li><li class="half_rhythm"><div>Persons w/severe heart block may require pacemaker implantation.</div></li></ul>
|
||
</td><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiologist can assist in determining need for anticoagulants & antibiotic prophylaxis for bacterial endocarditis.</td></tr><tr><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hearing deficits</b>
|
||
</td><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing aids may be required.</td><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Growth hormone deficiency</b>
|
||
</td><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Growth hormone therapy should be considered.</td><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Pituitary hypoplasia</b>
|
||
</td><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment per endocrinologist</td><td headers="hd_h_drrs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div></div></div><div id="drrs.Surveillance"><h3>Surveillance</h3><div id="drrs.T.recommended_surveillance_for_indi" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with <i>SALL4</i>-Related Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1373/table/drrs.T.recommended_surveillance_for_indi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__drrs.T.recommended_surveillance_for_indi_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_drrs.T.recommended_surveillance_for_indi_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_drrs.T.recommended_surveillance_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Ocular anomalies</b>
|
||
</td><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic exam</td><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per ophthalmologist</td></tr><tr><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Renal anomalies</b>
|
||
</td><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor renal function (e.g., serum creatinine), even if no impairment of renal function is detected on initial exam.</td><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Every 6-12 mos in 1st yrs of life</div></li><li class="half_rhythm"><div>If renal function remains normal, screening intervals may be extended.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Renal ultrasound</td><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Repeat if renal position anomalies could cause obstruction.</div></li><li class="half_rhythm"><div>Frequency depends on clinical situation.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiac anomalies</b>
|
||
</td><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram</td><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 1-5 yrs depending on nature & significance of cardiac malformation, as recommended by cardiologist</td></tr><tr><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiac conduction defects (incl those at risk for conduction defects)</b>
|
||
</td><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>EKG</div></li><li class="half_rhythm"><div>Consider Holter monitor.</div></li></ul>
|
||
</td><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually or more often, as recommended by cardiologist</td></tr><tr><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Thrombocytopenia</b>
|
||
<br />
|
||
<b>&/or leukocytosis</b>
|
||
</td><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CBC</td><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At least annually <sup>1</sup></td></tr><tr><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hearing</b>
|
||
</td><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologic eval</td><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per audiologist &/or ENT</td></tr><tr><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_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_drrs.T.recommended_surveillance_for_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess growth & for signs/symptoms of pituitary hypoplasia.</td><td headers="hd_h_drrs.T.recommended_surveillance_for_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">CBC = complete blood count</p></div></dd><dt>1. </dt><dd><div id="drrs.TF.6.1"><p class="no_margin">Data are sparse on the natural history of thrombocytopenia in individuals with <i>SALL4</i> pathogenic variants; thus, it is unknown at present if more severe complications may occur.</p></div></dd></dl></div></div></div></div><div id="drrs.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Drugs affecting renal clearance or the inner ear should be avoided in individuals with impaired renal function and/or hearing impairment.</p><p>Certain medications may be contraindicated in individuals with arrhythmias.</p></div><div id="drrs.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>Children of affected persons who are themselves not obviously affected should be tested for the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> present in the family because individuals with a <i>SALL4</i> pathogenic variant should undergo clinical evaluation for hearing problems, renal disease, eye disease, and heart defects.</p><p>See <a href="#drrs.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="drrs.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="drrs.Genetic_Counseling"><h2 id="_drrs_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="drrs.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>SALL4</i>-related disorders are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p></div><div id="drrs.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>Many individuals diagnosed with a <i>SALL4</i>-related disorder have an affected parent.</div></li><li class="half_rhythm"><div>A <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with a <i>SALL4</i>-related disorder may have the disorder as the result of a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. The proportion of individuals with a <i>SALL4</i>-related disorder caused by a <i>de novo</i> pathogenic variant is approximately 40%-50% [J Kohlhase, unpublished data].</div></li><li class="half_rhythm"><div>Recommendations for the evaluation of parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> who appears to be the only affected family member (i.e., a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case) include <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> for the <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband and/or physical examination, ophthalmologic examination for structural malformations of the eyes as well as eye movement disorders, examination of the limbs (x-rays of the forearms), examination of the heart, and ultrasound examination of the kidneys.</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> inherited a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> from a parent with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> (or somatic and germline) <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a>. Note: Testing of parental leukocyte DNA may not detect all instances of <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a> and will not detect a pathogenic variant that is present in the germ cells only.</div></li></ul></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with a <i>SALL4</i>-related disorder may appear to be negative because of reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> or failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> has demonstrated that neither parent is <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li></ul><p><b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The risk to the sibs of the proband depends on the genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is affected and/or has a <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the risk to the sibs is inheriting the pathogenic variant is 50%. The <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> of <i>SALL4</i>-related disorders is approximately 95% in <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> individuals but may be lower for certain pathogenic variants (see <a href="#drrs.Penetrance">Penetrance</a>).</div></li><li class="half_rhythm"><div>If the <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> cannot be detected in the leukocyte DNA of either parent, the <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> to sibs is estimated to be 1% because of the theoretic possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> [<a class="bk_pop" href="#drrs.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>If the parents have not been tested for the <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> but are clinically unaffected, sibs are still presumed to be at increased risk for a <i>SALL4</i>-related disorder because of the possibility of reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> in a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parent or the theoretic possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>.</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Each child of an individual with a <i>SALL4</i>-related disorder has a 50% chance of inheriting the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents: if a parent has a <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, his or her family members may be at risk.</p></div><div id="drrs.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#drrs.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 or at risk.</div></li></ul></div><div id="drrs.Prenatal_Testing_and_Preimplantatio"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p><b>For a pregnancy known to be at increased risk for a <i>SALL4</i>-related disorder.</b> Once the <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible. Although such testing can determine whether or not the fetus has inherited the <i>SALL4</i> pathogenic variant, it cannot predict which manifestations will be present or the severity of the manifestations. High-resolution ultrasound examination is therefore recommended to evaluate the fetus for phenotypic manifestations.</p><p><b>For a pregnancy not known to be at increased risk for a <i>SALL4</i>-related disorder.</b> A <i>SALL4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> may be detected for the first time in a family if radial malformations are detected on ultrasound examination as an incidental prenatal finding and prenatal genetic analysis reveals a <i>SALL4</i> pathogenic variant. If a larger <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> is found, <a class="def" href="/books/n/gene/glossary/def-item/chromosomal-microarray/">chromosomal microarray</a> analysis may be used to determine if neighboring genes, in additional to <i>SALL4</i>, are included in the deletion (see <a href="#drrs.Genetically_Related_Allelic_Disorde">Genetically Related Disorders</a>).</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="drrs.Resources"><h2 id="_drrs_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/duane-radial-ray-syndrome/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Duane-radial ray syndrome</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>American Society for Deaf Children</b>
|
||
</div><div><b>Phone:</b> 800-942-2732 (ASDC)</div><div><b>Email:</b> info@deafchildren.org</div><div>
|
||
<a href="https://deafchildren.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">deafchildren.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>National Association of the Deaf</b>
|
||
</div><div><b>Phone:</b> 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)</div><div><b>Fax:</b> 301-587-1791</div><div><b>Email:</b> nad.info@nad.org</div><div>
|
||
<a href="https://www.nad.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">nad.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>National Eye Institute</b>
|
||
</div><div><b>Phone:</b> 301-496-5248</div><div><b>Email:</b> 2020@nei.nih.gov</div><div>
|
||
<a href="https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/low-vision" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Low Vision</a>
|
||
</div></li></ul>
|
||
</div><div id="drrs.Molecular_Genetics"><h2 id="_drrs_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="drrs.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>SALL4-Related Disorders: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1373/table/drrs.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__drrs.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_drrs.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_drrs.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_drrs.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_drrs.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_drrs.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_drrs.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_drrs.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/57167" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>SALL4</i>
|
||
</a>
|
||
</td><td headers="hd_b_drrs.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=57167" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">20q13<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_b_drrs.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q9UJQ4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Sal-like protein 4</a>
|
||
</td><td headers="hd_b_drrs.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://databases.lovd.nl/shared/genes/SALL4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SALL4 database</a>
|
||
</td><td headers="hd_b_drrs.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=SALL4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SALL4</a>
|
||
</td><td headers="hd_b_drrs.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=SALL4[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SALL4</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="drrs.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="drrs.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for SALL4-Related Disorders (<a href="/omim/607323,607343" 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/NBK1373/table/drrs.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__drrs.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/607323" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">607323</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DUANE-RADIAL RAY SYNDROME; DRRS</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/607343" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">607343</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAL-LIKE 4; SALL4</td></tr></tbody></table></div></div><div id="drrs.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>SALL4</i> encodes sal-like protein 4 (SALL4), a C2H2 (Krüppel-like) zinc finger <a class="def" href="/books/n/gene/glossary/def-item/transcription-factor/">transcription factor</a> of the SAL type [<a class="bk_pop" href="#drrs.REF.kohlhase.2002.2979">Kohlhase et al 2002</a>]. SALL4 appears to be an essential developmental regulator. No embryonic or extra-embryonic endoderm stem cell lines can be established if Sall4 is missing. Sall4 interacts with Nanog and co-occupies Nanog <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> sites in embryonic stem cells [<a class="bk_pop" href="#drrs.REF.wu.2006.24090">Wu et al 2006</a>].</p><p>Apart from its role in embryonic and stem cell development, Sall4 is involved in malignant transformation. More than 1,000 putative <i>Sall4</i> target genes were identified, including many known to have roles in stem cell self-renewal and blood differentiation [<a class="bk_pop" href="#drrs.REF.yang.2008.805">Yang et al 2008</a>, <a class="bk_pop" href="#drrs.REF.gao.2013.1413">Gao et al 2013</a>]. Since human <i>SALL4</i> is upregulated in some tumor types, especially hepatocellular carcinoma [<a class="bk_pop" href="#drrs.REF.yong.2013.2266">Yong et al 2013</a>], cancer-related targets are being sought. One direct target is <i>ABCA3</i>, encoding an ATP-binding cassette drug transport protein, which contributes to chemotherapeutic drug resistance [<a class="bk_pop" href="#drrs.REF.jeong.2011.e18372">Jeong et al 2011</a>].</p><p><b>Mechanism of disease causation.</b>
|
||
<i>SALL4</i> pathogenic variants related to developmental disorders likely lead to <a class="def" href="/books/n/gene/glossary/def-item/haploinsufficiency/">haploinsufficiency</a> or some degree of loss of SALL4 function, since all but two pathogenic variants responsible for malformation syndromes are expected to undergo <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>-mediated decay, and deletions of the whole <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> appear to result in the same <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> [<a class="bk_pop" href="#drrs.REF.borozdin.2004a.e113">Borozdin et al 2004a</a>, <a class="bk_pop" href="#drrs.REF.kohlhase.2005.176">Kohlhase et al 2005</a>].</p><p>One <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, <a href="/books/NBK1373/table/drrs.T.notable_sall4_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobdrrsTnotablesall4pathogenicvariants">p.Arg905Ter</a>, is expected to escape <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>-mediated <a class="def" href="/books/n/gene/glossary/def-item/mrna/">mRNA</a> decay and to result in a truncated protein with one nonfunctional zinc finger <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a> [<a class="bk_pop" href="#drrs.REF.terhal.2006.222">Terhal et al 2006</a>].</p><p>Another <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, <a href="/books/NBK1373/table/drrs.T.notable_sall4_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobdrrsTnotablesall4pathogenicvariants">p.His888Arg</a>, exchanges one of the essential amino acids for zinc coordination in a zinc finger and is predicted to result in increased DNA binding of the respective zinc finger [<a class="bk_pop" href="#drrs.REF.miertus.2006.154">Miertus et al 2006</a>].</p><p>Missense variants reported to be causative for premature ovarian insufficiency have been reported to result in a gain of function [<a class="bk_pop" href="#drrs.REF.wang.2019.83">Wang et al 2019</a>]. Carriers of such variants do not show any of the malformations that are characteristic for <i>SALL4</i>-related malformation syndromes, whereas female subjects affected by such syndromes have not been reported to suffer from ovarian dysfunction.</p><div id="drrs.T.notable_sall4_pathogenic_variants" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Notable <i>SALL4</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1373/table/drrs.T.notable_sall4_pathogenic_variants/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__drrs.T.notable_sall4_pathogenic_variants_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_drrs.T.notable_sall4_pathogenic_variants_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_drrs.T.notable_sall4_pathogenic_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_drrs.T.notable_sall4_pathogenic_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_drrs.T.notable_sall4_pathogenic_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_drrs.T.notable_sall4_pathogenic_variants_1_1_1_1" rowspan="5" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_020436.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_020436<wbr style="display:inline-block"></wbr>.5</a>
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_065169.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_065169<wbr style="display:inline-block"></wbr>.1</a>
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</td><td headers="hd_h_drrs.T.notable_sall4_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.2663A>G</td><td headers="hd_h_drrs.T.notable_sall4_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.His888Arg</td><td headers="hd_h_drrs.T.notable_sall4_pathogenic_variants_1_1_1_4" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#drrs.Molecular_Pathogenesis">Molecular Pathogenesis</a>, <b>Mechanism of disease causation</b>.</td></tr><tr><td headers="hd_h_drrs.T.notable_sall4_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2713C>T</td><td headers="hd_h_drrs.T.notable_sall4_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg905Ter</td></tr><tr><td headers="hd_h_drrs.T.notable_sall4_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.541G>A</td><td headers="hd_h_drrs.T.notable_sall4_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Val181Met</td><td headers="hd_h_drrs.T.notable_sall4_pathogenic_variants_1_1_1_4" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Gain-of-function variants in premature ovarian dysfunction</td></tr><tr><td headers="hd_h_drrs.T.notable_sall4_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1790A>G</td><td headers="hd_h_drrs.T.notable_sall4_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Lys597Arg</td></tr><tr><td headers="hd_h_drrs.T.notable_sall4_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2279C>T</td><td headers="hd_h_drrs.T.notable_sall4_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Thr760Ile</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 author. <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></dl></div></div></div></div></div><div id="drrs.Chapter_Notes"><h2 id="_drrs_Chapter_Notes_">Chapter Notes</h2><div id="drrs.Acknowledgments"><h3>Acknowledgments</h3><p>The author's research has received funding from the Wilhelm-Sander-Stiftung of Germany, a nonprofit organization funding medical research, and from the Deutsche Forschungsgemeinschaft.</p></div><div id="drrs.Author_Notes"><h3>Author Notes</h3><p>SYNLAB Center for <a href="https://www.humangenetik-freiburg.de/?lang=en" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Human Genetics Freiburg</a></p></div><div id="drrs.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>17 March 2022 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>15 January 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>12 March 2008 (cd) Revision: <a class="def" href="/books/n/gene/glossary/def-item/fish/">FISH</a> analysis available on a clinical basis</div></li><li class="half_rhythm"><div>19 January 2007 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>16 August 2004 (ca) Review posted live</div></li><li class="half_rhythm"><div>1 March 2004 (jk) Original submission</div></li></ul></div></div><div id="drrs.References"><h2 id="_drrs_References_">References</h2><div id="drrs.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="drrs.REF.albaradie.2002.1195">Al-Baradie R, Yamada K, St Hilaire C, Chan WM, Andrews C, McIntosh N, Nakano M, Martonyi EJ, Raymond WR, Okumura S, Okihiro MM, Engle EC. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. <span><span class="ref-journal">Am J Hum Genet. </span>2002;<span class="ref-vol">71</span>:1195–9.</span> [<a href="/pmc/articles/PMC385096/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC385096</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12395297" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12395297</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="drrs.REF.borozdin.2004a.e113">Borozdin W, Boehm D, Leipoldt M, Wilhem C, Reardon W, Clayton-Smith J, Becker K, Muhlendyck H, Winter R, Giray O, Silan F, Kohlhase J. SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenetic mechanism. <span><span class="ref-journal">J Med Genet. </span>2004a;<span class="ref-vol">41</span>:e113. </span> [<a href="/pmc/articles/PMC1735888/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1735888</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15342710" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15342710</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="drrs.REF.borozdin.2007.830">Borozdin W, Graham JM Jr, Boehm D, Bamshad MJ, Spranger S, Burke L, Leipoldt M, Kohlhase J. Multigene deletions on chromosome 20q13.13-q13.2 including SALL4 result in an expanded phenotype of Okihiro syndrome plus developmental delay. <span><span class="ref-journal">Hum Mutat. </span>2007;<span class="ref-vol">28</span>:830.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17623483" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17623483</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="drrs.REF.borozdin.2004b.e102">Borozdin W, Wright MJ, Hennekam RC, Hannibal MC, Crow YJ, Neumann TE, Kohlhase J. Novel mutations in the gene SALL4 provide further evidence for acro-renal-ocular and Okihiro syndromes being allelic entities, and extend the phenotypic spectrum. <span><span class="ref-journal">J Med Genet. </span>2004b;<span class="ref-vol">41</span>:e102. </span> [<a href="/pmc/articles/PMC1735876/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1735876</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15286162" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15286162</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="drrs.REF.ferrell.1966.630">Ferrell RL, Jones B, Lucas RV Jr. Simultaneous occurrence of the Holt-Oram and the Duane syndromes. <span><span class="ref-journal">J Pediatr. </span>1966;<span class="ref-vol">69</span>:630–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/5921340" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5921340</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="drrs.REF.gao.2013.1413">Gao C, Dimitrov T, Yong KJ, Tatetsu H, Jeong HW, Luo HR, Bradner JE, Tenen DG, Chai L. 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SALL4 mutations in Okihiro syndrome (Duane-radial ray syndrome), acro-renal-ocular syndrome, and related disorders. <span><span class="ref-journal">Hum Mutat. </span>2005;<span class="ref-vol">26</span>:176–83.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16086360" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16086360</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="drrs.REF.kohlhase.2002.2979">Kohlhase J, Heinrich M, Schubert L, Liebers M, Kispert A, Laccone F, Turnpenny P, Winter RM, Reardon W. Okihiro syndrome is caused by SALL4 mutations. <span><span class="ref-journal">Hum Mol Genet. </span>2002;<span class="ref-vol">11</span>:2979–87.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12393809" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12393809</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="drrs.REF.kohlhase.2003.473">Kohlhase J, Schubert L, Liebers M, Rauch A, Becker K, Mohammed SN, Newbury-Ecob R, Reardon W. 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Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants. <span><span class="ref-journal">Eur J Hum Genet. </span>2019;<span class="ref-vol">27</span>:360–8.</span> [<a href="/pmc/articles/PMC6460573/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6460573</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30552424" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30552424</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="drrs.REF.wang.2010.224">Wang B, Li L, Xie X, Wang J, Yan J, Mu Y, Ma X. Genetic variation of SAL-Like 4 (SALL4) in ventricular septal defect. <span><span class="ref-journal">Int J Cardiol. </span>2010;<span class="ref-vol">145</span>:224–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19619907" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19619907</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="drrs.REF.wang.2019.83">Wang Q, Li D, Cai B, Chen Q, Li C, Wu Y, Jin L, Wang X, Zhang X, Zhang F. Whole-exome sequencing reveals SALL4 variants in premature ovarian insufficiency: an update on genotype-phenotype correlations. <span><span class="ref-journal">Hum Genet. </span>2019;<span class="ref-vol">138</span>:83–92.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30603774" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30603774</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="drrs.REF.wu.2006.24090">Wu Q, Chen X, Zhang J, Loh YH, Low TY, Zhang W, Zhang W, Sze SK, Lim B, Ng HH. Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells. <span><span class="ref-journal">J Biol Chem. </span>2006;<span class="ref-vol">281</span>:24090–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16840789" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16840789</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="drrs.REF.yang.2008.805">Yang J, Chai L, Gao C, Fowles TC, Alipio Z, Dang H, Xu D, Fink LM, Ward DC, Ma Y. SALL4 is a key regulator of survival and apoptosis in human leukemic cells. <span><span class="ref-journal">Blood. </span>2008;<span class="ref-vol">112</span>:805–13.</span> [<a href="/pmc/articles/PMC2481537/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2481537</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18487508" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18487508</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="drrs.REF.yong.2013.2266">Yong KJ, Gao C, Lim JS, Yan B, Yang H, Dimitrov T, Kawasaki A, Ong CW, Wong KF, Lee S, Ravikumar S, Srivastava S, Tian X, Poon RT, Fan ST, Luk JM, Dan YY, Salto-Tellez M, Chai L, Tenen DG. Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. <span><span class="ref-journal">N Engl J Med. </span>2013;<span class="ref-vol">368</span>:2266–76.</span> [<a href="/pmc/articles/PMC3781214/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3781214</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23758232" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23758232</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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