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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="MYRF-Related Cardiac Urogenital Syndrome" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2022/11/10" /><meta name="citation_author" content="Julie D Kaplan" /><meta name="citation_author" content="Blythe Stewart" /><meta name="citation_author" content="Lev Prasov" /><meta name="citation_author" content="Louise C Pyle" /><meta name="citation_pmid" content="36375006" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK586169/" /><meta name="citation_keywords" content="MYRF-Related Cardiac-Urogenital Syndrome" /><meta name="citation_keywords" content="MYRF-CUGS" /><meta name="citation_keywords" content="Myelin regulatory factor" /><meta name="citation_keywords" content="MYRF" /><meta name="citation_keywords" content="MYRF-Related Cardiac Urogenital Syndrome" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="MYRF-Related Cardiac Urogenital Syndrome" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Julie D Kaplan" /><meta name="DC.Contributor" content="Blythe Stewart" /><meta name="DC.Contributor" content="Lev Prasov" /><meta name="DC.Contributor" content="Louise C Pyle" /><meta name="DC.Date" content="2022/11/10" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK586169/" /><meta name="description" content="MYRF-related cardiac urogenital syndrome (MYRF-CUGS) is primarily characterized by anomalies of the internal and external genitalia, congenital heart defects, and eye anomalies. 46,XY individuals can have a range of anomalies of the genitalia, from isolated unilateral cryptorchidism to ambiguous genitalia to typical-appearing female genitalia. 46,XX individuals can have atypical internal genitalia including absent uterus, absent fallopian tubes, small or absent ovaries, absent vagina, or blind-ending vagina. A number of congenital heart defects have been described, with scimitar syndrome being the most common. Eye issues, present in a vast majority of affected individuals, include high hyperopia and nanophthalmos (an ocular malformation featuring short axial length due to small anterior and posterior segments with thickened choroid and sclera and normal lens volume). Because of the common nature of the eye anomalies, it has been suggested that this condition may be more accurately referred to as "MYRF-related ocular cardiac urogenital syndrome." Other features of the condition include a broad range of developmental delay /intellectual disability (DD/ID), from typical development and cognition to severe DD/ID; pulmonary abnormalities and diaphragmatic issues (congenital diaphragmatic hernia / diaphragmatic eventration); intestinal malrotation; and mild growth and feeding problems." /><meta name="og:title" content="MYRF-Related Cardiac Urogenital Syndrome" /><meta name="og:type" content="book" /><meta name="og:description" content="MYRF-related cardiac urogenital syndrome (MYRF-CUGS) is primarily characterized by anomalies of the internal and external genitalia, congenital heart defects, and eye anomalies. 46,XY individuals can have a range of anomalies of the genitalia, from isolated unilateral cryptorchidism to ambiguous genitalia to typical-appearing female genitalia. 46,XX individuals can have atypical internal genitalia including absent uterus, absent fallopian tubes, small or absent ovaries, absent vagina, or blind-ending vagina. A number of congenital heart defects have been described, with scimitar syndrome being the most common. Eye issues, present in a vast majority of affected individuals, include high hyperopia and nanophthalmos (an ocular malformation featuring short axial length due to small anterior and posterior segments with thickened choroid and sclera and normal lens volume). Because of the common nature of the eye anomalies, it has been suggested that this condition may be more accurately referred to as "MYRF-related ocular cardiac urogenital syndrome." Other features of the condition include a broad range of developmental delay /intellectual disability (DD/ID), from typical development and cognition to severe DD/ID; pulmonary abnormalities and diaphragmatic issues (congenital diaphragmatic hernia / diaphragmatic eventration); intestinal malrotation; and mild growth and feeding problems." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK586169/" /><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/myrf-cugs/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK586169/" /><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="#__NBK586169_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK586169_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/myh9/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/majeed/" 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="_NBK586169_"><span class="title" itemprop="name"><i>MYRF</i>-Related Cardiac Urogenital Syndrome</span></h1><p class="contrib-group"><span itemprop="author">Julie D Kaplan</span>, MD, <span itemprop="author">Blythe Stewart</span>, <span itemprop="author">Lev Prasov</span>, MD, PhD, and <span itemprop="author">Louise C Pyle</span>, MD, PhD.</p><a data-jig="ncbitoggler" href="#__NBK586169_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK586169_ai__"><div class="contrib half_rhythm"><span itemprop="author">Julie D Kaplan</span>, MD<div class="affiliation small">Cleveland Clinic Foundation<br />Cleveland, Ohio<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.fcc@3jnalpak" class="oemail">gro.fcc@3jnalpak</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Blythe Stewart</span><div class="affiliation small">University of Edinburgh<br />Edinburgh, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.ca.de.sms@6-trawets.b" class="oemail">ku.ca.de.sms@6-trawets.b</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Lev Prasov</span>, MD, PhD<div class="affiliation small">University of Michigan Medical School<br />Ann Arbor, Michigan<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.hcimu@vosarpl" class="oemail">ude.hcimu@vosarpl</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Louise C Pyle</span>, MD, PhD<div class="affiliation small">Children's National Medical Center<br />Washington, DC<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.cmnc@elypl" class="oemail">gro.cmnc@elypl</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">November 10, 2022</span>.</p><p><em>Estimated reading time: 27 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="myrf-cugs.Summary" itemprop="description"><h2 id="_myrf-cugs_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>MYRF</i>-related cardiac urogenital syndrome (<i>MYRF</i>-CUGS) is primarily characterized by anomalies of the internal and external genitalia, <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart defects, and eye anomalies. 46,XY individuals can have a range of anomalies of the genitalia, from <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> unilateral cryptorchidism to ambiguous genitalia to typical-appearing female genitalia. 46,XX individuals can have atypical internal genitalia including absent uterus, absent fallopian tubes, small or absent ovaries, absent vagina, or blind-ending vagina. A number of congenital heart defects have been described, with scimitar syndrome being the most common. Eye issues, present in a vast majority of affected individuals, include high hyperopia and nanophthalmos (an ocular malformation featuring short axial length due to small anterior and posterior segments with thickened choroid and sclera and normal lens volume). Because of the common nature of the eye anomalies, it has been suggested that this condition may be more accurately referred to as "<i>MYRF</i>-related ocular cardiac urogenital syndrome." Other features of the condition include a broad range of developmental delay /intellectual disability (DD/ID), from typical development and cognition to severe DD/ID; pulmonary abnormalities and diaphragmatic issues (congenital diaphragmatic hernia / diaphragmatic eventration); intestinal malrotation; and mild growth and feeding problems.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>MYRF</i>-CUGS 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> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variant in <i>MYRF</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>: Standard treatment for differences of sex development (DSD) conditions, including hormone therapy, psychosocial support, gender identity assessment, and surgical intervention (e.g., orchidopexy and/or hypospadias repair); thyroid replacement therapy for hypothyroidism; standard treatment of refractive error, nanophthalmos, DD/ID, <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart defects, diaphragmatic defects, pulmonary hypoplasia, intestinal malrotation, splenic anomalies, and renal anomalies.</p><p><i>Surveillance</i>: Measurement of growth parameters, assessment of developmental progress and educational needs, and monitoring for respiratory insufficiency at each visit; at least annual ophthalmic evaluations; monitoring for onset and progression of puberty at each visit from around age seven years until puberty is complete; assessment of mood, libido, energy, erectile function, acne, breast tenderness, and presence or progression of gynecomastia at each visit in undervirilized 46,XY adolescents and adults; DXA scan in individuals with DSD every three to five years after puberty, or annually if osteopenia is identified. For those on testosterone replacement therapy, measurement of serum testosterone levels at three-month intervals to help establish an optimal dose with subsequent annual measurements; measurement of hematocrit, prostate-specific antigen level, and digital rectal exam three, six, and 12 months after initiation of testosterone therapy and then annually; lipid profile and liver function tests annually.</p><p><i>Agents/circumstances to avoid</i>: Hormone replacement therapy in those with hormone-responsive cancers; oral androgens (e.g., methyltestosterone or fluoxymesterone) for long-term therapy due to liver toxicity.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>MYRF</i>-CUGS is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner. Many affected individuals reported to date 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>
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<i>MYRF</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. Each child of an individual with <i>MYRF</i>-CUGS has a 50% chance of inheriting the <i>MYRF</i> pathogenic variant. Manifestations within a family are highly variable, and offspring may have significantly more or fewer manifestations than the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>. Once the <i>MYRF</i> pathogenic variant has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p></div></div><div id="myrf-cugs.Diagnosis"><h2 id="_myrf-cugs_Diagnosis_">Diagnosis</h2><p>No consensus clinical diagnostic criteria for <i>MYRF</i>-related cardiac urogenital syndrome (<i>MYRF</i>-CUGS) have been published.</p><div id="myrf-cugs.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>MYRF</i>-CUGS <b>should be suspected</b> in individuals with any of the following clinical, imaging, and family history findings.</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Ambiguous genitalia, micropenis, hypospadias, and/or cryptorchidism in 46,XY individuals or müllerian anomalies in 46,XX individuals</div></li><li class="half_rhythm"><div>Eye anomalies including high hyperopia and nanophthalmos</div></li><li class="half_rhythm"><div>Congenital heart defects including hypoplastic left heart or scimitar syndrome (partial or total anomalous pulmonary venous return of the right lung to the inferior vena cava with dextroposition of the heart, right lung and pulmonary artery hypoplasia, and anomalous systemic blood supply to the lung)</div></li><li class="half_rhythm"><div>Congenital diaphragmatic hernia</div></li><li class="half_rhythm"><div>Pulmonary hypoplasia, even in the absence of a diaphragmatic abnormality</div></li></ul><p>
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<b>Imaging findings</b>
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</p><ul><li class="half_rhythm"><div>Hypoplasia or aplasia of ovaries and/or müllerian structures in 46,XX individuals</div></li><li class="half_rhythm"><div>Presence of müllerian structures in 46,XY individuals</div></li><li class="half_rhythm"><div>Intestinal malrotation</div></li></ul><p><b>Family history.</b> Most probands with <i>MYRF</i>-CUGS reported to date have 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>, and thus represent a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case (i.e., a single occurrence in a family). Occasionally, the family history may be consistent with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> inheritance (e.g., affected males and females in multiple generations). The presentation can be extremely variable and parents may be very mildly affected.</p></div><div id="myrf-cugs.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>MYRF</i>-CUGS <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with <a href="#myrf-cugs.Suggestive_Findings">suggestive findings</a> and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variant in <i>MYRF</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK586169/table/myrf-cugs.T.molecular_genetic_testing_us/?report=objectonly" target="object" rid-ob="figobmyrfcugsTmoleculargenetictestingus">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [<a class="bk_pop" href="#myrf-cugs.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>MYRF</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.</p><p>Molecular genetic testing approaches can include a combination of <b><a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing</b> (single-gene testing, <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>) and <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>) depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p><p>Gene-targeted testing requires that the clinician determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing does not. Individuals with the distinctive findings described in <a href="#myrf-cugs.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#myrf-cugs.Option_1">Option 1</a>), whereas those in whom the diagnosis of <i>MYRF</i>-CUGS has not been considered are more likely to be diagnosed using genomic testing (see <a href="#myrf-cugs.Option_2">Option 2</a>).</p><div id="myrf-cugs.Option_1"><h4>Option 1</h4><p>When the phenotypic findings suggest the diagnosis of <i>MYRF</i>-CUGS, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> approaches can include <b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b> or use of a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of <i>MYRF</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-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> to detect exon and whole-gene deletions or duplications.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A differences of sex development, <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart disease, or congenital diaphragmatic hernia <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>MYRF</i> and other genes of interest (see <a href="#myrf-cugs.Differential_Diagnosis">Differential Diagnosis</a>) is most likely 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 <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. 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. Because <i>MYRF</i>-CUGS is a relatively newly recognized condition, multigene panels often do not include this gene. (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.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul></div><div id="myrf-cugs.Option_2"><h4>Option 2</h4><p>When the diagnosis of <i>MYRF</i>-CUGS has not been considered because an individual has atypical or subtle phenotypic features, comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing may be considered.</p><p><b>Comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> is likely involved. <b>Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="myrf-cugs.T.molecular_genetic_testing_us" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>MYRF</i>-Related Cardiac Urogenital Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK586169/table/myrf-cugs.T.molecular_genetic_testing_us/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myrf-cugs.T.molecular_genetic_testing_us_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_myrf-cugs.T.molecular_genetic_testing_us_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_myrf-cugs.T.molecular_genetic_testing_us_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_myrf-cugs.T.molecular_genetic_testing_us_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</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_myrf-cugs.T.molecular_genetic_testing_us_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MYRF</i>
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</td><td headers="hd_h_myrf-cugs.T.molecular_genetic_testing_us_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_myrf-cugs.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <sup>4</sup></td></tr><tr><td headers="hd_h_myrf-cugs.T.molecular_genetic_testing_us_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>5</sup></td><td headers="hd_h_myrf-cugs.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported <sup>4</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="myrf-cugs.TF.1.1"><p class="no_margin">See <a href="/books/NBK586169/#myrf-cugs.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="myrf-cugs.TF.1.2"><p class="no_margin">See <a href="#myrf-cugs.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="myrf-cugs.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="myrf-cugs.TF.1.4"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bk_pop" href="#myrf-cugs.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd><dt>5. </dt><dd><div id="myrf-cugs.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></dl></div></div></div></div></div></div><div id="myrf-cugs.Clinical_Characteristics"><h2 id="_myrf-cugs_Clinical_Characteristics_">Clinical Characteristics</h2><div id="myrf-cugs.Clinical_Description"><h3>Clinical Description</h3><p>To date, 54 individuals with <i>MYRF</i>-related cardiac urogenital syndrome (<i>MYRF</i>-CUGS) (more than 20 unpublished, and 32 published plus an extremely large multiplex family) have been identified with a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>MYRF</i> [Authors, personal observation; <a class="bk_pop" href="#myrf-cugs.REF.chitayat.2018.2041">Chitayat et al 2018</a>; <a class="bk_pop" href="#myrf-cugs.REF.pinz.2018.969">Pinz et al 2018</a>; <a class="bk_pop" href="#myrf-cugs.REF.qi.2018.e1007822">Qi et al 2018</a>; <a class="bk_pop" href="#myrf-cugs.REF.garnai.2019.e1008130">Garnai et al 2019</a>; <a class="bk_pop" href="#myrf-cugs.REF.guo.2019.2904">Guo et al 2019</a>; <a class="bk_pop" href="#myrf-cugs.REF.hamanaka.2019.2319">Hamanaka et al 2019</a>; <a class="bk_pop" href="#myrf-cugs.REF.rossetti.2019.1376">Rossetti et al 2019</a>; <a class="bk_pop" href="#myrf-cugs.REF.siggs.2019.527">Siggs et al 2019</a>; <a class="bk_pop" href="#myrf-cugs.REF.xiao.2019.1077">Xiao et al 2019</a>; <a class="bk_pop" href="#myrf-cugs.REF.globa.2022.810782">Globa et al 2022</a>; <a class="bk_pop" href="#myrf-cugs.REF.gupta.2022.2187">Gupta et al 2022</a>]. The following description of the phenotypic features associated with <i>MYRF</i>-CUGS is based on these reports.</p><div id="myrf-cugs.T.myrfrelated_cardiac_urogenit" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p><i>MYRF</i>-Related Cardiac Urogenital Syndrome: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK586169/table/myrf-cugs.T.myrfrelated_cardiac_urogenit/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myrf-cugs.T.myrfrelated_cardiac_urogenit_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons<br />w/Feature</th><th id="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_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_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Genital anomalies (internal &/or external)</td><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">32/36 (89%)</td><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Genital anomalies can be present in both 46,XX & 46,XY persons.</td></tr><tr><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eye anomalies</td><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">16/19 (84%)</td><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">High hyperopia or nanophthalmos are predominant.</td></tr><tr><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental delay / intellectual disability</td><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15/20 (75%)</td><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">When present, can range from mild speech delay only to ID (lowest reported IQ: 63) <sup>1</sup></td></tr><tr><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Congenital heart defects</td><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">26/38 (68%)</td><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Congenital diaphragmatic hernia</td><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15/48 (31%)</td><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Some affected persons have diaphragmatic eventration.</td></tr><tr><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Primary pulmonary hypoplasia</td><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10/33 (30%)</td><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Of 33 persons who did NOT have CDH, 10 had pulmonary hypoplasia.</td></tr><tr><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gastrointestinal issue</td><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5 affected persons</td><td headers="hd_h_myrf-cugs.T.myrfrelated_cardiac_urogenit_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3 w/intestinal malrotation, 2 w/splenic anomalies</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">CDH = <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> diaphragmatic hernia; ID = intellectual disability; IQ = intelligence quotient</p></div></dd><dt>1. </dt><dd><div id="myrf-cugs.TF.2.1"><p class="no_margin">Normal IQ level is considered greater than or equal to 70.</p></div></dd></dl></div></div></div><p><b>Variations in genitalia</b> may be the only finding in an individual with <i>MYRF</i>-CUGS and manifestations may be subtle.</p><ul><li class="half_rhythm"><div><b>46,XY individuals.</b> The majority of reported individuals have a 46,XY <a class="def" href="/books/n/gene/glossary/def-item/karyotype/">karyotype</a>. The genitourinary anomalies are very broad and range from <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> unilateral cryptorchidism to typically appearing female genitalia. Common physical findings may include micropenis, hypospadias, chordee, small testes, bifid scrotum, and/or persistent urachus. Müllerian structures including uterus and vagina (typically hypoplastic) may be present. Consistent with the full spectrum of nonbinary (ambiguous) genitalia, some individuals have varying degrees of testicular dysgenesis including Sertoli and/or Leydig cell hyperplasia, paucity of germ cells, tubular atrophy, and decreased fertility / infertility [<a class="bk_pop" href="#myrf-cugs.REF.hamanaka.2019.2319">Hamanaka et al 2019</a>, <a class="bk_pop" href="#myrf-cugs.REF.globa.2022.810782">Globa et al 2022</a>, <a class="bk_pop" href="#myrf-cugs.REF.gupta.2022.2187">Gupta et al 2022</a>].</div></li><li class="half_rhythm"><div><b>XX individuals.</b> Only six affected individuals have been reported with a 46,XX chromosomal complement. Of these, three had atypical internal genitalia, including absent uterus, fallopian tubes, small or absent ovaries, absent vagina, or blind-ending vagina.</div></li></ul><p><b>Ophthalmic involvement.</b> Of 19 individuals with well described and deeply evaluated eye morphology, 16 had high hyperopia (farsightedness). Some were evaluated because of clinical concerns, and some were seen because of their <i>MYRF</i>-CUGS diagnosis. Some were ascertained from cohorts of individuals with nanopthalmos, so this particular finding may be an overestimate. These 19 individuals do not include the family reported by <a class="bk_pop" href="#myrf-cugs.REF.garnai.2019.e1008130">Garnai et al [2019]</a>, nor do they include an additional large multiplex family that had ocular phenotyping only, as these individuals may have the ocular-limited allelic condition (see <a href="#myrf-cugs.Genetically_Related_Allelic_Di">Genetically Related Disorders</a>). Overall, nanopthalmos / high hyperopia appears to be one of the most common features of <i>MYRF</i>-CUGS (see <a href="#myrf-cugs.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>).</p><p>Nanophthalmos is associated with secondary complications including amblyopia, esotropia, angle closure glaucoma, and spontaneous and postsurgical choroidal effusions [<a class="bk_pop" href="#myrf-cugs.REF.carricondo.2018.2735465">Carricondo et al 2018</a>]. Peripheral chorioretinal scarring and mild retinal pigment epithelial mottling have been reported in some affected individuals and may represent a primary finding in individuals with <i>MYRF</i>-CUGS as opposed to sequela of nanophthalmos [<a class="bk_pop" href="#myrf-cugs.REF.garnai.2019.e1008130">Garnai et al 2019</a>, <a class="bk_pop" href="#myrf-cugs.REF.hagedorn.2020.388">Hagedorn et al 2020</a>].</p><p><b>Developmental delay (DD) and intellectual disability (ID).</b> There is a broad range of DD/ID from typical development and cognition to severe developmental delay and intellectual disability. Severity and rates of intellectual disability or delayed developmental milestones may be affected by cardiopulmonary defects. Of the 15 individuals who had DD/ID:</p><ul><li class="half_rhythm"><div>Three had speech delay;</div></li><li class="half_rhythm"><div>Eight had global delays or severe delay (7 of the 8 had cardiopulmonary issues that required extensive hospitalizations and surgeries);</div></li><li class="half_rhythm"><div>Of individuals without cardiopulmonary malformations, only one was reported with a developmental disorder, in this case autism spectrum disorder.</div></li></ul><p><b>Cardiovascular anomalies.</b> The spectrum of cardiovascular anomalies is broad, ranging from <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> dextrocardia to hypoplastic left heart syndrome. Scimitar syndrome (see <a href="#myrf-cugs.Suggestive_Findings">Suggestive Findings</a>) is also commonly reported. Other <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart defects that have been reported:</p><ul><li class="half_rhythm"><div>Atrial septal defect</div></li><li class="half_rhythm"><div>Ventriculoseptal defect</div></li><li class="half_rhythm"><div>Aortic arch hypoplasia</div></li><li class="half_rhythm"><div>Coarctation of the aorta</div></li><li class="half_rhythm"><div>Bicuspid aortic valve</div></li><li class="half_rhythm"><div>Aortic atresia</div></li><li class="half_rhythm"><div>Mitral valve atresia</div></li><li class="half_rhythm"><div>Tetralogy of Fallot</div></li></ul><p><b>Pulmonary abnormalities and diaphragmatic issues.</b> Of deeply phenotyped individuals, approximately half have either <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> diaphragmatic hernia (CDH) or pulmonary hypoplasia without CDH. CDH can be left-sided or right-sided, with left-sided predominance. Diaphragmatic eventration has also been reported.</p><p><b>Gastrointestinal issues.</b> Although not a prominent feature, three individuals have been reported with intestinal malrotation [<a class="bk_pop" href="#myrf-cugs.REF.chitayat.2018.2041">Chitayat et al 2018</a>; Authors, personal observation].</p><ul><li class="half_rhythm"><div>There are further reports of affected individuals having gastroesophagal reflux disease, poor feeding, and G-tube dependence, although some of these issues may be secondary to cardiopulmonary disease.</div></li><li class="half_rhythm"><div>One individual had an accessory spleen [<a class="bk_pop" href="#myrf-cugs.REF.qi.2018.e1007822">Qi et al 2018</a>] and another had a cleft spleen [<a class="bk_pop" href="#myrf-cugs.REF.pinz.2018.969">Pinz et al 2018</a>].</div></li><li class="half_rhythm"><div>There has also been one report of a 46,XY individual with hepatotesticular fusion and splenotesticular fusion [<a class="bk_pop" href="#myrf-cugs.REF.chitayat.2018.2041">Chitayat et al 2018</a>] and one individual with appendiculo-umbilical fistula [Author, personal observation].</div></li></ul><p>
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<b>Growth/feeding</b>
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</p><ul><li class="half_rhythm"><div>One individual is reported to have short stature [<a class="bk_pop" href="#myrf-cugs.REF.qi.2018.e1007822">Qi et al 2018</a>]; intrauterine growth restriction was found in another individual [Authors, personal observation].</div></li><li class="half_rhythm"><div>Microcephaly has been observed in three affected individuals [Authors, personal observation].</div></li><li class="half_rhythm"><div>Poor feeding, which may be secondary to neurologic issues and the effects of severe cardiopulmonary disease, has also been reported.</div></li></ul><p><b>Dysmorphology.</b> The majority of reported individuals who were evaluated have no recognizable <a class="def" href="/books/n/gene/glossary/def-item/dysmorphic/">dysmorphic</a> features. Widely spaced eyes have been observed in three affected individuals [<a class="bk_pop" href="#myrf-cugs.REF.chitayat.2018.2041">Chitayat et al 2018</a>; Author, personal observation].</p><p><b>Other rarely reported features.</b> The following have been reported in a few known affected individuals to date. It is unclear if these findings are rare features of <i>MYRF</i>-CUGS or rare co-occurrences of two unrelated findings.</p><ul><li class="half_rhythm"><div>
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<b>Neurologic findings</b>
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</div><ul><li class="half_rhythm"><div>Hypotonia has been reported in three affected individuals.</div></li><li class="half_rhythm"><div>One individual with an autism spectrum disorder diagnosis has been reported; this individual had no major cardiopulmonary disease.</div></li><li class="half_rhythm"><div>One individual who underwent brain MRI had a posterior fossa cyst [<a class="bk_pop" href="#myrf-cugs.REF.hagedorn.2020.388">Hagedorn et al 2020</a>].</div></li><li class="half_rhythm"><div>Two affected individuals had delayed myelination patterns noted on brain MRI.</div></li></ul></li><li class="half_rhythm"><div><b>Endocrinologic.</b> One affected individual had thymic fibrosis and involution [<a class="bk_pop" href="#myrf-cugs.REF.pinz.2018.969">Pinz et al 2018</a>], and another had hypothyroidism [Authors, personal observation].</div></li><li class="half_rhythm"><div><b>Renal.</b> One affected individual with a horseshoe kidney with associated hydronephrosis has been reported [<a class="bk_pop" href="#myrf-cugs.REF.rossetti.2019.1376">Rossetti et al 2019</a>].</div></li></ul></div><div id="myrf-cugs.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>Large families with nanophthalmos as the predominant feature have been found to harbor pathogenic variants that are predicted to alter or truncate the C terminus of the MYRF protein (see <a href="#myrf-cugs.Genetically_Related_Allelic_Di">Genetically Related Disorders</a>); however, it is unclear how comprehensively these individuals were evaluated for other features of <i>MYRF</i>-CUGS. It is unknown if these pathogenic variants cause only an ocular <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> or if they predispose to the ocular findings in individuals with <i>MYRF</i>-CUGS.</p><ul><li class="half_rhythm"><div>The <i>MYRF</i> <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <a href="/books/NBK586169/table/myrf-cugs.T.notable_myrf_pathogenic_vari/?report=objectonly" target="object" rid-ob="figobmyrfcugsTnotablemyrfpathogenicvari">c.3376-1G>A</a> has been associated with nanophthalmos [<a class="bk_pop" href="#myrf-cugs.REF.garnai.2019.e1008130">Garnai et al 2019</a>]. Four of 41 sampled individuals in the large family with this pathogenic variant have cardiac defects.</div></li><li class="half_rhythm"><div>Truncating/altering C-terminal pathogenic variants (<a class="def" href="/books/n/gene/glossary/def-item/splicing/">splicing</a> or single-base <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a>) predispose to <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> high hyperopia and nanophthalmos [<a class="bk_pop" href="#myrf-cugs.REF.garnai.2019.e1008130">Garnai et al 2019</a>, <a class="bk_pop" href="#myrf-cugs.REF.guo.2019.2904">Guo et al 2019</a>, <a class="bk_pop" href="#myrf-cugs.REF.siggs.2019.527">Siggs et al 2019</a>].</div></li></ul></div><div id="myrf-cugs.Nomenclature"><h3>Nomenclature</h3><p>Because nanopthalmos /high hyperopia appears to be one of the most common features in <i>MYRF</i>-CUGS, the authors suggest that the disorder be referred to as <i>MYRF</i>-related ocular cardiac urogenital syndrome or <i>MYRF</i>-OCUGS.</p></div><div id="myrf-cugs.Prevalence"><h3>Prevalence</h3><p>The prevalence of <i>MYRF</i>-CUGS is unknown; it has been identified in more than 56 individuals.</p></div></div><div id="myrf-cugs.Genetically_Related_Allelic_Di"><h2 id="_myrf-cugs_Genetically_Related_Allelic_Di_">Genetically Related (Allelic) Disorders</h2><p><b>Nanophthalmos/hyperopia.</b> It is unclear whether certain pathogenic variants in <i>MYRF</i> can lead to <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> nanophthalmos/hyperopia without other features of <i>MYRF</i>-related cardiac urogenital syndrome (<i>MYRF</i>-CUGS) (see <a href="#myrf-cugs.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>). Some of the individuals reported with "isolated" eye findings were not sufficiently evaluated for features of <i>MYRF</i>-CUGS. Additionally, some of these individuals have related family members with the same pathogenic <i>MYRF</i> variant who have other system manifestations consistent with the <i>MYRF</i>-CUGS spectrum. For example, in one large kindred in which nanophthalmos segregated with a pathogenic <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variant in <i>MYRF</i>, several of the affected individuals had dextrocardia and one had pulmonary hypoplasia [<a class="bk_pop" href="#myrf-cugs.REF.garnai.2019.e1008130">Garnai et al 2019</a>]. In another family of five affected individuals, the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> had nanophthalmos only and the father had nanophthalmos and unilateral cryptorchidism; the other three individuals had more classic <i>MYRF</i>-CUGS findings [<a class="bk_pop" href="#myrf-cugs.REF.gupta.2022.2187">Gupta et al 2022</a>].</p><p><b>Mild encephalitis / encephalopathy with reversible myelin vacuolization.</b> This <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> was described by <a class="bk_pop" href="#myrf-cugs.REF.kurahashi.2018.98">Kurahashi et al [2018]</a> in nine individuals from two unrelated families and was attributed to a specific <i>MYRF</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, c.1208A>G (p.Gln403Arg). It is unclear if this phenotype is distinct from <i>MYRF</i>-CUGS or is at one end of the phenotypic spectrum; thus far, there has been no reported overlap.</p></div><div id="myrf-cugs.Differential_Diagnosis"><h2 id="_myrf-cugs_Differential_Diagnosis_">Differential Diagnosis</h2><div id="myrf-cugs.T.genes_of_interest_in_the_dif" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of <i>MYRF</i>-Related Cardiac Urogenital Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK586169/table/myrf-cugs.T.genes_of_interest_in_the_dif/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myrf-cugs.T.genes_of_interest_in_the_dif_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Key Features</th><th id="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing Features / Comment</th></tr></thead><tbody><tr><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FAM111A</i>
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</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Kenny-Caffey syndrome type 2 (KCS2) (See <a href="/books/n/gene/fam111a-dysp/"><i>FAM111A</i>-Related Skeletal Dysplasias</a>.)</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nanophthalmos, short stature, hypocalcemia, thickening medullary & cortical bone</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">KCS2 is assoc w/macrocephaly & low birth weight. <sup>1</sup></td></tr><tr><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GATA4</i>
|
||
</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Testicular anomalies ± <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart disease (TACHD) (OMIM <a href="https://omim.org/entry/615542" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615542</a>)</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CHD, GU anomalies incl ambiguous genitalia</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CDH, ocular, & pulmonary anomalies are not reported in TACHD. <sup>2</sup></td></tr><tr><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>MFRP</i>
|
||
</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MFRP-related nanophthalmos (OMIM <a href="https://omim.org/entry/609549" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">609549</a>)</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nanophthalmos, retinal degeneration</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Syndromic features are not reported in <i>MFRP</i>-related nanophthalmos. <sup>3</sup></td></tr><tr><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>NR2F2</i>
|
||
</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">46,XX sex reversal (SRXX5) (OMIM <a href="https://omim.org/entry/618901" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">618901</a>)</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">46,XX ambiguous genitalia or sex reversal, müllerian anomalies, HLHS, CDH (1 person)</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">SRXX5 is assoc w/ambiguous (nonbinary) genitalia in 46,XX persons (vs 46,XY persons in CUGS) & eyelid anomalies; hyperopia is not reported. <sup>4</sup></td></tr><tr><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PIGL</i>
|
||
</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PIGL</i>-related disorder <sup>5</sup></td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CDH, ambiguous genitalia (1 family)</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PIGL</i>-related disorder is assoc w/coloboma, vermian hypoplasia, & cleft palate. <sup>5</sup></td></tr><tr><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PRSS56</i>
|
||
</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PRSS56</i>-related nanophthalmos <sup>6</sup></td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nanophthalmos, posterior microphthalmos</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Syndromic features are not reported in <i>PRDD56</i>-related nanophthalmos. <sup>6</sup></td></tr><tr><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>RLIM</i>
|
||
</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Tonne-Kalscheuer syndrome (TOKAS) (OMIM <a href="https://omim.org/entry/300978" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">300978</a>)</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DD, microcephaly, CHD, CDH, GU anomalies (cryptorchidism, hypospadias, micropenis)</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">TOKAS is assoc w/hypertelorism, a long, narrow face, & micrognathia. <sup>7</sup></td></tr><tr><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SPECC1L</i>
|
||
</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Teebi hypertelorism syndrome 1 (TBHS1) (OMIM <a href="https://omim.org/entry/145420" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">145420</a>)</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypertelorism, CDH, CHD, müllerian anomalies</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In TBHS1, CDH is rare, pulmonary hypoplasia is only reported as secondary to CDH or omphalocele, hypertelorism is a prominent feature, & CHD are limited to ASD/VSD. <sup>8</sup></td></tr><tr><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TMEM98</i>
|
||
</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>TMEM98</i>-related nanophthalmos (OMIM <a href="https://omim.org/entry/615972" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615972</a>)</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nanophthalmos</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Syndromic features have not been reported in <i>TMEM98</i>-related nanophthalmos. <sup>9</sup></td></tr><tr><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>WT1</i>
|
||
</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Meacham syndrome (See <a href="/books/n/gene/wt1-dis/"><i>WT1</i> Disorder</a>.)</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CDH, pulmonary dysplasia, complex CHD, & GU abnormalities incl ambiguous genitalia & gonadal dysgenesis</td><td headers="hd_h_myrf-cugs.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">A person w/clinical diagnosis of Meacham syndrome was later found to have <i>MYRF</i>-CUGS. <sup>10</sup></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; CDH = <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> diaphragmatic hernia; CHD = congenital heart defects; GU = genitourinary; HLHS = hypoplastic left heart syndrome; <i>MYRF</i>-CUGS = <i>MYRF</i>-related cardiac urogenital syndrome; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; 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="myrf-cugs.TF.3.1"><p class="no_margin">
|
||
<a class="bk_pop" href="#myrf-cugs.REF.unger.2013.990">Unger et al [2013]</a>
|
||
</p></div></dd><dt>2. </dt><dd><div id="myrf-cugs.TF.3.2"><p class="no_margin">
|
||
<a class="bk_pop" href="#myrf-cugs.REF._elik.2022.469">Çelik et al [2022]</a>
|
||
</p></div></dd><dt>3. </dt><dd><div id="myrf-cugs.TF.3.3"><p class="no_margin">
|
||
<a class="bk_pop" href="#myrf-cugs.REF.zenteno.2009.1794">Zenteno et al [2009]</a>
|
||
</p></div></dd><dt>4. </dt><dd><div id="myrf-cugs.TF.3.4"><p class="no_margin">
|
||
<a class="bk_pop" href="#myrf-cugs.REF.bashamboo.2018.487">Bashamboo et al [2018]</a>
|
||
</p></div></dd><dt>5. </dt><dd><div id="myrf-cugs.TF.3.5"><p class="no_margin">
|
||
<a class="bk_pop" href="#myrf-cugs.REF.winterpaquette.2022.104501">Winter-Paquette et al [2022]</a>
|
||
</p></div></dd><dt>6. </dt><dd><div id="myrf-cugs.TF.3.6"><p class="no_margin">
|
||
<a class="bk_pop" href="#myrf-cugs.REF.nair.2011.579">Nair et al [2011]</a>
|
||
</p></div></dd><dt>7. </dt><dd><div id="myrf-cugs.TF.3.7"><p class="no_margin">
|
||
<a class="bk_pop" href="#myrf-cugs.REF.mehvari.2020.e1418">Mehvari et al [2020]</a>
|
||
</p></div></dd><dt>8. </dt><dd><div id="myrf-cugs.TF.3.8"><p class="no_margin">
|
||
<a class="bk_pop" href="#myrf-cugs.REF.zhang.2020.103851">Zhang et al [2020]</a>
|
||
</p></div></dd><dt>9. </dt><dd><div id="myrf-cugs.TF.3.9"><p class="no_margin">
|
||
<a class="bk_pop" href="#myrf-cugs.REF.awadalla.2014.970">Awadalla et al [2014]</a>
|
||
</p></div></dd><dt>10. </dt><dd><div id="myrf-cugs.TF.3.10"><p class="no_margin">
|
||
<a class="bk_pop" href="#myrf-cugs.REF.tanaka.2021.68">Tanaka et al [2021]</a>
|
||
</p></div></dd></dl></div></div></div><p><a href="/books/n/gene/fryns/">Fryns syndrome</a> is characterized by diaphragmatic defects, pulmonary hypoplasia, characteristic facial features, and short distal phalanges. Associated anomalies can include polyhydramnios, cloudy corneas and/or microphthalmia, orofacial clefting, renal dysplasia / renal cortical cysts, and/or malformations involving the brain, cardiovascular system, gastrointestinal system, and/or genitalia. Genetic heterogeneity for Fryns syndrome is likely. Biallelic pathogenic variants in <i>PIGN</i> have been identified in at least ten individuals with Fryns syndrome [<a class="bk_pop" href="#myrf-cugs.REF.brady.2014.487">Brady et al 2014</a>, <a class="bk_pop" href="#myrf-cugs.REF.mcinerneyleo.2016.695">McInerney-Leo et al 2016</a>, <a class="bk_pop" href="#myrf-cugs.REF.alessandri.2018.340">Alessandri et al 2018</a>].</p><p><b>PAGOD syndrome</b> (OMIM <a href="https://omim.org/entry/202660" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">202660</a>). PAGOD (<i>p</i>ulmonary hypoplasia, <i>ag</i>onadism, <i>o</i>mphalocele, and <i>d</i>iaphragmatic hernia) syndrome and <i>MYRF</i>-related cardiac urogenital syndrome have significant clinical overlap [<a class="bk_pop" href="#myrf-cugs.REF.rossetti.2019.1376">Rossetti et al 2019</a>]. Hypoplastic left heart syndrome has been reported in several individuals with PAGOD. Significant undervirilization in 46,XY individuals or ambiguous genitalia is common [<a class="bk_pop" href="#myrf-cugs.REF.gavrilova.2009.2241">Gavrilova et al 2009</a>]. The molecular basis of PAGOD is unknown at this time.</p></div><div id="myrf-cugs.Management"><h2 id="_myrf-cugs_Management_">Management</h2><p>No clinical practice guidelines for <i>MYRF</i>-related cardiac urogenital syndrome (<i>MYRF</i>-CUGS) have been published.</p><div id="myrf-cugs.Evaluations_Following_Initial"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <i>MYRF</i>-CUGS, the evaluations summarized in <a href="/books/NBK586169/table/myrf-cugs.T.recommended_evaluations_foll/?report=objectonly" target="object" rid-ob="figobmyrfcugsTrecommendedevaluationsfoll">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="myrf-cugs.T.recommended_evaluations_foll" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with <i>MYRF</i>-Related Cardiac Urogenital Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK586169/table/myrf-cugs.T.recommended_evaluations_foll/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myrf-cugs.T.recommended_evaluations_foll_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_myrf-cugs.T.recommended_evaluations_foll_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_myrf-cugs.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Constitutional</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of growth parameters</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To identify short stature & microcephaly</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genitourinary</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Thorough physical exam for phallic length, opening of urethral meatus, & location of gonads in 46,XY persons</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If gonads are not palpable, pelvic & abdominal ultrasound may be considered.</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Consider pelvic ultrasound.</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In 46,XX & 46,XY neonates & pubertal/postpubertal females <sup>1</sup></td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Renal ultrasound</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for structure & hydronephrosis.</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Endocrine</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hormonal eval as directed by endocrinologist</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For those w/46,XY DSD</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Consider TSH & free T4.</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for hypothyroidism in those w/poor growth &/or DD</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_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_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmic eval</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for eye anomalies & refractive error</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Development</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To incl motor, adaptive, cognitive, & speech-language eval</div></li><li class="half_rhythm"><div>Eval for early intervention / special education</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiovascular</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart defects</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Respiratory</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical assessment of breathing status & auscultation</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl assessment of work of breathing & oxygen saturation, if clinically indicated</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Chest radiograph</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for pulmonary hypoplasia & diaphragmatic hernia</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal/</b>
|
||
<br />
|
||
<b>Feeding <sup>2</sup></b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gastroenterology / nutrition / feeding team eval</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To incl eval of aspiration risk & nutritional status, esp in those w/cardiac &/or pulmonary malformations, delayed milestones, or neurologic deficits</div></li><li class="half_rhythm"><div>Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Consider upper GI exam w/small bowel follow through.</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To evaluate for malrotation</div></li><li class="half_rhythm"><div>This is esp important when a PEG or gastrostomy tube is being considered.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Consider abdominal ultrasound.</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for splenic anomalies & renal anomalies</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_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_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>3</sup></td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_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>MYRF</i>-CUGS to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family support</b>
|
||
<br />
|
||
<b>& resources</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myrf-cugs.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for:
|
||
<ul><li class="half_rhythm"><div>Community or <a href="#myrf-cugs.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Social work involvement for parental support;</div></li><li class="half_rhythm"><div>Home nursing referral.</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">DD = developmental delay; DSD = differences of sex development; PEG = percutaneous gastrostomy; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; <i>MYRF</i>-CUGS = <i>MYRF</i>-related cardiac urogenital syndrome; TSH = thyroid-stimulating hormone</p></div></dd><dt>1. </dt><dd><div id="myrf-cugs.TF.4.1"><p class="no_margin">Müllerian structures may be difficult to visualize on imaging in individuals who are not exposed to estrogen. Therefore, inability to visualize internal müllerian structures on imaging does not rule out their presence. Examination under anesthesia and/or laparoscopy may be required to detect the presence of müllerian structures and to define any müllerian anomalies.</p></div></dd><dt>2. </dt><dd><div id="myrf-cugs.TF.4.2"><p class="no_margin">Growth and feeding issues are often secondary complications in affected individuals with cardiopulmonary issues.</p></div></dd><dt>3. </dt><dd><div id="myrf-cugs.TF.4.3"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="myrf-cugs.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in cardiology, endocrinology, genetics, gastroenterology, gynecology, ophthalmology, pulmonology, psychology, and urology (see <a href="/books/NBK586169/table/myrf-cugs.T.treatment_of_manifestations/?report=objectonly" target="object" rid-ob="figobmyrfcugsTtreatmentofmanifestations">Table 5</a>).</p><div id="myrf-cugs.T.treatment_of_manifestations" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with <i>MYRF</i>-Related Cardiac Urogenital Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK586169/table/myrf-cugs.T.treatment_of_manifestations/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myrf-cugs.T.treatment_of_manifestations_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_myrf-cugs.T.treatment_of_manifestations_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_myrf-cugs.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Undervirilization or ambiguous (nonbinary) genitalia in 46,XY persons</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard therapy per DSD team <sup>1</sup></td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Which may incl hormonal therapy, psychosocial support, gender identity assessment, & surgical intervention (e.g., orchidopexy &/or hypospadias repair)</td></tr><tr><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Low or absent serum testosterone levels <sup>2</sup></b>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>After age 14 yrs, low-dose testosterone replacement therapy can be initiated <sup>3, 4</sup>: testosterone enanthate <sup>5</sup> is given IM <sup>6</sup> every 3-4 wks starting at 100 mg & ↑ by 50 mg every 6 mos to 200-400 mg.</div></li><li class="half_rhythm"><div>In adulthood, the treatment should plateau, at best possible dosage, typically between 50 & 400 mg every 2-4 wks.</div></li></ul>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>If person has short stature & is eligible for growth hormone therapy, either delay testosterone therapy or give at lower doses initially to maximize growth potential.</div></li><li class="half_rhythm"><div>Side effects incl pain assoc w/injection & large variations of serum testosterone concentration between injections, resulting in ↑ risk of mood swings.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Ovarian hypoplasia</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to gynecologist or reproductive endocrinologist for discussion of initiating/continuing HRT & fertility options</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hypothyroidism</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Thyroid replacement therapy</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per endocrinologist</td></tr><tr><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Refractive error, amblyopia, angle closure glaucoma, nanophthalmos</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per ophthalmologist</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Developmental delay /</b>
|
||
<br />
|
||
<b>Intellectual disability</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#myrf-cugs.Developmental_Delay__Intellect">Developmental Delay / Intellectual Disability Management Issues</a>.</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Structural cardiac abnormalities</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per cardiologist</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Diaphragmatic hernia</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per surgeon & pulmonologist</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Pulmonary hypoplasia</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per pulmonologist</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Intestinal malrotation</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per surgeon & gastroenterologist</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Splenic anomalies</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per immunologist</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Renal anomalies / Hydronephrosis</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per urologist &/or nephrologist</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family/Community</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ensure appropriate social work involvement to connect families w/local resources, respite, & support.</div></li><li class="half_rhythm"><div>Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.</div></li></ul>
|
||
</td><td headers="hd_h_myrf-cugs.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ongoing assessment of need for learning or developmental supports</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">DSD = differences of sex development; HRT = hormone replacement therapy; IM = intramuscular</p></div></dd><dt>1. </dt><dd><div id="myrf-cugs.TF.5.1"><p class="no_margin">The DSD team should include geneticist, endocrinologist, psychologist, urologist, and possibly gynecologist. If a multidisciplinary team is unavailable, these specialties can be consulted individually.</p></div></dd><dt>2. </dt><dd><div id="myrf-cugs.TF.5.2"><p class="no_margin">Prior to initiating treatment with supplemental testosterone in adults, perform a digital rectal examination and measurement of prostate-specific antigen, abnormalities of which would be a contraindication to the treatment.</p></div></dd><dt>3. </dt><dd><div id="myrf-cugs.TF.5.3"><p class="no_margin">Physicians should check for the most current preparations and dosage recommendations before initiating testosterone replacement therapy.</p></div></dd><dt>4. </dt><dd><div id="myrf-cugs.TF.5.4"><p class="no_margin">Initial high doses of testosterone should be avoided to prevent priapism.</p></div></dd><dt>5. </dt><dd><div id="myrf-cugs.TF.5.5"><p class="no_margin">Injection of testosterone enanthate is the preferred method of replacement therapy because of low cost and easy, at-home regulation of dosage.</p></div></dd><dt>6. </dt><dd><div id="myrf-cugs.TF.5.6"><p class="no_margin">Alternative delivery systems that result in a more stable dosing include transdermal patches (scrotal and nonscrotal) and transdermal gels. Testosterone-containing gels, however, are associated with the risk of interpersonal transfer, which can be reduced by the use of newer hydroalcoholic gels.</p></div></dd></dl></div></div></div><div id="myrf-cugs.Developmental_Delay__Intellect"><h4>Developmental Delay / Intellectual Disability Management Issues</h4><p>The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.</p><p><b>Ages 0-3 years.</b> Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.</p><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:</p><ul><li class="half_rhythm"><div>IEP services:</div><ul><li class="half_rhythm"><div>An IEP provides specially designed instruction and related services to children who qualify.</div></li><li class="half_rhythm"><div>IEP services will be reviewed annually to determine whether any changes are needed.</div></li><li class="half_rhythm"><div>Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.</div></li><li class="half_rhythm"><div>Vision consultants should be a part of the child's IEP team to support access to academic material.</div></li><li class="half_rhythm"><div>PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</div></li><li class="half_rhythm"><div>As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.</div></li></ul></li><li class="half_rhythm"><div>A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.</div></li><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div><div id="myrf-cugs.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p>
|
||
<b>Gross motor dysfunction</b>
|
||
</p><ul><li class="half_rhythm"><div>Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).</div></li><li class="half_rhythm"><div>Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).</div></li></ul><p><b>Fine motor dysfunction.</b> Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.</p><p><b>Communication.</b> Speech-language therapy is recommended for those with speech delay.</p></div></div><div id="myrf-cugs.Surveillance"><h3>Surveillance</h3><div id="myrf-cugs.T.recommended_surveillance_for" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with <i>MYRF</i>-Related Cardiac Urogenital Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK586169/table/myrf-cugs.T.recommended_surveillance_for/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myrf-cugs.T.recommended_surveillance_for_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_myrf-cugs.T.recommended_surveillance_for_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_myrf-cugs.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Constitutional</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of growth parameters</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_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_myrf-cugs.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor for onset & progression of puberty.</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit starting at age ~7 yrs until puberty is completed</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Low testosterone</b>
|
||
<br />
|
||
<b>levels</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment of mood, libido, energy, erectile function, acne, breast tenderness, & presence or progression of gynecomastia</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit in undervirilized 46,XY adolescents & adults</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>For those on</b>
|
||
<br />
|
||
<b>testosterone</b>
|
||
<br />
|
||
<b>replacement</b>
|
||
<br />
|
||
<b>therapy</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of serum testosterone levels</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At 3-mo intervals (prior to next injection) to evaluate nadir testosterone concentrations <sup>1</sup>; once optimal dose is established, annual measurement is sufficient.</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Digital rectal exam & measurement of PSA in adults <sup>2</sup></td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">3, 6, & 12 mos after initiation of testosterone therapy; then annually</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Measurement of hematocrit <sup>3</sup></td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Lipid profile & liver function tests</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_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_myrf-cugs.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmic eval</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annuall, or as clinically indicated if features of amblyopia, strabismus, or angle closure glaucoma are present</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Development</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental progress & educational needs.</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Respiratory</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor for evidence of respiratory insufficiency.</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Osteopenia</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DXA scan in persons w/DSD</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 3-5 yrs after puberty, or annually if osteopenia has been identified</td></tr><tr><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family/</b>
|
||
<br />
|
||
<b>Community</b>
|
||
</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> if new questions arise (e.g., family planning).</td><td headers="hd_h_myrf-cugs.T.recommended_surveillance_for_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">DXA = dual-energy x-ray absorptiometry; DSD = differences of sex development; PSA = prostate-specific antigen</p></div></dd><dt>1. </dt><dd><div id="myrf-cugs.TF.6.1"><p class="no_margin">Concentrations lower than 200 ng/dL or higher than 500 ng/dL may require adjustment of total dose or frequency.</p></div></dd><dt>2. </dt><dd><div id="myrf-cugs.TF.6.2"><p class="no_margin">To evaluate for the presence of an overt prostate cancer, which would be a contraindication to supplemental testosterone treatment</p></div></dd><dt>3. </dt><dd><div id="myrf-cugs.TF.6.3"><p class="no_margin">Increased hematocrit may lead to a subsequent risk of hypoxia and sleep apnea.</p></div></dd></dl></div></div></div></div><div id="myrf-cugs.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Contraindications to hormone replacement therapy include hormone-responsive cancers.</p><p>Oral androgens such as methyltestosterone and fluoxymesterone should not be given in hormone replacement therapy (especially for long-term therapy) because of liver toxicity.</p></div><div id="myrf-cugs.Evaluation_of_Relatives_at_Ris"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of screening and treatment measures. Intrafamilial variability of affected individuals is high, and features may be previously underappreciated in a family.</p><p>See <a href="#myrf-cugs.Related_Genetic_Counseling_Iss">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="myrf-cugs.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="myrf-cugs.Genetic_Counseling"><h2 id="_myrf-cugs_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="myrf-cugs.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>MYRF</i>-related cardiac urogenital syndrome (<i>MYRF</i>-CUGS) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p></div><div id="myrf-cugs.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 with <i>MYRF</i>-CUGS reported to date 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>
|
||
<i>MYRF</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>In some families, individuals with <i>MYRF</i>-CUGS have the disorder as the result of a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> inherited from a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parent [<a class="bk_pop" href="#myrf-cugs.REF.gupta.2022.2187">Gupta et al 2022</a>]. Of note, the presentation of <i>MYRF</i>-CUGS can be extremely variable within families and a heterozygous parent may be asymptomatic or very mildly affected.</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> to confirm their genetic status, determine their need for screening and treatment (see <a href="#myrf-cugs.Management">Management</a>), and to allow reliable <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> counseling.</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 class="half_rhythm">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 class="half_rhythm">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><div class="half_rhythm">* A parent with somatic and <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> for a <i>MYRF</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> may be asymptomatic or mildly/minimally affected [<a class="bk_pop" href="#myrf-cugs.REF.garnai.2019.e1008130">Garnai et al 2019</a>].</div></li></ul></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 clinical/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 is known to have the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.</div></li><li class="half_rhythm"><div>The manifestations of <i>MYRF</i>-CUGS within a family are highly variable and sibs who inherit a <i>MYRF</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> may have significantly more or fewer manifestations than the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>. Molecular genetic testing is recommended for the sibs of the proband to determine their need for screening and treatment (see <a href="#myrf-cugs.Management">Management</a>).</div></li><li class="half_rhythm"><div>If the <i>MYRF</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 slightly greater than that of the general population because of the possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a> [<a class="bk_pop" href="#myrf-cugs.REF.garnai.2019.e1008130">Garnai et al 2019</a>].</div></li><li class="half_rhythm"><div>If the parents have not been tested for the <i>MYRF</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> but are clinically unaffected, the risk to the sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for <i>MYRF</i>-CUGS because of the possibility of <a class="def" href="/books/n/gene/glossary/def-item/variable-expressivity/">variable expressivity</a> in a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parent or 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>
|
||
</p><ul><li class="half_rhythm"><div>Each child of an individual with <i>MYRF</i>-CUGS has a 50% chance of inheriting the <i>MYRF</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>Manifestations within a family are highly variable and offspring may have significantly more or fewer manifestations than the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li></ul><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 the <i>MYRF</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the parent's family members may be at risk.</p></div><div id="myrf-cugs.Related_Genetic_Counseling_Iss"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#myrf-cugs.Evaluation_of_Relatives_at_Ris">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="myrf-cugs.Prenatal_Testing_and_Preimplan"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>MYRF</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="myrf-cugs.Resources"><h2 id="_myrf-cugs_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>Accord Alliance</b>
|
||
</div><div><b>Phone:</b> 602-492-4144</div><div>
|
||
<a href="http://www.AccordAlliance.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.AccordAlliance.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>CDH International</b>
|
||
</div><div><b>Email:</b> info@cdhi.org</div><div>
|
||
<a href="https://cdhi.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">cdhi.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>DSD Families</b>
|
||
</div><div>United Kingdom</div><div><b>Email:</b> info@dsdfamilies.org</div><div>
|
||
<a href="https://dsdfamilies.org/charity" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.dsdfamilies.org/charity</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>InterConnect</b>
|
||
</div><div>
|
||
<a href="https://interconnect.support/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://interconnect.support/</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><li class="half_rhythm"><div>
|
||
<b>The Children's Heart Foundation</b>
|
||
</div><div><b>Phone:</b> 847-634-6474</div><div><b>Email:</b> info@childrensheartfoundation.org</div><div>
|
||
<a href="http://www.childrensheartfoundation.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.childrensheartfoundation.org</a>
|
||
</div></li></ul>
|
||
</div><div id="myrf-cugs.Molecular_Genetics"><h2 id="_myrf-cugs_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="myrf-cugs.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>MYRF-Related Cardiac Urogenital Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK586169/table/myrf-cugs.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myrf-cugs.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_myrf-cugs.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_myrf-cugs.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_myrf-cugs.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_myrf-cugs.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_myrf-cugs.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_myrf-cugs.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/745" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>MYRF</i>
|
||
</a>
|
||
</td><td headers="hd_b_myrf-cugs.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=745" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">11q12<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_b_myrf-cugs.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q9Y2G1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Myelin regulatory factor</a>
|
||
</td><td headers="hd_b_myrf-cugs.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=MYRF" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MYRF</a>
|
||
</td><td headers="hd_b_myrf-cugs.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MYRF[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MYRF</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="myrf-cugs.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
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<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="myrf-cugs.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for MYRF-Related Cardiac Urogenital Syndrome (<a href="/omim/608329,618280" 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/NBK586169/table/myrf-cugs.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myrf-cugs.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/608329" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">608329</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MYELIN REGULATORY FACTOR; MYRF</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/618280" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">618280</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CARDIAC-UROGENITAL SYNDROME; CUGS</td></tr></tbody></table></div></div><div id="myrf-cugs.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>MYRF</i> encodes myelin regulatory factor, a membrane-bound <a class="def" href="/books/n/gene/glossary/def-item/transcription-factor/">transcription factor</a> which is proteolytically cleaved into its C- and N-terminal domains. The C-terminal fragment remains in the endoplasmic reticulum while the N-terminal region, which contains the DNA-binding <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a>, travels to the nucleus, where it promotes the expression of target genes. <i>MYRF</i> has been shown to be expressed in a wide range of tissues including the heart, lung, diaphragm, eye, and coelomic epithelium of the fetal gonads. The coelomic epithelium of fetal gonads forms the germinal epithelium, which may account for the differences of sex development <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> seen in some individuals with pathogenic variants in <i>MYRF</i>. It has therefore been postulated that <i>MYRF</i> may be involved in the development of coelomic epithelium-derived cells and tissues.</p><p><b>Mechanism of disease causation.</b> Loss of function</p><div id="myrf-cugs.T.notable_myrf_pathogenic_vari" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Notable <i>MYRF</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK586169/table/myrf-cugs.T.notable_myrf_pathogenic_vari/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myrf-cugs.T.notable_myrf_pathogenic_vari_lrgtbl__"><table><thead><tr><th id="hd_h_myrf-cugs.T.notable_myrf_pathogenic_vari_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_myrf-cugs.T.notable_myrf_pathogenic_vari_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_myrf-cugs.T.notable_myrf_pathogenic_vari_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_myrf-cugs.T.notable_myrf_pathogenic_vari_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_myrf-cugs.T.notable_myrf_pathogenic_vari_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nucleotide/NM_001127392.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_001127392<wbr style="display:inline-block"></wbr>.3</a>
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</td><td headers="hd_h_myrf-cugs.T.notable_myrf_pathogenic_vari_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.3376-1G>A</td><td headers="hd_h_myrf-cugs.T.notable_myrf_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_myrf-cugs.T.notable_myrf_pathogenic_vari_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pathogenic variant assoc w/nanophthalmos [<a class="bk_pop" href="#myrf-cugs.REF.garnai.2019.e1008130">Garnai et al 2019</a>]</td></tr></tbody></table></div></div></div></div><div id="myrf-cugs.Chapter_Notes"><h2 id="_myrf-cugs_Chapter_Notes_">Chapter Notes</h2><div id="myrf-cugs.Author_Notes"><h3>Author Notes</h3><p><b>Louisa (Louise) C Pyle, MD, PhD</b> is a clinical geneticist and physician-scientist specializing in genetics of genitourinary (GU) differences and cancer. Dr Pyle's clinical interests are diagnostic evaluation and care for individuals with intersex (I) traits and differences of sex development (DSD), and other GU differences. She focuses on multidisciplinary integration, molecular diagnosis, and cancer predisposition counseling for her patients and their families. Dr Pyle's research applies genomics and human models to understand vulnerability to infertility and germ cell tumor (GCT). She has identified and characterized clinical risk factors that predispose people to GCT by studying individuals diagnosed with this malignancy, as well as patients carrying a diagnosis of I/DSD. Dr Pyle's goal is to supply new tools that will facilitate improved care for people with I/DSD traits. Web page: <a href="https://childrensnational.org/visit/find-a-provider/louise-pyle" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">childrensnational.org/visit/find-a-provider/louise-pyle</a></p><p><b>Lev Prasov, MD, PhD,</b> is a physician-scientist practicing ophthalmic genetics. His clinical interests are in the diagnostic evaluation and treatment of inherited ocular disorders with specific interests in disorders of refractive error, glaucoma, ocular malformations and inherited retinal diseases. Dr Prasov's research seeks to identify novel genes and pathways in inherited ocular conditions with the hope of developing or improving therapies for these conditions. He uses a combination of human genetics and mammalian and cell culture models to identify and validate disease genes and to identify novel pathways for pathogenesis. Web page: <a href="https://prasov.lab.medicine.umich.edu/about" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">prasov.lab.medicine.umich.edu/about</a></p><p><b>Julie D Kaplan, MD,</b> is Medical Director and Clinical Geneticist for the Center for Personalized Genetic Healthcare in Cleveland Clinic's Genomic Medicine Institute. Her clinical interests include dysmorphology, prenatal genetics, DSD, and international genetics. Web page: <a href="https://my.clevelandclinic.org/staff/29174-julie-kaplan" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">my.clevelandclinic.org/staff/29174-julie-kaplan</a></p></div><div id="myrf-cugs.Acknowledgments"><h3>Acknowledgments</h3><p>We thank all of the patients and their families for their participation in our studies.</p><p>Dr Pyle's work has been supported by T32GM008638 and K08CA248704. Dr Prasov's work has been supported in part by K08EY032098 and the Glaucoma Research Foundation.</p></div><div id="myrf-cugs.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>10 November 2022 (ma) Review posted live</div></li><li class="half_rhythm"><div>22 June 2022 (jk) Original submission</div></li></ul></div></div><div id="myrf-cugs.References"><h2 id="_myrf-cugs_References_">References</h2><div id="myrf-cugs.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.alessandri.2018.340">Alessandri JL, Gordon CT, Jacquemont ML, Gruchy N, Ajeawung NF, Benoist G, Oufadem M, Chebil A, Duffourd Y, Dumont C, Gérard M, Kuentz P, Jouan T, Filippini F, Nguyen TTM, Alibeu O, Bole-Feysot C, Nitschké P, Omarjee A, Ramful D, Randrianaivo H, Doray B, Faivre L, Amiel J, Campeau PM, Thevenon J. Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome. <span><span class="ref-journal">Eur J Hum Genet. </span>2018;<span class="ref-vol">26</span>:340–9.</span> [<a href="/pmc/articles/PMC5839001/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5839001</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29330547" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29330547</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.awadalla.2014.970">Awadalla MS, Burdon KP, Souzeau E, Landers J, Hewitt AW, Sharma S, Craig JE. Mutation in TMEM98 in a large white kindred with autosomal dominant nanophthalmos linked to 17p12-q12. <span><span class="ref-journal">JAMA Ophthalmol. </span>2014;<span class="ref-vol">132</span>:970–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24852644" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24852644</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.bashamboo.2018.487">Bashamboo A, Eozenou C, Jorgensen A, Bignon-Topalovic J, Siffroi JP, Hyon C, Tar A, Nagy P, Sólyom J, Halász Z, Paye-Jaouen A, Lambert S, Rodriguez-Buritica D, Bertalan R, Martinerie L, Rajpert-De Meyts E, Achermann JC, McElreavey K. Loss of function of the nuclear receptor NR2F2, encoding COUP-TF2, causes testis development and cardiac defects in 46,XX children. <span><span class="ref-journal">Am J Hum Genet. </span>2018;<span class="ref-vol">102</span>:487–93.</span> [<a href="/pmc/articles/PMC5985285/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5985285</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29478779" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29478779</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.brady.2014.487">Brady PD, Moerman P, De Catte L, Deprest J, Devriendt K, Vermeesch JR. Exome sequencing identifies a recessive PIGN splice site mutation as a cause of syndromic congenital diaphragmatic hernia. <span><span class="ref-journal">Eur J Med Genet. </span>2014;<span class="ref-vol">57</span>:487–93.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24852103" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24852103</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.carricondo.2018.2735465">Carricondo PC, Andrade T, Prasov L, Ayres BM, Moroi SE. Nanophthalmos: a review of the clinical spectrum and genetics. <span><span class="ref-journal">J Ophthalmol. </span>2018;<span class="ref-vol">2018</span>:2735465. </span> [<a href="/pmc/articles/PMC5971257/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5971257</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29862063" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29862063</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF._elik.2022.469">Çelik N, Küçük Kurtulgan H, Kılıçbay F, Tunç G, Kömürlüoğlu A, Taşcı O, Çağlar Şimşek CE, Çınar T, Sıdar Duman Y. 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An additional individual with a de novo variant in myelin regulatory factor (MYRF) with cardiac and urogenital anomalies: further proof of causality: comments on the article by Pinz et al. <span><span class="ref-journal">Am J Med Genet A. </span>2018;<span class="ref-vol">176</span>:2041–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30070761" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30070761</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.garnai.2019.e1008130">Garnai SJ, Brinkmeier ML, Emery B, Aleman TS, Pyle LC, Veleva-Rotse B, Sisk RA, Rozsa FW, Ozel AB, Li JZ, Moroi SE, Archer SM, Lin CM, Sheskey S, Wiinikka-Buesser L, Eadie J, Urquhart JE, Black GCM, Othman MI, Boehnke M, Sullivan SA, Skuta GL, Pawar HS, Katz AE, Huryn LA, Hufnagel RB. Genomic Ascertainment Cohort, Camper SA, Richards JE, Prasov L. 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Vitamin A deficiency in an infant with PAGOD syndrome. <span><span class="ref-journal">Am J Med Genet A. </span>2009;<span class="ref-vol">149A</span>:2241–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19760653" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19760653</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.globa.2022.810782">Globa E, Zelinska N, Shcherbak Y, Bignon-Topalovic J, Bashamboo A, McElreavey K. Disorders of sex development in a large Ukrainian cohort: clinical diversity and genetic findings. <span><span class="ref-journal">Front Endocrinol (Lausanne). </span>2022;<span class="ref-vol">13</span>:810782. </span> [<a href="/pmc/articles/PMC9012099/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9012099</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35432193" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35432193</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.guo.2019.2904">Guo C, Zhao Z, Chen D, He S, Sun N, Li Z, Liu J, Zhang D, Zhang J, Li J, Zhang M, Ge J, Liu X, Zhang X, Fan Z. 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Diverse clinical manifestations and intrafamilial variability due to an inherited recurrent MYRF variant. <span><span class="ref-journal">Am J Med Genet A. </span>2022;<span class="ref-vol">188</span>:2187–91.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/35365939" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35365939</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.hagedorn.2020.388">Hagedorn J, Avdic A, Schnieders MJ, Roos BR, Kwon YH, Drack AV, Boese EA, Fingert JH. 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De novo variants in myelin regulatory factor (MYRF) as candidates of a new syndrome of cardiac and urogenital anomalies. <span><span class="ref-journal">Am J Med Genet A. </span>2018;<span class="ref-vol">176</span>:969–72.</span> [<a href="/pmc/articles/PMC5867271/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5867271</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29446546" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29446546</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.qi.2018.e1007822">Qi H, Yu L, Zhou X, Wynn J, Zhao H, Guo Y, Zhu N, Kitaygorodsky A, Hernan R, Aspelund G, Lim FY, Crombleholme T, Cusick R, Azarow K, Danko ME, Chung D, Warner BW, Mychaliska GB, Potoka D, Wagner AJ, ElFiky M, Wilson JM, Nickerson D, Bamshad M, High FA, Longoni M, Donahoe PK, Chung WK, Shen Y. De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders. <span><span class="ref-journal">PLoS Genet. </span>2018;<span class="ref-vol">14</span>:e1007822. </span> [<a href="/pmc/articles/PMC6301721/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6301721</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30532227" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30532227</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.richards.2015.405">Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. <span><span class="ref-journal">Genet Med. </span>2015;<span class="ref-vol">17</span>:405–24.</span> [<a href="/pmc/articles/PMC4544753/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4544753</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25741868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25741868</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.rossetti.2019.1376">Rossetti LZ, Glinton K, Yuan B, Liu P, Pillai N, Mizerik E, Magoulas P, Rosenfeld JA, Karaviti L, Sutton VR, Lalani SR, Scott DA. Review of the phenotypic spectrum associated with haploinsufficiency of MYRF. <span><span class="ref-journal">Am J Med Genet A. </span>2019;<span class="ref-vol">179</span>:1376–82.</span> [<a href="/pmc/articles/PMC6557668/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6557668</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31069960" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31069960</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.siggs.2019.527">Siggs OM, Souzeau E, Breen J, Qassim A, Zhou T, Dubowsky A, Ruddle JB, Craig JE. Autosomal dominant nanophthalmos and high hyperopia associated with a C-terminal frameshift variant in MYRF. <span><span class="ref-journal">Mol Vis. </span>2019;<span class="ref-vol">25</span>:527–34.</span> [<a href="/pmc/articles/PMC6817736/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6817736</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31700225" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31700225</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.stenson.2020.1197">Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. <span><span class="ref-journal">Hum Genet. </span>2020;<span class="ref-vol">139</span>:1197–207.</span> [<a href="/pmc/articles/PMC7497289/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7497289</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32596782" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32596782</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.tanaka.2021.68">Tanaka H, Isojima T, Kimura Y, Inuzuka R, Kitanaka S. Novel de novo MYRF gene mutation: A possible cause for several clinically overlapping syndromes. <span><span class="ref-journal">Congenit Anom (Kyoto). </span>2021;<span class="ref-vol">61</span>:68–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/33179293" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33179293</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.unger.2013.990">Unger S, Górna MW, Le Béchec A, Do Vale-Pereira S, Bedeschi MF, Geiberger S, Grigelioniene G, Horemuzova E, Lalatta F, Lausch E, Magnani C, Nampoothiri S, Nishimura G, Petrella D, Rojas-Ringeling F, Utsunomiya A, Zabel B, Pradervand S, Harshman K, Campos-Xavier B, Bonafé L, Superti-Furga G, Stevenson B, Superti-Furga A. FAM111A mutations result in hypoparathyroidism and impaired skeletal development. <span><span class="ref-journal">Am J Hum Genet. </span>2013;<span class="ref-vol">92</span>:990–5.</span> [<a href="/pmc/articles/PMC3675238/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3675238</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23684011" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23684011</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.winterpaquette.2022.104501">Winter-Paquette LM, Al Suwaidi HH, Sajjad Y, Bricker L. Congenital diaphragmatic hernia and early lethality in PIGL-related disorder. <span><span class="ref-journal">Eur J Med Genet. </span>2022;<span class="ref-vol">65</span>:104501. </span> [<a href="https://pubmed.ncbi.nlm.nih.gov/35378319" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35378319</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.xiao.2019.1077">Xiao X, Sun W, Ouyang J, Li S, Jia X, Tan Z, Hejtmancik JF, Zhang Q. Novel truncation mutations in MYRF cause autosomal dominant high hyperopia mapped to 11p12-q13.3. <span><span class="ref-journal">Hum Genet. </span>2019;<span class="ref-vol">138</span>:1077–90.</span> [<a href="/pmc/articles/PMC6745028/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6745028</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31172260" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31172260</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.zenteno.2009.1794">Zenteno JC, Buentello-Volante B, Quiroz-González MA, Quiroz-Reyes MA. Compound heterozygosity for a novel and a recurrent MFRP gene mutation in a family with the nanophthalmos-retinitis pigmentosa complex. <span><span class="ref-journal">Mol Vis. </span>2009;<span class="ref-vol">15</span>:1794–8.</span> [<a href="/pmc/articles/PMC2742641/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2742641</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19753314" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19753314</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myrf-cugs.REF.zhang.2020.103851">Zhang T, Wu Q, Zhu L, Wu D, Yang R, Qi M, Huang X. A novel SPECC1L mutation causing Teebi hypertelorism syndrome: Expanding phenotypic and genetic spectrum. <span><span class="ref-journal">Eur J Med Genet. </span>2020;<span class="ref-vol">63</span>:103851. </span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31953237" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31953237</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Phelan-McDermid Syndrome-SHANK3 Related.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Phelan-McDermid Syndrome-SHANK3 Related.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Phelan K, Rogers RC, Boccuto L. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301510" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Dietz H. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/28406602" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Myhre Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Myhre Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Lin AE, Brunetti-Pierri N, Lindsay ME, Schimmenti LA, Starr LJ. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301570" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Alpha-Mannosidosis.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Alpha-Mannosidosis.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Ficicioglu C, Stepien KM. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=36375006" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=36375006" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67d4ab1d67c23b31e0fce55f">MYRF-Related Cardiac Urogenital Syndrome - GeneReviews®</a><div class="ralinkpop offscreen_noflow">MYRF-Related Cardiac Urogenital Syndrome - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=2" href="/portal/utils/pageresolver.fcgi?recordid=67d4ab1c67c23b31e0fce2f0">Table B. [OMIM Entries for MYRF-Related Cardiac Urogenital Syndrome (View All in...</a><div class="ralinkpop offscreen_noflow">Table B. [OMIM Entries for MYRF-Related Cardiac Urogenital Syndrome (View All in OMIM)]. - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=3" href="/portal/utils/pageresolver.fcgi?recordid=67d4ab04cde49f3df7215012">RecName: Full=Myelin regulatory factor; AltName: Full=Myelin gene regulatory fac...</a><div class="ralinkpop offscreen_noflow">RecName: Full=Myelin regulatory factor; AltName: Full=Myelin gene regulatory factor; Contains: RecName: Full=Myelin regulatory factor, N-terminal; Contains: RecName: Full=Myelin regulatory factor, C-terminal<div class="brieflinkpopdesc">gi|182637560|sp|Q9Y2G1.3|MYRF_HUMAN</div></div><div class="tertiary">Protein</div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=4" href="/portal/utils/pageresolver.fcgi?recordid=67d4aaf984f3725e5982af5c">Encephalitis/encephalopathy, mild, with reversible myelin vacuolization</a><div class="ralinkpop offscreen_noflow">Encephalitis/encephalopathy, mild, with reversible myelin vacuolization<div class="brieflinkpopdesc"></div></div><div class="tertiary">MedGen</div></li><li class="ra_qry two_line"><a class="htb" ref="log$=activity&linkpos=5" href="/portal/utils/pageresolver.fcgi?recordid=67d4aaf7cde49f3df7212a30">C4722446[conceptid] <span class="number">(1)</span></a><div class="tertiary">MedGen</div></li></ul><p class="HTOn">Your browsing activity is empty.</p><p class="HTOff">Activity recording is turned off.</p><p id="turnOn" class="HTOff"><a href="javascript:historyDisplayState('HTOn')">Turn recording back on</a></p><a class="seemore" href="/sites/myncbi/recentactivity">See more...</a></div></div></div>
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