664 lines
138 KiB
Text
664 lines
138 KiB
Text
<!DOCTYPE html>
|
|
<html xmlns="http://www.w3.org/1999/xhtml" xml:lang="en" class="no-js no-jr">
|
|
<head>
|
|
<!-- For pinger, set start time and add meta elements. -->
|
|
<script type="text/javascript">var ncbi_startTime = new Date();</script>
|
|
|
|
<!-- Logger begin -->
|
|
<meta name="ncbi_db" content="books">
|
|
<meta name="ncbi_pdid" content="book-part">
|
|
<meta name="ncbi_acc" content="NBK1481">
|
|
<meta name="ncbi_domain" content="gene">
|
|
<meta name="ncbi_report" content="reader">
|
|
<meta name="ncbi_type" content="fulltext">
|
|
<meta name="ncbi_objectid" content="">
|
|
<meta name="ncbi_pcid" content="/NBK1481/?report=reader">
|
|
<meta name="ncbi_pagename" content="3-M Syndrome - GeneReviews® - NCBI Bookshelf">
|
|
<meta name="ncbi_bookparttype" content="chapter">
|
|
<meta name="ncbi_app" content="bookshelf">
|
|
<!-- Logger end -->
|
|
|
|
<!--component id="Page" label="meta"/-->
|
|
<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>3-M Syndrome - GeneReviews® - NCBI Bookshelf</title>
|
|
<meta charset="utf-8">
|
|
<meta name="apple-mobile-web-app-capable" content="no">
|
|
<meta name="viewport" content="initial-scale=1,minimum-scale=1,maximum-scale=1,user-scalable=no">
|
|
<meta name="jr-col-layout" content="auto">
|
|
<meta name="jr-prev-unit" content="/books/n/gene/del2q37_2/?report=reader">
|
|
<meta name="jr-next-unit" content="/books/n/gene/mdel3q29/?report=reader">
|
|
<meta name="bk-toc-url" content="/books/n/gene/?report=toc">
|
|
<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE">
|
|
<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
|
|
<meta name="citation_title" content="3-M Syndrome">
|
|
<meta name="citation_publisher" content="University of Washington, Seattle">
|
|
<meta name="citation_date" content="2025/02/27">
|
|
<meta name="citation_author" content="Rhoda Akilapa">
|
|
<meta name="citation_author" content="Melita Irving">
|
|
<meta name="citation_author" content="Muriel Holder-Espinasse">
|
|
<meta name="citation_pmid" content="20301654">
|
|
<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1481/">
|
|
<meta name="citation_keywords" content="Three M Syndrome">
|
|
<meta name="citation_keywords" content="3M Syndrome">
|
|
<meta name="citation_keywords" content="3-M Syndrome">
|
|
<meta name="citation_keywords" content="Coiled-coil domain-containing protein 8">
|
|
<meta name="citation_keywords" content="Cullin-7">
|
|
<meta name="citation_keywords" content="Obscurin-like protein 1">
|
|
<meta name="citation_keywords" content="CCDC8">
|
|
<meta name="citation_keywords" content="CUL7">
|
|
<meta name="citation_keywords" content="OBSL1">
|
|
<meta name="citation_keywords" content="Three M Syndrome">
|
|
<link rel="schema.DC" href="http://purl.org/DC/elements/1.0/">
|
|
<meta name="DC.Title" content="3-M Syndrome">
|
|
<meta name="DC.Type" content="Text">
|
|
<meta name="DC.Publisher" content="University of Washington, Seattle">
|
|
<meta name="DC.Contributor" content="Rhoda Akilapa">
|
|
<meta name="DC.Contributor" content="Melita Irving">
|
|
<meta name="DC.Contributor" content="Muriel Holder-Espinasse">
|
|
<meta name="DC.Date" content="2025/02/27">
|
|
<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1481/">
|
|
<meta name="description" content="3-M syndrome is characterized by severe pre- and postnatal growth deficiency (final height five standard deviations below the mean), characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum, thick vermilion of the upper and low lips, and pointed chin), and normal intelligence. Additional features of 3-M syndrome include short, broad neck, prominent trapezii, pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta, clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips, prominent heels, and pes planus. Males with 3-M syndrome can have hypogonadism and occasionally hypospadias.">
|
|
<meta name="og:title" content="3-M Syndrome">
|
|
<meta name="og:type" content="book">
|
|
<meta name="og:description" content="3-M syndrome is characterized by severe pre- and postnatal growth deficiency (final height five standard deviations below the mean), characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum, thick vermilion of the upper and low lips, and pointed chin), and normal intelligence. Additional features of 3-M syndrome include short, broad neck, prominent trapezii, pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta, clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips, prominent heels, and pes planus. Males with 3-M syndrome can have hypogonadism and occasionally hypospadias.">
|
|
<meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK1481/">
|
|
<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/gr_3ms/?report=reader">
|
|
<link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK1481/">
|
|
<link href="https://fonts.googleapis.com/css?family=Archivo+Narrow:400,700,400italic,700italic&subset=latin" rel="stylesheet" type="text/css">
|
|
<link rel="stylesheet" href="/corehtml/pmc/jatsreader/ptpmc_3.22/css/libs.min.css">
|
|
<link rel="stylesheet" href="/corehtml/pmc/jatsreader/ptpmc_3.22/css/jr.min.css">
|
|
<meta name="format-detection" content="telephone=no">
|
|
<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">
|
|
<link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_reader.min.css" type="text/css">
|
|
<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>
|
|
|
|
<link rel="shortcut icon" href="//www.ncbi.nlm.nih.gov/favicon.ico">
|
|
<meta name="ncbi_phid" content="CE8E6EEC7C81FDC10000000000B60094.m_5">
|
|
<meta name='referrer' content='origin-when-cross-origin'/><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3852956/3849091.css"></head>
|
|
<body>
|
|
<!-- Book content! -->
|
|
|
|
|
|
<div id="jr" data-jr-path="/corehtml/pmc/jatsreader/ptpmc_3.22/"><div class="jr-unsupported"><table class="modal"><tr><td><span class="attn inline-block"></span><br />Your browser does not support the NLM PubReader view.<br />Go to <a href="/pmc/about/pr-browsers/">this page</a> to see a list of supported browsers<br />or return to the <br /><a href="/books/NBK1481/?report=classic">regular view</a>.</td></tr></table></div><div id="jr-ui" class="hidden"><nav id="jr-head"><div class="flexh tb"><div id="jr-tb1"><a id="jr-links-sw" class="hidden" title="Links"><svg xmlns="http://www.w3.org/2000/svg" version="1.1" x="0px" y="0px" viewBox="0 0 70.6 85.3" style="enable-background:new 0 0 70.6 85.3;vertical-align:middle" xml:space="preserve" width="24" height="24">
|
|
<style type="text/css">.st0{fill:#939598;}</style>
|
|
<g>
|
|
<path class="st0" d="M36,0C12.8,2.2-22.4,14.6,19.6,32.5C40.7,41.4-30.6,14,35.9,9.8"></path>
|
|
<path class="st0" d="M34.5,85.3c23.2-2.2,58.4-14.6,16.4-32.5c-21.1-8.9,50.2,18.5-16.3,22.7"></path>
|
|
<path class="st0" d="M34.7,37.1c66.5-4.2-4.8-31.6,16.3-22.7c42.1,17.9,6.9,30.3-16.4,32.5h1.7c-66.2,4.4,4.8,31.6-16.3,22.7 c-42.1-17.9-6.9-30.3,16.4-32.5"></path>
|
|
</g>
|
|
</svg> Books</a></div><div class="jr-rhead f1 flexh"><div class="head"><a href="/books/n/gene/del2q37_2/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="body"><div class="t">3-M Syndrome</div><div class="j">GeneReviews® [Internet]</div></div><div class="tail"><a href="/books/n/gene/mdel3q29/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></div><div id="jr-tb2"><a id="jr-bkhelp-sw" class="btn wsprkl hidden" title="Help with NLM PubReader">?</a><a id="jr-help-sw" class="btn wsprkl hidden" title="Settings and typography in NLM PubReader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 512 512" preserveAspectRatio="none"><path d="M462,283.742v-55.485l-29.981-10.662c-11.431-4.065-20.628-12.794-25.274-24.001 c-0.002-0.004-0.004-0.009-0.006-0.013c-4.659-11.235-4.333-23.918,0.889-34.903l13.653-28.724l-39.234-39.234l-28.72,13.652 c-10.979,5.219-23.68,5.546-34.908,0.889c-0.005-0.002-0.01-0.003-0.014-0.005c-11.215-4.65-19.933-13.834-24-25.273L283.741,50 h-55.484l-10.662,29.981c-4.065,11.431-12.794,20.627-24.001,25.274c-0.005,0.002-0.009,0.004-0.014,0.005 c-11.235,4.66-23.919,4.333-34.905-0.889l-28.723-13.653l-39.234,39.234l13.653,28.721c5.219,10.979,5.545,23.681,0.889,34.91 c-0.002,0.004-0.004,0.009-0.006,0.013c-4.649,11.214-13.834,19.931-25.271,23.998L50,228.257v55.485l29.98,10.661 c11.431,4.065,20.627,12.794,25.274,24c0.002,0.005,0.003,0.01,0.005,0.014c4.66,11.236,4.334,23.921-0.888,34.906l-13.654,28.723 l39.234,39.234l28.721-13.652c10.979-5.219,23.681-5.546,34.909-0.889c0.005,0.002,0.01,0.004,0.014,0.006 c11.214,4.649,19.93,13.833,23.998,25.271L228.257,462h55.484l10.595-29.79c4.103-11.538,12.908-20.824,24.216-25.525 c0.005-0.002,0.009-0.004,0.014-0.006c11.127-4.628,23.694-4.311,34.578,0.863l28.902,13.738l39.234-39.234l-13.66-28.737 c-5.214-10.969-5.539-23.659-0.886-34.877c0.002-0.005,0.004-0.009,0.006-0.014c4.654-11.225,13.848-19.949,25.297-24.021 L462,283.742z M256,331.546c-41.724,0-75.548-33.823-75.548-75.546s33.824-75.547,75.548-75.547 c41.723,0,75.546,33.824,75.546,75.547S297.723,331.546,256,331.546z"></path></svg></a><a id="jr-fip-sw" class="btn wsprkl hidden" title="Find"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 550 600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-rtoc-sw" class="btn wsprkl hidden" title="Table of Contents"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M20,20h10v8H20V20zM36,20h44v8H36V20zM20,37.33h10v8H20V37.33zM36,37.33h44v8H36V37.33zM20,54.66h10v8H20V54.66zM36,54.66h44v8H36V54.66zM20,72h10v8 H20V72zM36,72h44v8H36V72z"></path></svg></a></div></div></nav><nav id="jr-dash" class="noselect"><nav id="jr-dash" class="noselect"><div id="jr-pi" class="hidden"><a id="jr-pi-prev" class="hidden" title="Previous page"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a><div class="pginfo">Page <i class="jr-pg-pn">0</i> of <i class="jr-pg-lp">0</i></div><a id="jr-pi-next" class="hidden" title="Next page"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div><div id="jr-is-tb"><a id="jr-is-sw" class="btn wsprkl hidden" title="Switch between Figures/Tables strip and Progress bar"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><rect x="10" y="40" width="20" height="20"></rect><rect x="40" y="40" width="20" height="20"></rect><rect x="70" y="40" width="20" height="20"></rect></svg></a></div><nav id="jr-istrip" class="istrip hidden"><a id="jr-is-prev" href="#" class="hidden" title="Previous"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M80,40 60,65 80,90 70,90 50,65 70,40z M50,40 30,65 50,90 40,90 20,65 40,40z"></path><text x="35" y="25" textLength="60" style="font-size:25px">Prev</text></svg></a><a id="jr-is-next" href="#" class="hidden" title="Next"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M20,40 40,65 20,90 30,90 50,65 30,40z M50,40 70,65 50,90 60,90 80,65 60,40z"></path><text x="15" y="25" textLength="60" style="font-size:25px">Next</text></svg></a></nav><nav id="jr-progress"></nav></nav></nav><aside id="jr-links-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">NCBI Bookshelf</div></div><div class="cnt lol f1"><a href="/books/">Home</a><a href="/books/browse/">Browse All Titles</a><a class="btn share" target="_blank" rel="noopener noreferrer" href="https://www.facebook.com/sharer/sharer.php?u=https://www.ncbi.nlm.nih.gov/books/NBK1481/"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 33 33" style="vertical-align:middle" width="24" height="24" preserveAspectRatio="none"><g><path d="M 17.996,32L 12,32 L 12,16 l-4,0 l0-5.514 l 4-0.002l-0.006-3.248C 11.993,2.737, 13.213,0, 18.512,0l 4.412,0 l0,5.515 l-2.757,0 c-2.063,0-2.163,0.77-2.163,2.209l-0.008,2.76l 4.959,0 l-0.585,5.514L 18,16L 17.996,32z"></path></g></svg> Share on Facebook</a><a class="btn share" target="_blank" rel="noopener noreferrer" href="https://twitter.com/intent/tweet?url=https://www.ncbi.nlm.nih.gov/books/NBK1481/&text=3-M%20Syndrome"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 33 33" style="vertical-align:middle" width="24" height="24"><g><path d="M 32,6.076c-1.177,0.522-2.443,0.875-3.771,1.034c 1.355-0.813, 2.396-2.099, 2.887-3.632 c-1.269,0.752-2.674,1.299-4.169,1.593c-1.198-1.276-2.904-2.073-4.792-2.073c-3.626,0-6.565,2.939-6.565,6.565 c0,0.515, 0.058,1.016, 0.17,1.496c-5.456-0.274-10.294-2.888-13.532-6.86c-0.565,0.97-0.889,2.097-0.889,3.301 c0,2.278, 1.159,4.287, 2.921,5.465c-1.076-0.034-2.088-0.329-2.974-0.821c-0.001,0.027-0.001,0.055-0.001,0.083 c0,3.181, 2.263,5.834, 5.266,6.438c-0.551,0.15-1.131,0.23-1.73,0.23c-0.423,0-0.834-0.041-1.235-0.118 c 0.836,2.608, 3.26,4.506, 6.133,4.559c-2.247,1.761-5.078,2.81-8.154,2.81c-0.53,0-1.052-0.031-1.566-0.092 c 2.905,1.863, 6.356,2.95, 10.064,2.95c 12.076,0, 18.679-10.004, 18.679-18.68c0-0.285-0.006-0.568-0.019-0.849 C 30.007,8.548, 31.12,7.392, 32,6.076z"></path></g></svg> Share on Twitter</a></div></aside><aside id="jr-rtoc-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Table of Content</div></div><div class="cnt lol f1"><a href="/books/n/gene/?report=reader">Title Information</a><a href="/books/n/gene/toc/?report=reader">Table of Contents Page</a></div></aside><aside id="jr-help-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Settings</div></div><div class="cnt f1"><div id="jr-typo-p" class="typo"><div><a class="sf btn wsprkl">A-</a><a class="lf btn wsprkl">A+</a></div><div><a class="bcol-auto btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 200 100" preserveAspectRatio="none"><text x="10" y="70" style="font-size:60px;font-family: Trebuchet MS, ArialMT, Arial, sans-serif" textLength="180">AUTO</text></svg></a><a class="bcol-1 btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M15,25 85,25zM15,40 85,40zM15,55 85,55zM15,70 85,70z"></path></svg></a><a class="bcol-2 btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M5,25 45,25z M55,25 95,25zM5,40 45,40z M55,40 95,40zM5,55 45,55z M55,55 95,55zM5,70 45,70z M55,70 95,70z"></path></svg></a></div></div><div class="lol"><a class="" href="/books/NBK1481/?report=classic">Switch to classic view</a><a href="/books/NBK1481/pdf/Bookshelf_NBK1481.pdf">PDF (510K)</a><a href="/books/NBK1481/?report=printable">Print View</a></div></div></aside><aside id="jr-bkhelp-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Help</div></div><div class="cnt f1 lol"><a id="jr-helpobj-sw" data-path="/corehtml/pmc/jatsreader/ptpmc_3.22/" data-href="/corehtml/pmc/jatsreader/ptpmc_3.22/img/bookshelf/help.xml" href="">Help</a><a href="mailto:info@ncbi.nlm.nih.gov?subject=PubReader%20feedback%20%2F%20NBK1481%20%2F%20sid%3ACE8B5AF87C7FFCB1_0191SID%20%2F%20phid%3ACE8E6EEC7C81FDC10000000000B60094.4">Send us feedback</a><a id="jr-about-sw" data-path="/corehtml/pmc/jatsreader/ptpmc_3.22/" data-href="/corehtml/pmc/jatsreader/ptpmc_3.22/img/bookshelf/about.xml" href="">About PubReader</a></div></aside><aside id="jr-objectbox" class="thidden hidden"><div class="jr-objectbox-close wsprkl">✘</div><div class="jr-objectbox-inner cnt"><div class="jr-objectbox-drawer"></div></div></aside><nav id="jr-pm-left" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Previous Page</text></svg></nav><nav id="jr-pm-right" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Next Page</text></svg></nav><nav id="jr-fip" class="hidden"><nav id="jr-fip-term-p"><input type="search" placeholder="search this page" id="jr-fip-term" autocorrect="off" autocomplete="off" /><a id="jr-fip-mg" class="wsprkl btn" title="Find"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 550 600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-fip-done" class="wsprkl btn" title="Dismiss find">✘</a></nav><nav id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK1481_"><span class="title" itemprop="name">3-M Syndrome</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Three M Syndrome, 3M Syndrome</div><p class="contribs">Akilapa R, Irving M, Holder-Espinasse M.</p><p class="fm-aai"><a href="#_NBK1481_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 23 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="gr_3ms.Summary" itemprop="description"><h2 id="_gr_3ms_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>3-M syndrome is characterized by severe pre- and postnatal growth deficiency (final height five standard deviations below the mean), characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum, thick vermilion of the upper and low lips, and pointed chin), and normal intelligence. Additional features of 3-M syndrome include short, broad neck, prominent trapezii, pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta, clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips, prominent heels, and pes planus. Males with 3-M syndrome can have hypogonadism and occasionally hypospadias.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of 3-M syndrome is established in a proband with prenatal-onset persistent growth deficiency and the characteristic clinical and radiographic features and/or biallelic pathogenic variants in <i>CCDC8</i>, <i>CUL7</i>, or <i>OBSL1</i> identified by molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Referral to pediatric endocrinologist for consideration of growth hormone in prepubertal children. Physical therapy, occupational therapy, and community child health services are important in ensuring necessary adaptations for short stature are put in place to maximize access to the individual's environment. Surgical limb lengthening may also be an option. Orthopedic evaluation in individuals with hip dislocation, scoliosis, and significant joint laxity is essential. Management of hypogonadism per endocrinologist. Urology referral may be needed for hypospadias. In neonates with severe respiratory distress, neonatal/pediatric intensive care team input and follow up with a pediatric respiratory physician.</p><p><i>Surveillance:</i> Monitor growth every six to 12 months on standard growth charts, with special attention to growth velocity. Assess for joint hypermobility and kyphoscoliosis annually. Assess for hip dislocation at each visit in infancy especially in those with delayed walking. Consider echocardiogram in adolescence to evaluate aortic root diameter.</p><p><i>Evaluation of relatives at risk:</i> It is appropriate to evaluate sibs of a proband for short stature and, if present, 3-M syndrome to ensure a correct diagnosis is made in affected sibs.</p><p><i>Pregnancy management:</i> Follow pregnancy management guidelines as for women with other forms of dwarfism or small stature to reduce the risk of premature birth.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>3-M syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a <i>CCDC8</i>, <i>CUL7</i>, or <i>OBSL1</i> pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the 3-M syndrome-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.</p></div></div><div id="gr_3ms.Diagnosis"><h2 id="_gr_3ms_Diagnosis_">Diagnosis</h2><p>No consensus clinical diagnostic criteria for 3-M syndrome have been published.</p><div id="gr_3ms.Suggestive_Findings"><h3>Suggestive Findings</h3><p>3-M syndrome <b>should be suspected</b> in a proband with a combination of the following clinical, radiographic, and family history features.</p><p>
|
|
<b>Clinical features</b>
|
|
</p><ul><li class="half_rhythm"><div><b>Short stature</b> of prenatal onset [<a class="bibr" href="#gr_3ms.REF.lugli.2016.232" rid="gr_3ms.REF.lugli.2016.232">Lugli et al 2016</a>]. Typical height is five standard deviations below the mean for age and sex [<a class="bibr" href="#gr_3ms.REF.shapiro.2017.485" rid="gr_3ms.REF.shapiro.2017.485">Shapiro et al 2017</a>].</div></li><li class="half_rhythm"><div><b>Facial features.</b> Relatively large head, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum, thick vermilion of the upper and low lips, and pointed chin. In infancy, facial nevus simplex and infraorbital fullness [<a class="bibr" href="#gr_3ms.REF.hu.2017.159" rid="gr_3ms.REF.hu.2017.159">Hu et al 2017</a>, <a class="bibr" href="#gr_3ms.REF.t_ys_z.2021.104346" rid="gr_3ms.REF.t_ys_z.2021.104346">Tüysüz et al 2021</a>]. Facial appearance varies among affected individuals [<a class="bibr" href="#gr_3ms.REF.van_der_wal.2001.241" rid="gr_3ms.REF.van_der_wal.2001.241">van der Wal et al 2001</a>, <a class="bibr" href="#gr_3ms.REF.marik.2002.419" rid="gr_3ms.REF.marik.2002.419">Marik et al 2002</a>] and changes with age [<a class="bibr" href="#gr_3ms.REF.akal_n.2024.68" rid="gr_3ms.REF.akal_n.2024.68">Akalın et al 2024</a>].</div></li><li class="half_rhythm"><div><b>Musculoskeletal features.</b> Short broad neck, prominent trapezii, pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta, clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips, prominent heels, and pes planus</div></li><li class="half_rhythm"><div><b>Genitourinary anomalies in males.</b> Hypogonadism and hypospadias</div></li><li class="half_rhythm"><div><b>Intelligence.</b> Typically normal</div></li></ul><p><b>Radiographic features</b> are subtle and may include the following (most often present after age two years):</p><ul><li class="half_rhythm"><div><b>Long bones</b> are slender with diaphyseal constriction and flared metaphyses. The femoral necks can be short.</div></li><li class="half_rhythm"><div><b>Vertebral bodies</b> are tall with reduced anterior-posterior and transverse diameter (especially in the lumbar region), anterior wedging of the thoracic vertebral bodies, and irregular upper and lower end plates; thoracic kyphoscoliosis; spina bifida occulta.</div></li><li class="half_rhythm"><div><b>Thorax</b> is relatively broad with slender, horizontal ribs. Pectus carinatum/excavatum is common [<a class="bibr" href="#gr_3ms.REF.hu.2017.159" rid="gr_3ms.REF.hu.2017.159">Hu et al 2017</a>, <a class="bibr" href="#gr_3ms.REF.t_ys_z.2021.104346" rid="gr_3ms.REF.t_ys_z.2021.104346">Tüysüz et al 2021</a>].</div></li><li class="half_rhythm"><div><b>Pelvic bones</b> are small, especially the pubis and the ischium. The iliac wings are flared, and the obturator foramina are small, although the latter may be positional.</div></li><li class="half_rhythm"><div><b>Bone age</b> can be slightly delayed or normal. The metacarpal index and vertebral index are increased.</div></li><li class="half_rhythm"><div><b>Other</b>
|
|
<b>findings</b> include dolichocephaly, flattened coronal suture, elbow dysplasia, shortened ulna, pseudoepiphyses of the second metacarpal bone, and prominent talus.</div></li></ul><p><b>Family history</b> is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.</p></div><div id="gr_3ms.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of 3-M syndrome <b>can be established</b> in a proband with prenatal-onset persistent growth deficiency and the characteristic clinical and radiographic features described in <a href="#gr_3ms.Suggestive_Findings">Suggestive Findings</a>, and/or i biallelic pathogenic (or likely pathogenic) variants in one of the genes listed in <a href="/books/NBK1481/table/gr_3ms.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobgr3msTmoleculargenetictestingused">Table 1</a> identified by molecular genetic testing (see <a href="/books/NBK1481/table/gr_3ms.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobgr3msTmoleculargenetictestingused">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bibr" href="#gr_3ms.REF.richards.2015.405" rid="gr_3ms.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of biallelic variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (multigene panel) and <b>comprehensive</b>
|
|
<b>genomic testing</b> (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see <a href="#gr_3ms.Option_1">Option 1</a>), whereas comprehensive genomic testing does not (see <a href="#gr_3ms.Option_2">Option 2</a>).</p><div id="gr_3ms.Option_1"><h4>Option 1</h4><p>When the phenotypic and laboratory findings suggest the diagnosis of 3-M syndrome, molecular genetic testing approaches can include use of a <b>multigene panel</b>.</p><p><b>A multigene panel</b> that includes <i>CCDC8</i>, <i>CUL7</i>, <i>OBSL1</i>, and other genes of interest (see <a href="#gr_3ms.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</p><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</p><p>Note: Targeted analysis for known founder pathogenic variants in <i>CUL7</i> can be performed first in individuals of Maghrebian ancestry (<a href="/books/NBK1481/table/gr_3ms.T.pathogenic_variants_referenced/?report=objectonly" target="object" rid-ob="figobgr3msTpathogenicvariantsreferenced">c.4451_4452delTG</a>) [<a class="bibr" href="#gr_3ms.REF.khachnaouizaafrane.2022.104448" rid="gr_3ms.REF.khachnaouizaafrane.2022.104448">Khachnaoui-Zaafrane et al 2022</a>] and Yakut ancestry (<a href="/books/NBK1481/table/gr_3ms.T.pathogenic_variants_referenced/?report=objectonly" target="object" rid-ob="figobgr3msTpathogenicvariantsreferenced">c.4581dupT</a>) [<a class="bibr" href="#gr_3ms.REF.maksimova.2007.772" rid="gr_3ms.REF.maksimova.2007.772">Maksimova et al 2007</a>]. <i>OBSL1</i>
|
|
<a href="/books/NBK1481/table/gr_3ms.T.pathogenic_variants_referenced/?report=objectonly" target="object" rid-ob="figobgr3msTpathogenicvariantsreferenced">c.1273dupA (p.Thr425AsnfsTer40)</a> is an emerging founder pathogenic variant in the Turkish population [<a class="bibr" href="#gr_3ms.REF.akal_n.2024.68" rid="gr_3ms.REF.akal_n.2024.68">Akalın et al 2024</a>].</p></div><div id="gr_3ms.Option_2"><h4>Option 2</h4><p>When the diagnosis of 3-M syndrome is not considered because an individual has atypical phenotypic features, <b>comprehensive</b>
|
|
<b>genomic testing</b> does not require the clinician to determine which gene is likely involved. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figgr3msTmoleculargenetictestingused"><a href="/books/NBK1481/table/gr_3ms.T.molecular_genetic_testing_used/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobgr3msTmoleculargenetictestingused"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="gr_3ms.T.molecular_genetic_testing_used"><a href="/books/NBK1481/table/gr_3ms.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobgr3msTmoleculargenetictestingused">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in 3-M Syndrome </p></div></div></div></div></div><div id="gr_3ms.Clinical_Characteristics"><h2 id="_gr_3ms_Clinical_Characteristics_">Clinical Characteristics</h2><div id="gr_3ms.Clinical_Description"><h3>Clinical Description</h3><p><b>Neonatal period.</b> Some children with 3-M syndrome present in the neonatal period with feeding difficulties requiring early feeding support [<a class="bibr" href="#gr_3ms.REF.hu.2017.159" rid="gr_3ms.REF.hu.2017.159">Hu et al 2017</a>]. A small proportion of infants suffer from significant respiratory distress and/or recurrent respiratory tract infections in early life that can be life threatening [<a class="bibr" href="#gr_3ms.REF.deeb.2015.150012" rid="gr_3ms.REF.deeb.2015.150012">Deeb et al 2015</a>]. This is more common in the Yakut population, in which 41% of affected infants had asphyxia and respiratory distress at birth and 25.6% required mechanical ventilation [<a class="bibr" href="#gr_3ms.REF.maksimova.2007.772" rid="gr_3ms.REF.maksimova.2007.772">Maksimova et al 2007</a>].</p><p><b>Growth deficiency.</b> The most striking feature of 3-M syndrome is severe intrauterine growth restriction. Birth length is 40-42 cm, whereas the head size is normal for gestational age. Catch-up growth does not occur; final height is five to six standard deviations below the mean for age and sex [<a class="bibr" href="#gr_3ms.REF.van_der_wal.2001.241" rid="gr_3ms.REF.van_der_wal.2001.241">van der Wal et al 2001</a>, <a class="bibr" href="#gr_3ms.REF.t_ys_z.2021.104346" rid="gr_3ms.REF.t_ys_z.2021.104346">Tüysüz et al 2021</a>, <a class="bibr" href="#gr_3ms.REF.akal_n.2024.68" rid="gr_3ms.REF.akal_n.2024.68">Akalın et al 2024</a>], resulting in proportionate short stature.</p><p>Most children with 3-M syndrome are evaluated for growth hormone (GH) deficiency. A small proportion are found to have partial or significant GH deficiency [<a class="bibr" href="#gr_3ms.REF.van_der_wal.2001.241" rid="gr_3ms.REF.van_der_wal.2001.241">van der Wal et al 2001</a>, <a class="bibr" href="#gr_3ms.REF.clayton.2012.335" rid="gr_3ms.REF.clayton.2012.335">Clayton et al 2012</a>, <a class="bibr" href="#gr_3ms.REF.deeb.2015.150012" rid="gr_3ms.REF.deeb.2015.150012">Deeb et al 2015</a>, <a class="bibr" href="#gr_3ms.REF.karacan_k___kali.2023.104828" rid="gr_3ms.REF.karacan_k___kali.2023.104828">Karacan Küçükali et al 2023</a>, <a class="bibr" href="#gr_3ms.REF.akal_n.2024.68" rid="gr_3ms.REF.akal_n.2024.68">Akalın et al 2024</a>]. A growing number of children have also been found to have GH insensitivity demonstrated by failure of insulin-like growth factor 1 (IGF-1) generation [<a class="bibr" href="#gr_3ms.REF.akal_n.2024.68" rid="gr_3ms.REF.akal_n.2024.68">Akalın et al 2024</a>]. Treatment with GH has shown variable results, with a good response in some individuals and poor response in others. Recombinant human IGF-1 therapy has been tried in one individual with <i>CUL7</i>-related 3-M syndrome with a poor response and significant side effects [<a class="bibr" href="#gr_3ms.REF.yang.2020.1609" rid="gr_3ms.REF.yang.2020.1609">Yang & Patni 2020</a>]. Given the varying response to treatment, a trial of GH therapy with close monitoring of growth velocity and measurement of serum IGF-1 levels should be considered [<a class="bibr" href="#gr_3ms.REF.clayton.2012.335" rid="gr_3ms.REF.clayton.2012.335">Clayton et al 2012</a>, <a class="bibr" href="#gr_3ms.REF.deeb.2015.150012" rid="gr_3ms.REF.deeb.2015.150012">Deeb et al 2015</a>, <a class="bibr" href="#gr_3ms.REF.karacan_k___kali.2023.104828" rid="gr_3ms.REF.karacan_k___kali.2023.104828">Karacan Küçükali et al 2023</a>, <a class="bibr" href="#gr_3ms.REF.akal_n.2024.68" rid="gr_3ms.REF.akal_n.2024.68">Akalın et al 2024</a>].</p><p><b>Facial features.</b> Infants with 3-M syndrome have a relatively large head, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum, thick vermilion of the upper and low lips, pointed chin, nevus simplex, and infraorbital fullness [<a class="bibr" href="#gr_3ms.REF.hu.2017.159" rid="gr_3ms.REF.hu.2017.159">Hu et al 2017</a>, <a class="bibr" href="#gr_3ms.REF.t_ys_z.2021.104346" rid="gr_3ms.REF.t_ys_z.2021.104346">Tüysüz et al 2021</a>]. Facial appearance varies among affected individuals [<a class="bibr" href="#gr_3ms.REF.van_der_wal.2001.241" rid="gr_3ms.REF.van_der_wal.2001.241">van der Wal et al 2001</a>, <a class="bibr" href="#gr_3ms.REF.marik.2002.419" rid="gr_3ms.REF.marik.2002.419">Marik et al 2002</a>] and changes over time, with the triangular face, long philtrum, and pointed chin becoming more pronounced, and loss of the nevus simplex and infraorbital fullness.</p><p><b>Musculoskeletal features</b> present by early childhood and variably include short, broad neck, prominent trapezii, pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, and hyperlordosis. Spina bifida occulta, clinodactyly of the fifth fingers, transverse palmar crease, generalized or distal joint hypermobility, prominent heels, and pes planus are reported. Developmental dysplasia of the hips has been reported with delayed diagnosis [<a class="bibr" href="#gr_3ms.REF.badina.2011.114" rid="gr_3ms.REF.badina.2011.114">Badina et al 2011</a>]. Bilateral congenital hip dislocation has been reported in other individuals [<a class="bibr" href="#gr_3ms.REF.khachnaouizaafrane.2022.104448" rid="gr_3ms.REF.khachnaouizaafrane.2022.104448">Khachnaoui-Zaafrane et al 2022</a>]. Transverse grooves in the lower rib cage have been reported [<a class="bibr" href="#gr_3ms.REF.hu.2017.159" rid="gr_3ms.REF.hu.2017.159">Hu et al 2017</a>, <a class="bibr" href="#gr_3ms.REF.t_ys_z.2021.104346" rid="gr_3ms.REF.t_ys_z.2021.104346">Tüysüz et al 2021</a>].</p><p>
|
|
<b>Radiographic features</b>
|
|
</p><ul><li class="half_rhythm"><div>The <b>long bones</b> are slender with diaphyseal constriction and flared metaphyses; these appear to be the main radiologic features of 3-M syndrome. Increased radiolucency is unusual [<a class="bibr" href="#gr_3ms.REF.van_der_wal.2001.241" rid="gr_3ms.REF.van_der_wal.2001.241">van der Wal et al 2001</a>]. The metacarpal index, used to document slender long bones, is usually high.</div></li><li class="half_rhythm"><div>The <b>vertebral bodies</b> are tall with reduced anterior-posterior and transverse diameter, especially in the lumbar region. Reduced anterior-posterior diameter of the vertebral bodies becomes more apparent with increasing age. Calculation of the vertebral index at different ages reveals that the vertebral index of L1 is a useful tool to document 3-M syndrome, although tall vertebrae are a nonspecific finding that may be secondary to scoliosis or hypotonia. Anterior wedging of thoracic vertebral bodies, irregular upper and lower end plates, thoracic kyphoscoliosis, and spina bifida occulta are also features of 3-M syndrome.</div></li><li class="half_rhythm"><div><b>Thorax</b> is broad with slender and horizontal ribs.</div></li><li class="half_rhythm"><div><b>Pelvic bones</b> are small, especially the pubis and the ischium. The iliac wings are flared, and the obturator foramina are small, although the latter may be positional.</div></li><li class="half_rhythm"><div><b>Bone age</b> can be slightly delayed but has been reported to be normal in some individuals [<a class="bibr" href="#gr_3ms.REF.hu.2017.159" rid="gr_3ms.REF.hu.2017.159">Hu et al 2017</a>].</div></li><li class="half_rhythm"><div><b>Other</b>
|
|
<b>findings</b> include dolichocephaly, flattened coronal suture, elbow dysplasia, shortened ulna, pseudoepiphyses of the second metacarpal bone, clinodactyly of the fifth fingers, dislocated hips, and prominent talus.</div></li></ul><p><b>Genitourinary anomalies in males</b> may include gonadal dysfunction and subfertility or infertility as documented by high follicle-stimulating hormone (FSH) levels, low testicular volume, and abnormal semen analysis [<a class="bibr" href="#gr_3ms.REF.van_der_wal.2001.241" rid="gr_3ms.REF.van_der_wal.2001.241">van der Wal et al 2001</a>]. Hypospadias has been seen in a few males with 3-M syndrome. Note: Female gonadal function appears normal.</p><p><b>Other.</b> Aortic root dilatation has been reported in two sibs with 3-M syndrome [<a class="bibr" href="#gr_3ms.REF.akal_n.2024.68" rid="gr_3ms.REF.akal_n.2024.68">Akalın et al 2024</a>].</p></div><div id="gr_3ms.Phenotype_Correlations_by_Gene"><h3>Phenotype Correlations by Gene</h3><p>Individuals with <i>CUL7-</i>related 3-M syndrome have been shown to have shorter stature than those with <i>OBSL1</i>-related 3-M syndrome [<a class="bibr" href="#gr_3ms.REF.t_ys_z.2021.104346" rid="gr_3ms.REF.t_ys_z.2021.104346">Tüysüz et al 2021</a>, <a class="bibr" href="#gr_3ms.REF.akal_n.2024.68" rid="gr_3ms.REF.akal_n.2024.68">Akalın et al 2024</a>]. Otherwise, the clinical and radiographic features seen in <i>CUL7</i> and <i>OBSL1</i> are indistinguishable.</p><p>The number of reported individuals with <i>CCDC8</i>-related 3-M syndrome is too small to draw any gene-specific phenotype correlations. One study suggests a better GH response in individuals with <i>CCDC8</i>-related 3-M syndrome. Further data is needed to support this theory.</p></div><div id="gr_3ms.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>The <i>CUL7</i> founder pathogenic variant reported in the Yakut population, <a href="/books/NBK1481/table/gr_3ms.T.pathogenic_variants_referenced/?report=objectonly" target="object" rid-ob="figobgr3msTpathogenicvariantsreferenced">c.4581dupT</a>, may be associated with an increased risk of respiratory distress in the neonatal period. <a class="bibr" href="#gr_3ms.REF.maksimova.2007.772" rid="gr_3ms.REF.maksimova.2007.772">Maksimova et al [2007]</a> reported 41.9% of children homozygous for this variant presented with asphyxia and respiratory distress at birth, and 25.6% of these children required mechanical ventilation.</p></div><div id="gr_3ms.Nomenclature"><h3>Nomenclature</h3><p>3-M syndrome may also be referred to as Le Merrer syndrome or Yakut short stature syndrome. Individuals previously reported to have dolichospondylic dysplasia [<a class="bibr" href="#gr_3ms.REF.elliott.2002.351" rid="gr_3ms.REF.elliott.2002.351">Elliott et al 2002</a>] and Gloomy face syndrome are now understood to have 3-M syndrome [<a class="bibr" href="#gr_3ms.REF.unger.2023.1164" rid="gr_3ms.REF.unger.2023.1164">Unger et al 2023</a>].</p></div><div id="gr_3ms.Prevalence"><h3>Prevalence</h3><p>3-M syndrome is rare. The prevalence is not known; approximately 250 affected individuals have been reported in the literature since the first published report in 1975 [<a class="bibr" href="#gr_3ms.REF.miller.1975.39" rid="gr_3ms.REF.miller.1975.39">Miller et al 1975</a>]. 3-M syndrome is more common in offspring of consanguineous parents, particularly in regions where founder pathogenic variants have been identified.</p><p>A <i>CUL7</i> founder pathogenic variant, <a href="/books/NBK1481/table/gr_3ms.T.pathogenic_variants_referenced/?report=objectonly" target="object" rid-ob="figobgr3msTpathogenicvariantsreferenced">c.4451_4452delTG</a>, has been identified in the Maghreb population in Tunisia [<a class="bibr" href="#gr_3ms.REF.khachnaouizaafrane.2022.104448" rid="gr_3ms.REF.khachnaouizaafrane.2022.104448">Khachnaoui-Zaafrane et al 2022</a>] and the Yakut population (<a href="/books/NBK1481/table/gr_3ms.T.pathogenic_variants_referenced/?report=objectonly" target="object" rid-ob="figobgr3msTpathogenicvariantsreferenced">c.4581dupT</a>) [<a class="bibr" href="#gr_3ms.REF.maksimova.2007.772" rid="gr_3ms.REF.maksimova.2007.772">Maksimova et al 2007</a>].</p><p>A recurrent pathogenic variant in <i>OBSL1</i> (<a href="/books/NBK1481/table/gr_3ms.T.pathogenic_variants_referenced/?report=objectonly" target="object" rid-ob="figobgr3msTpathogenicvariantsreferenced">c.1273dupA</a>) appears to be an emerging founder variant in the Turkish population [<a class="bibr" href="#gr_3ms.REF.huber.2011.143" rid="gr_3ms.REF.huber.2011.143">Huber et al 2011</a>, <a class="bibr" href="#gr_3ms.REF.keskin.2017.91" rid="gr_3ms.REF.keskin.2017.91">Keskin et al 2017</a>, <a class="bibr" href="#gr_3ms.REF.simsekkiper.2019.1157" rid="gr_3ms.REF.simsekkiper.2019.1157">Simsek-Kiper et al 2019</a>, <a class="bibr" href="#gr_3ms.REF.t_ys_z.2021.104346" rid="gr_3ms.REF.t_ys_z.2021.104346">Tüysüz et al 2021</a>, <a class="bibr" href="#gr_3ms.REF.akal_n.2024.68" rid="gr_3ms.REF.akal_n.2024.68">Akalın et al 2024</a>].</p></div></div><div id="gr_3ms.Genetically_Related_Allelic_Disor"><h2 id="_gr_3ms_Genetically_Related_Allelic_Disor_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with germline pathogenic variants in <i>CCDC8</i>, <i>CUL7</i>, or <i>OBSL1</i>.</p></div><div id="gr_3ms.Differential_Diagnosis"><h2 id="_gr_3ms_Differential_Diagnosis_">Differential Diagnosis</h2><p>Intrauterine growth restriction is a nonspecific finding that occurs in approximately 0.17% of all live-born children. 3-M syndrome must be distinguished from other genetic (see <a href="/books/NBK1481/table/gr_3ms.T.disorders_of_known_genetic_caus/?report=objectonly" target="object" rid-ob="figobgr3msTdisordersofknowngeneticcaus">Table 2</a>) and acquired intrauterine growth restriction-malformation syndromes.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figgr3msTdisordersofknowngeneticcaus"><a href="/books/NBK1481/table/gr_3ms.T.disorders_of_known_genetic_caus/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobgr3msTdisordersofknowngeneticcaus"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="gr_3ms.T.disorders_of_known_genetic_caus"><a href="/books/NBK1481/table/gr_3ms.T.disorders_of_known_genetic_caus/?report=objectonly" target="object" rid-ob="figobgr3msTdisordersofknowngeneticcaus">Table 2. </a></h4><p class="float-caption no_bottom_margin">Disorders of Known Genetic Cause to Consider in the Differential Diagnosis of 3-M Syndrome </p></div></div><p>
|
|
<b>Other</b>
|
|
</p><ul><li class="half_rhythm"><div><b>Dubowitz syndrome</b> (OMIM <a href="https://omim.org/entry/223370" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">223370</a>), an intrauterine growth restriction syndrome of unknown genetic cause, is distinguished from 3-M syndrome by microcephaly, eczema, characteristic facial features (small face with sloping forehead, broad nasal bridge, shallow supraorbital ridge, broad nasal tip, short palpebral fissures, telecanthus, ptosis, dysplastic ears), and intellectual disability.</div></li><li class="half_rhythm"><div><b>Fetal alcohol syndrome,</b> an acquired intrauterine growth restriction syndrome, is distinguished from 3-M syndrome by microcephaly, decreased subcutaneous fat, hirsutism, nail hypoplasia, characteristic facial features, and intellectual disability.</div></li></ul></div><div id="gr_3ms.Management"><h2 id="_gr_3ms_Management_">Management</h2><p>No clinical practice guidelines for 3-M syndrome have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.</p><div id="gr_3ms.Evaluations_Following_Initial_Dia"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease in an individual diagnosed with 3-M syndrome, the evaluations summarized in <a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_recommended_evaluat/?report=objectonly" target="object" rid-ob="figobgr3msT3msyndromerecommendedevaluat">Table 3</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figgr3msT3msyndromerecommendedevaluat"><a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_recommended_evaluat/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobgr3msT3msyndromerecommendedevaluat"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="gr_3ms.T.3m_syndrome_recommended_evaluat"><a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_recommended_evaluat/?report=objectonly" target="object" rid-ob="figobgr3msT3msyndromerecommendedevaluat">Table 3. </a></h4><p class="float-caption no_bottom_margin">3-M Syndrome: Recommended Evaluations Following Initial Diagnosis </p></div></div></div><div id="gr_3ms.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see <a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_treatment_of_manife/?report=objectonly" target="object" rid-ob="figobgr3msT3msyndrometreatmentofmanife">Table 4</a>). The predominant management issues are ultimate adult stature and growth.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figgr3msT3msyndrometreatmentofmanife"><a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_treatment_of_manife/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobgr3msT3msyndrometreatmentofmanife"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="gr_3ms.T.3m_syndrome_treatment_of_manife"><a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_treatment_of_manife/?report=objectonly" target="object" rid-ob="figobgr3msT3msyndrometreatmentofmanife">Table 4. </a></h4><p class="float-caption no_bottom_margin">3-M Syndrome: Treatment of Manifestations </p></div></div></div><div id="gr_3ms.Surveillance"><h3>Surveillance</h3><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in <a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_recommended_surveil/?report=objectonly" target="object" rid-ob="figobgr3msT3msyndromerecommendedsurveil">Table 5</a> are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figgr3msT3msyndromerecommendedsurveil"><a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_recommended_surveil/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobgr3msT3msyndromerecommendedsurveil"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="gr_3ms.T.3m_syndrome_recommended_surveil"><a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_recommended_surveil/?report=objectonly" target="object" rid-ob="figobgr3msT3msyndromerecommendedsurveil">Table 5. </a></h4><p class="float-caption no_bottom_margin">3-M Syndrome: Recommended Surveillance </p></div></div></div><div id="gr_3ms.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to evaluate sibs of a proband for short stature and, if present, 3-M syndrome to ensure a correct diagnosis is made in affected sibs. Evaluations can include:</p><ul><li class="half_rhythm"><div>Molecular genetic testing if the pathogenic variants in the family are known;</div></li><li class="half_rhythm"><div>Physical examination and skeletal survey for the characteristic clinical and radiographic features if the pathogenic variants in the family are not known.</div></li></ul><p>See <a href="#gr_3ms.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="gr_3ms.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Management of pregnancy for affected women is the same as that for women with other forms of dwarfism or small stature, which is mainly to reduce the risk of premature birth.</p></div><div id="gr_3ms.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="gr_3ms.Genetic_Counseling"><h2 id="_gr_3ms_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="gr_3ms.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>3-M syndrome is inherited in an autosomal recessive manner.</p></div><div id="gr_3ms.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
|
<b>Parents of a proband</b>
|
|
</p><ul><li class="half_rhythm"><div>The parents of an affected child are presumed to be heterozygous for a 3-M syndrome-related pathogenic variant.</div></li><li class="half_rhythm"><div>If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a <i>CCDC8</i>, <i>CUL7</i>, or <i>OBSL1</i> pathogenic variant and to allow reliable recurrence risk assessment.</div></li><li class="half_rhythm"><div>If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a <i>de novo</i> event in the proband or as a postzygotic <i>de novo</i> event in a mosaic parent [<a class="bibr" href="#gr_3ms.REF.j_nsson.2017.519" rid="gr_3ms.REF.j_nsson.2017.519">Jónsson et al 2017</a>]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:</div><ul><li class="half_rhythm"><div>A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;</div></li><li class="half_rhythm"><div>Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.</div></li></ul></li><li class="half_rhythm"><div>Heterozygotes (carriers) are typically asymptomatic.</div></li></ul><p>
|
|
<b>Sibs of a proband</b>
|
|
</p><ul><li class="half_rhythm"><div>If both parents are known to be heterozygous for a <i>CCDC8</i>, <i>CUL7</i>, or <i>OBSL1</i> pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are typically asymptomatic.</div></li></ul><p><b>Offspring of a proband.</b> The offspring of an individual with 3-M syndrome are obligate heterozygotes (carriers) for a 3-M syndrome-related pathogenic variant.</p><p><b>Other family members.</b> Each sib of the proband's parents is at a 50% risk of being a carrier of 3-M syndrome-related pathogenic variant.</p></div><div id="gr_3ms.Carrier_Heterozygote_Detection"><h3>Carrier (Heterozygote) Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the 3-M syndrome-related pathogenic variants in the family.</p></div><div id="gr_3ms.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#gr_3ms.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk sibs 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 testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.</div></li><li class="half_rhythm"><div>Carrier testing should be considered for the reproductive partners of individuals affected with 3-M syndrome and individuals known to be carriers of a <i>CCDC8</i>, <i>CUL7</i>, or <i>OBSL1</i> pathogenic variant, particularly if consanguinity is likely. Founder variants have been identified in several populations (see <a href="/books/NBK1481/table/gr_3ms.T.pathogenic_variants_referenced/?report=objectonly" target="object" rid-ob="figobgr3msTpathogenicvariantsreferenced">Table 7</a>).</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bibr" href="#gr_3ms.REF.huang.2022.389" rid="gr_3ms.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="gr_3ms.Prenatal_Testing_and_Preimplantat"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p><b>Molecular genetic testing.</b> Once the 3-M syndrome-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.</p><p><b>Ultrasound examination.</b> Short long bones have been reported prenatally in 3-M syndrome, with a diagnosis being made at 24 weeks' gestation in one report [<a class="bibr" href="#gr_3ms.REF.hu.2017.159" rid="gr_3ms.REF.hu.2017.159">Hu et al 2017</a>]. Frontal bossing and bilateral temporal narrowing were also detected. These findings are not specific for 3-M syndrome but would suggest a skeletal dysplasia and would be highly suggestive of 3-M syndrome if the parents are known to be carriers.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="gr_3ms.Resources"><h2 id="_gr_3ms_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/?report=reader">here</a>.</i></p>
|
|
<ul><li class="half_rhythm"><div>
|
|
<b>Human Growth Foundation</b>
|
|
</div><div>
|
|
<a href="https://www.hgfound.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">hgfound.org</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>Little People of America</b>
|
|
</div><div><b>Phone:</b> 888-LPA-2001; 714-368-3689</div><div><b>Fax:</b> 707-721-1896</div><div><b>Email:</b> info@lpaonline.org</div><div>
|
|
<a href="https://www.lpaonline.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">lpaonline.org</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>MAGIC Foundation</b>
|
|
</div><div><b>Phone:</b> 630-836-8200</div><div><b>Email:</b> contactus@magicfoundation.org</div><div>
|
|
<a href="https://www.magicfoundation.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">magicfoundation.org</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>UCLA International Skeletal Dysplasia Registry (ISDR)</b>
|
|
</div><div><b>Phone:</b> 310-825-8998</div><div>
|
|
<a href="https://www.uclahealth.org/ortho/isdr" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">International Skeletal Dysplasia Registry</a>
|
|
</div></li></ul>
|
|
</div><div id="gr_3ms.Molecular_Genetics"><h2 id="_gr_3ms_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 class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figgr3msmolgenTA"><a href="/books/NBK1481/table/gr_3ms.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobgr3msmolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="gr_3ms.molgen.TA"><a href="/books/NBK1481/table/gr_3ms.molgen.TA/?report=objectonly" target="object" rid-ob="figobgr3msmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">3-M Syndrome: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figgr3msmolgenTB"><a href="/books/NBK1481/table/gr_3ms.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobgr3msmolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="gr_3ms.molgen.TB"><a href="/books/NBK1481/table/gr_3ms.molgen.TB/?report=objectonly" target="object" rid-ob="figobgr3msmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for 3-M Syndrome (View All in OMIM) </p></div></div><div id="gr_3ms.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>CUL7</i> encodes cullin-7. This large protein acts as a scaffold for the assembly of E3 ubiquitin ligase by binding to ROC1, a small RING finger protein. Cullin-7 is expressed in the cytoplasm and localizes to the centrosome. It is essential for successful anaphase and telophase during mitosis by regulating microtubule dynamics.</p><p><i>OBSL1</i> encodes obscurin-like protein 1 (OBSL1), which acts as a cytoskeletal adaptor.</p><p><i>CCDC8</i> encodes coiled-coil domain-containing protein 8 (CCDC8).</p><p>A study by <a class="bibr" href="#gr_3ms.REF.yan.2014.791" rid="gr_3ms.REF.yan.2014.791">Yan et al [2014]</a> identified that cullin-7, OBSL1, and CCDC8 function within the same pathway and physically interact to form a joint complex known as the 3-M E3 complex. This complex is believed to be critical in microtubule regulation.</p><p>Further research by <a class="bibr" href="#gr_3ms.REF.wang.2019.4393" rid="gr_3ms.REF.wang.2019.4393">Wang et al [2019]</a> demonstrated that CCDC8 localizes to the plasma membrane, where it anchors the 3-M E3 complex. Loss of function in any of the 3-M syndrome-causing genes disrupts the ubiquitylation of membrane-associated LL5β, impairing the regulation of cell migration.</p><p><b>Mechanism of disease causation.</b> Loss of function</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figgr3msT3msyndromegenespecificlabora"><a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_genespecific_labora/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobgr3msT3msyndromegenespecificlabora"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="gr_3ms.T.3m_syndrome_genespecific_labora"><a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_genespecific_labora/?report=objectonly" target="object" rid-ob="figobgr3msT3msyndromegenespecificlabora">Table 6. </a></h4><p class="float-caption no_bottom_margin">3-M Syndrome: Gene-Specific Laboratory Considerations </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figgr3msTpathogenicvariantsreferenced"><a href="/books/NBK1481/table/gr_3ms.T.pathogenic_variants_referenced/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobgr3msTpathogenicvariantsreferenced"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="gr_3ms.T.pathogenic_variants_referenced"><a href="/books/NBK1481/table/gr_3ms.T.pathogenic_variants_referenced/?report=objectonly" target="object" rid-ob="figobgr3msTpathogenicvariantsreferenced">Table 7. </a></h4><p class="float-caption no_bottom_margin">Pathogenic Variants Referenced in This <i>GeneReview</i> by Gene </p></div></div></div></div><div id="gr_3ms.Chapter_Notes"><h2 id="_gr_3ms_Chapter_Notes_">Chapter Notes</h2><div id="gr_3ms.Author_Notes"><h3>Author Notes</h3><p><b>Rhoda Akilapa, BMBS, BMedSci</b><br />Skeletal Dysplasia Service, Evelina Children's Hospital, London<br />Clinical Genetics Service, Guy's & St Thomas' Hospital, London<br />Email: <a href="mailto:dev@null" data-email="ku.shn.ttsg@apalika.adohr" class="oemail">ku.shn.ttsg@apalika.adohr</a></p><p>Dr Akilapa is happy to communicate with persons who have any questions regarding diagnosis of 3-M syndrome or other considerations.</p><p><b>Melita Irving, MBBS, MD</b><br />Skeletal Dysplasia Service, Evelina Children's Hospital, London<br />Clinical Genetics Service, Guy's & St Thomas' Hospital, London<br />Email: <a href="mailto:dev@null" data-email="ku.shn.ttsg@gnivri.atilem" class="oemail">ku.shn.ttsg@gnivri.atilem</a></p><p>Dr Irving is also interested in hearing from clinicians treating families affected by 3-M syndrome and other skeletal dysplasias in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.</p><p><b>Muriel Holder-Espinasse, MD, PhD</b><br />Clinical Genetics Service, Guy's & St Thomas' Hospital, London<br />Email: <a href="mailto:dev@null" data-email="ku.shn.ttsg@redloh.leirum" class="oemail">ku.shn.ttsg@redloh.leirum</a></p></div><div id="gr_3ms.Author_History"><h3>Author History</h3><p>Rhoda Akilapa, BMBS, BMedSci (2025-present)<br />Muriel Holder-Espinasse, MD, PhD (2002-present)<br />Melita Irving, MBBS, MD (2019-present)<br />Robin M Winter, FRCP, F Med Sci; Institute of Child Health, London (2002-2004 *)</p><p>* Robin Winter was Professor of Clinical Genetics and Dysmorphology at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust. He contributed nearly 300 papers to medical journals on a wide breadth of topics and was an editor of the journal <i>Clinical Dysmorphology</i> and co-author of the London Dysmorphology and Neurogenetics Databases. Professor Winter died January 10, 2004, after a brief illness.</p></div><div id="gr_3ms.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>27 February 2025 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>7 February 2019 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>26 January 2012 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>30 March 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>23 June 2006 (ca) Comprehensive update posted live</div></li><li class="half_rhythm"><div>11 May 2004 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>25 March 2002 (me) Review posted live</div></li><li class="half_rhythm"><div>31 January 2002 (mhe) Original submission</div></li></ul></div></div><div id="gr_3ms.References"><h2 id="_gr_3ms_References_">References</h2><div id="gr_3ms.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.akal_n.2024.68">Akalın
|
|
A, Özalkak
|
|
Ş, Yıldırım
|
|
R, Karakaya
|
|
AA, Kolbaşı
|
|
B, Durmuşalioğlu
|
|
EA, Kökali
|
|
F, Ürel-Demir
|
|
G, Öz
|
|
V, Ünal
|
|
E, Atik
|
|
T, Şimşek-Kiper
|
|
PÖ, Elcioglu
|
|
NH. Clinical and molecular spectrum along with genotype-phenotype correlation of 25 patients diagnosed with 3 M syndrome: a study from Turkey.
|
|
Eur J Pediatr.
|
|
2024;184:68.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/39643721" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 39643721</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.badina.2011.114">Badina
|
|
A, Pejin
|
|
Z, Odent
|
|
T, Buzescu
|
|
A, Huber
|
|
C, Cormier-Daire
|
|
V, Glorion
|
|
C, Pannier
|
|
S.
|
|
Hip dislocation in 3-M syndrome: risk of misdiagnosis.
|
|
Clin Dysmorphol.
|
|
2011; 20:114–6.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/21383554" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21383554</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.clayton.2012.335">Clayton
|
|
PE, Hanson
|
|
D, Magee
|
|
L, Murray
|
|
PG, Saunders
|
|
E, Abu-Amero
|
|
SN, Moore
|
|
GE, Black
|
|
GC. Exploring the spectrum of 3-M syndrome, a primordial short stature disorder of disrupted ubiquitination.
|
|
Clin Endocrinol (Oxf). 2012;77:335-42.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/22624670" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22624670</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.deeb.2015.150012">Deeb
|
|
A, Afandi
|
|
O, Attia
|
|
S, Fatih
|
|
AE. 3-M syndrome: a novel CUL7 mutation associated with respiratory distress and a good response to GH therapy.
|
|
Endocrinol Diabetes Metab Case Rep.
|
|
2015;2015:150012.
|
|
[<a href="/pmc/articles/PMC4418346/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4418346</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25945256" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25945256</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.elliott.2002.351">Elliott
|
|
AM, Graham
|
|
JM
|
|
Jr, Curry
|
|
CJ, Pal
|
|
T, Rimoin
|
|
DL, Lachman
|
|
RS. Spectrum of dolichospondylic dysplasia: two new patients with distinctive findings.
|
|
Am J Med Genet.
|
|
2002;113:351–61.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/12457407" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12457407</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.hanson.2011.148">Hanson
|
|
D, Murray
|
|
PG, O'Sullivan
|
|
J, Urquhart
|
|
J, Daly
|
|
S, Bhaskar
|
|
SS, Biesecker
|
|
LG, Skae
|
|
M, Smith
|
|
C, Cole
|
|
T, Kirk
|
|
J, Chandler
|
|
K, Kingston
|
|
H, Donnai
|
|
D, Clayton
|
|
PE, Black
|
|
GC. Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth.
|
|
Am J Hum Genet.
|
|
2011;89:148–53.
|
|
[<a href="/pmc/articles/PMC3135816/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3135816</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21737058" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21737058</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.hanson.2009.801">Hanson
|
|
D, Murray
|
|
PG, Sud
|
|
A, Temtamy
|
|
SA, Aglan
|
|
M, Superti-Furga
|
|
A, Holder
|
|
SE, Urquhart
|
|
J, Hilton
|
|
E, Manson
|
|
FDC, Scambler
|
|
P, Black
|
|
GCM, Clayton
|
|
PE. The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1.
|
|
Am J Hum Genet.
|
|
2009;84:801–6.
|
|
[<a href="/pmc/articles/PMC2694976/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2694976</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19481195" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19481195</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.holderespinasse.2014.22">Holder-Espinasse
|
|
M, Irving
|
|
M, Cormier-Daire
|
|
V. Clinical utility gene card for: 3-M syndrome - update 2013.
|
|
Eur J Hum Genet.
|
|
2014;22.
|
|
[<a href="/pmc/articles/PMC3953895/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3953895</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23900270" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23900270</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.hu.2017.159">Hu
|
|
X, Li
|
|
H, Gui
|
|
B, Xu
|
|
Y, Wang
|
|
J, Li
|
|
N, Su
|
|
J, Zhang
|
|
S, Song
|
|
Y, Wang
|
|
Y, Luo
|
|
J, Fan
|
|
X, Wang
|
|
J, Chen
|
|
S, Gong
|
|
C, Shen
|
|
Y. Prenatal and early diagnosis of Chinese 3-M syndrome patients with novel pathogenic variants.
|
|
Clin Chim Acta.
|
|
2017;474:159-64.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/28969986" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28969986</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.huang.2022.389">Huang
|
|
SJ, Amendola
|
|
LM, Sternen
|
|
DL. Variation among DNA banking consent forms: points for clinicians to bank on.
|
|
J Community Genet.
|
|
2022;13:389-97.
|
|
[<a href="/pmc/articles/PMC9314484/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9314484</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35834113" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35834113</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.huber.2009.395">Huber
|
|
C, Delezoide
|
|
A-L, Guimiot
|
|
F, Baumann
|
|
C, Malan
|
|
V, Le Merrer
|
|
M, Bezerra Da Silva
|
|
D, Bonneau
|
|
D, Chatelain
|
|
P, Chu
|
|
C, Clark
|
|
R, Cox
|
|
H, Edery
|
|
P, Edouard
|
|
T, Fano
|
|
V, Gibson
|
|
K, Gillessen-Kaesbach
|
|
G, Giovannucci-Uzielli
|
|
M-L, Graul-Neumann
|
|
LM, van Hagen
|
|
J-M, van Hest
|
|
L, Horovitz
|
|
D, Melki
|
|
J, Partsch
|
|
C-J, Plauchu
|
|
H, Rajab
|
|
A, Rossi
|
|
M, Sillence
|
|
D, Steichen-Gersdorf
|
|
E, Stewart
|
|
H, Unger
|
|
S, Zenker
|
|
M, Munnich
|
|
A, Cormier-Daire
|
|
V. A large-scale mutation search reveals genetic heterogeneity in 3M syndrome.
|
|
Eur J Hum Genet.
|
|
2009;17:395–400.
|
|
[<a href="/pmc/articles/PMC2986175/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2986175</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19225462" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19225462</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.huber.2011.143">Huber
|
|
C, Munnich
|
|
A, Cormier-Daire
|
|
V.
|
|
The 3M syndrome.
|
|
Best Pract Res Clin Endocrinol Metab.
|
|
2011;25:143–51.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/21396581" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21396581</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.j_nsson.2017.519">Jónsson
|
|
H, Sulem
|
|
P, Kehr
|
|
B, Kristmundsdottir
|
|
S, Zink
|
|
F, Hjartarson
|
|
E, Hardarson
|
|
MT, Hjorleifsson
|
|
KE, Eggertsson
|
|
HP, Gudjonsson
|
|
SA, Ward
|
|
LD, Arnadottir
|
|
GA, Helgason
|
|
EA, Helgason
|
|
H, Gylfason
|
|
A, Jonasdottir
|
|
A, Jonasdottir
|
|
A, Rafnar
|
|
T, Frigge
|
|
M, Stacey
|
|
SN, Th Magnusson
|
|
O, Thorsteinsdottir
|
|
U, Masson
|
|
G, Kong
|
|
A, Halldorsson
|
|
BV, Helgason
|
|
A, Gudbjartsson
|
|
DF, Stefansson
|
|
K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.
|
|
Nature.
|
|
2017;549:519-22.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/28959963" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28959963</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.karacan_k___kali.2023.104828">Karacan Küçükali
|
|
G, Keskin
|
|
M, Aycan
|
|
Z, Savaş-Erdeve
|
|
Ş, Çetinkaya
|
|
S.
|
|
3M syndrome: Evaluating the clinical and laboratory features and the response of the growth hormone treatment: single center experience.
|
|
Eur J Med Genet.
|
|
2023;66:104828.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/37673300" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 37673300</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.keskin.2017.91">Keskin
|
|
M, Muratoglu Sahin
|
|
N, Kurnaz
|
|
E, Bayramoglu
|
|
E, Savas Erdeve
|
|
S, Aycan
|
|
Z, Cetinkaya
|
|
S.
|
|
A rare cause of short stature: 3M syndrome in a patient with novel mutation in OBSL1 gene.
|
|
J Clin Res Pediatr Endocrinol.
|
|
2017;9:91-4.
|
|
[<a href="/pmc/articles/PMC5363173/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5363173</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27796265" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27796265</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.khachnaouizaafrane.2022.104448">Khachnaoui-Zaafrane
|
|
K, Ouertani
|
|
I, Zanati
|
|
A, Kandara
|
|
H, Maazoul
|
|
F, Mrad
|
|
R.
|
|
3M syndrome: A Tunisian seven-cases series.
|
|
Eur J Med Genet.
|
|
2022;65:104448.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/35150935" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35150935</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.lugli.2016.232">Lugli
|
|
L, Bertucci
|
|
E, Mazza
|
|
V, Elmakky
|
|
A, Ferrari
|
|
F, Neuhaus
|
|
C, Percesepe
|
|
A.
|
|
Pre- and post-natal growth in two sisters with 3-M syndrome.
|
|
Eur J Med Genet.
|
|
2016;59:232–6.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/26850509" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26850509</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.maksimova.2007.772">Maksimova
|
|
N, Hara
|
|
K, Miyashia
|
|
A, Nikolaeva
|
|
I, Shiga
|
|
A, Nogovicina
|
|
A, Sukhomyasova
|
|
A, Argunov
|
|
V, Shvedova
|
|
A, Ikeuchi
|
|
T, Nishizawa
|
|
M, Kuwano
|
|
R, Onodera
|
|
O (2007) Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia.
|
|
J Med Genet.
|
|
44:772-8.
|
|
[<a href="/pmc/articles/PMC2652813/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2652813</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17675530" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17675530</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.marik.2002.419">Marik
|
|
I, Marikova
|
|
O, Kuklik
|
|
M, Zemkova
|
|
D, Kozlowski
|
|
K.
|
|
3-M syndrome in two sisters.
|
|
J Paediatr Child Health.
|
|
2002;38:419–22.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/12174011" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12174011</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.miller.1975.39">Miller
|
|
JD, McKusick
|
|
VA, Malvaux
|
|
P, Temtamy
|
|
S, Salinas
|
|
C. The 3-M syndrome: a heritable low birthweight dwarfism.
|
|
Birth Defects Orig Artic Ser.
|
|
1975;11:39–47.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/1218233" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1218233</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.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, Committee
|
|
ALQA. 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.
|
|
Genet Med.
|
|
2015;17:405-24.
|
|
[<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></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.shapiro.2017.485">Shapiro
|
|
L, Chatterjee
|
|
S, Ramadan
|
|
DG, Davies
|
|
KM, Savage
|
|
MO, Metherell
|
|
LA, Storr
|
|
HL. Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity.
|
|
Eur J Endocrinol.
|
|
2017;177:485–501.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/28870985" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28870985</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.simsekkiper.2019.1157">Simsek-Kiper
|
|
PO, Taskiran
|
|
E, Kosukcu
|
|
C, Arslan
|
|
UE, Cormier-Daire
|
|
V, Gonc
|
|
N, Ozon
|
|
A, Alikasifoglu
|
|
A, Kandemir
|
|
N, Utine
|
|
GE, Alanay
|
|
Y, Alikasifoglu
|
|
M, Boduroglu
|
|
K. Further expanding the mutational spectrum and investigation of genotype-phenotype correlation in 3M syndrome.
|
|
Am J Med Genet A.
|
|
2019;179:1157-72.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/30980518" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30980518</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.t_ys_z.2021.104346">Tüysüz
|
|
B, Alp Ünkar
|
|
Z, Turan
|
|
H, Gezdirici
|
|
A, Uludağ Alkaya
|
|
D, Kasap
|
|
B, Yeşil
|
|
G, Vural
|
|
M, Ercan
|
|
O.
|
|
Natural history of facial and skeletal features from neonatal period to adulthood in a 3M syndrome cohort with biallelic CUL7 or OBSL1 variants.
|
|
Eur J Med Genet.
|
|
2021;64:104346.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/34597859" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34597859</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.unger.2023.1164">Unger
|
|
S, Ferreira
|
|
CR, Mortier
|
|
GR, Ali
|
|
H, Bertola
|
|
DR, Calder
|
|
A, Cohn
|
|
DH, Cormier-Daire
|
|
V, Girisha
|
|
KM, Hall
|
|
C, Krakow
|
|
D, Makitie
|
|
O, Mundlos
|
|
S, Nishimura
|
|
G, Robertson
|
|
SP, Savarirayan
|
|
R, Sillence
|
|
D, Simon
|
|
M, Sutton
|
|
VR, Warman
|
|
ML, Superti-Furga
|
|
A. Nosology of genetic skeletal disorders: 2023 revision.
|
|
Am J Med Genet A.
|
|
2023;191:1164-209.
|
|
[<a href="/pmc/articles/PMC10081954/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10081954</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/36779427" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36779427</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.van_der_wal.2001.241">van der Wal
|
|
G, Otten
|
|
BJ, Brunner
|
|
HG, van der Burgt
|
|
I. 3-M syndrome: description of six new patients with review of the literature.
|
|
Clin Dysmorphol.
|
|
2001;10:241–52.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/11665997" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11665997</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.wang.2019.4393">Wang
|
|
P, Yan
|
|
F, Li
|
|
Z, Yu
|
|
Y, Parnell
|
|
SE, Xiong
|
|
Y. Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development.
|
|
J Clin Invest.
|
|
2019;129:4393-407.
|
|
[<a href="/pmc/articles/PMC6763242/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6763242</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31343991" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31343991</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.yan.2014.791">Yan
|
|
J, Yan
|
|
F, Li
|
|
Z, Sinnott
|
|
B, Cappell
|
|
KM, Yu
|
|
Y, Mo
|
|
J, Duncan
|
|
JA, Chen
|
|
X, Cormier-Daire
|
|
V, Whitehurst
|
|
AW, Xiong
|
|
Y. The 3M complex maintains microtubule and genome integrity.
|
|
Mol Cell.
|
|
2014;54:791-804.
|
|
[<a href="/pmc/articles/PMC4165194/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4165194</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24793695" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24793695</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="gr_3ms.REF.yang.2020.1609">Yang
|
|
M, Patni
|
|
N. Effect of recombinant human insulin-like growth factor 1 therapy in a child with 3-M syndrome-1 with CUL7 gene mutation.
|
|
J Pediatr Endocrinol Metab.
|
|
2020;33:1609-12.
|
|
[<a href="https://pubmed.ncbi.nlm.nih.gov/32924381" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32924381</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1481_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Rhoda Akilapa</span>, BMBS, BMedSci<div class="affiliation small">Clinical Genetics Department<br />Guy's and St Thomas' NHS Trust<br />London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.shn.ttsg@apalika.adohr" class="oemail">ku.shn.ttsg@apalika.adohr</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Melita Irving</span>, MBBS, MD(Res)<div class="affiliation small">Clinical Genetics Department<br />Guy's and St Thomas' NHS Trust<br />London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.shn.ttsg@gnivri.atilem" class="oemail">ku.shn.ttsg@gnivri.atilem</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Muriel Holder-Espinasse</span>, MD, PhD<div class="affiliation small">Clinical Genetics Department<br />Guy's and St Thomas' NHS Trust<br />London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.shn.ttsg@redloh.leirum" class="oemail">ku.shn.ttsg@redloh.leirum</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">March 25, 2002</span>; Last Update: <span itemprop="dateModified">February 27, 2025</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
|
|
a registered trademark of the University of Washington, Seattle. All rights
|
|
reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
|
|
hereby granted to reproduce, distribute, and translate copies of content materials for
|
|
noncommercial research purposes only, provided that (i) credit for source (<a href="http://www.genereviews.org/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">http://www.genereviews.org/</a>) and copyright (© 1993-2025 University of
|
|
Washington) are included with each copy; (ii) a link to the original material is provided
|
|
whenever the material is published elsewhere on the Web; and (iii) reproducers,
|
|
distributors, and/or translators comply with the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
|
|
Disclaimer</a>. No further modifications are allowed. For clarity, excerpts
|
|
of GeneReviews chapters for use in lab reports and clinic notes are a permitted
|
|
use.</p><p class="small">For more information, see the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
|
|
Disclaimer</a>.</p><p class="small">For questions regarding permissions or whether a specified use is allowed,
|
|
contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Akilapa R, Irving M, Holder-Espinasse M. 3-M Syndrome. 2002 Mar 25 [Updated 2025 Feb 27]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/del2q37_2/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/mdel3q29/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobgr3msTmoleculargenetictestingused"><div id="gr_3ms.T.molecular_genetic_testing_used" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in 3-M Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1481/table/gr_3ms.T.molecular_genetic_testing_used/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gr_3ms.T.molecular_genetic_testing_used_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene <sup>1, 2</sup></th><th id="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_2" style="text-align:left;vertical-align:middle;">Proportion of 3-M Syndrome Attributed to Pathogenic Variants in Gene</th><th id="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>3</sup> Identified by Method</th></tr><tr><th headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_3" id="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>4</sup></th><th headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_3" id="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></th></tr></thead><tbody><tr><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>CCDC8</i>
|
|
</td><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1% <sup>6</sup></td><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_3 hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <sup>6</sup></td><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_3 hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported <sup>6</sup></td></tr><tr><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>CUL7</i>
|
|
</td><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">65% <sup>7</sup></td><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_3 hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <sup>7</sup></td><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_3 hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported <sup>7</sup></td></tr><tr><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>OBSL1</i>
|
|
</td><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">34% <sup>7, 8</sup></td><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_3 hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <sup>7</sup></td><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_3 hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported <sup>7, 8</sup></td></tr><tr><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown <sup>9</sup></td><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td><td headers="hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_1_3 hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_2_1 hd_h_gr_3ms.T.molecular_genetic_testing_used_1_1_2_2" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;">NA</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">NA = not applicable</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="gr_3ms.TF.1.1"><p class="no_margin">Genes are listed alphabetically.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="gr_3ms.TF.1.2"><p class="no_margin">See <a href="/books/NBK1481/?report=reader#gr_3ms.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="gr_3ms.TF.1.3"><p class="no_margin">See <a href="#gr_3ms.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="gr_3ms.TF.1.4"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="gr_3ms.TF.1.5"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="gr_3ms.TF.1.6"><p class="no_margin">
|
|
<a class="bibr" href="#gr_3ms.REF.hanson.2011.148" rid="gr_3ms.REF.hanson.2011.148">Hanson et al [2011]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="gr_3ms.TF.1.7"><p class="no_margin"><a class="bibr" href="#gr_3ms.REF.huber.2009.395" rid="gr_3ms.REF.huber.2009.395">Huber et al [2009]</a>, <a class="bibr" href="#gr_3ms.REF.huber.2011.143" rid="gr_3ms.REF.huber.2011.143">Huber et al [2011]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>8. </dt><dd><div id="gr_3ms.TF.1.8"><p class="no_margin"><a class="bibr" href="#gr_3ms.REF.hanson.2009.801" rid="gr_3ms.REF.hanson.2009.801">Hanson et al [2009]</a>, <a class="bibr" href="#gr_3ms.REF.hu.2017.159" rid="gr_3ms.REF.hu.2017.159">Hu et al [2017]</a>, <a class="bibr" href="#gr_3ms.REF.simsekkiper.2019.1157" rid="gr_3ms.REF.simsekkiper.2019.1157">Simsek Kiper et al [2019]</a>, <a class="bibr" href="#gr_3ms.REF.t_ys_z.2021.104346" rid="gr_3ms.REF.t_ys_z.2021.104346">Tüysüz et al [2021]</a>, <a class="bibr" href="#gr_3ms.REF.akal_n.2024.68" rid="gr_3ms.REF.akal_n.2024.68">Akalın et al [2024]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>9. </dt><dd><div id="gr_3ms.TF.1.9"><p class="no_margin">Pathogenic variants in <i>CCDC8</i>, <i>CUL7</i>, and <i>OBSL1</i> do not account for 100% of 3-M syndrome; it is postulated that pathogenic variants in other genes may be involved [<a class="bibr" href="#gr_3ms.REF.huber.2011.143" rid="gr_3ms.REF.huber.2011.143">Huber et al 2011</a>].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobgr3msTdisordersofknowngeneticcaus"><div id="gr_3ms.T.disorders_of_known_genetic_caus" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Disorders of Known Genetic Cause to Consider in the Differential Diagnosis of 3-M Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1481/table/gr_3ms.T.disorders_of_known_genetic_caus/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gr_3ms.T.disorders_of_known_genetic_caus_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_2" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Clinical Features of Disorder</th></tr><tr><th headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_4" id="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/3-M syndrome</th><th headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_4" id="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from 3-M syndrome</th></tr></thead><tbody><tr><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Genetically heterogeneous <sup>1</sup></td><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/rss/?report=reader">Silver-Russell syndrome</a> (SRS)</td><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 2.</td><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_4 hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">IUGR & postnatal growth deficiency</td><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_4 hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>SRS often shows limb length asymmetry.</div></li><li class="half_rhythm"><div>Characteristic radiologic features of 3-M syndrome are absent.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>TRIM37</i>
|
|
</td><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mulibrey nanism (OMIM <a href="https://omim.org/entry/253250" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">253250</a>)</td><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_4 hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">IUGR</td><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_4 hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>IUGR is often less severe than in infants w/3-M syndrome.</div></li><li class="half_rhythm"><div>Characteristic facial features incl high forehead & pseudohydrocephalic skull configuration.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>IGF1R</i>
|
|
</td><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>IGF1R</i> deficiency (OMIM <a href="https://omim.org/entry/270450" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">270450</a>)</td><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />AD</td><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_4 hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">IUGR & postnatal growth deficiency</td><td headers="hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_1_4 hd_h_gr_3ms.T.disorders_of_known_genetic_caus_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Microcephaly & ID are common in more severely affected persons w/biallelic pathogenic variants but can be absent in heterozygous persons w/milder manifestations.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="gr_3ms.TF.2.1"><p class="no_margin">Hypomethylation of the imprinting control region 1 at 11p15.5 causes SRS in 35%-67% of individuals, and maternal uniparental disomy of chromosome 7 causes SRS in 7%-10% of individuals. See Silver-Russell syndrome, <a href="/books/n/gene/rss/?report=reader#rss.Diagnosis">Diagnosis</a> for other genetic causes.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="gr_3ms.TF.2.2"><p class="no_margin">In most families, a proband with SRS represents a simplex case and has a <i>de novo</i> epigenetic or genetic alteration; rare familial cases have been reported. Reliable SRS recurrence risk assessment requires identification of the causative genetic mechanism in the proband.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobgr3msT3msyndromerecommendedevaluat"><div id="gr_3ms.T.3m_syndrome_recommended_evaluat" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>3-M Syndrome: Recommended Evaluations Following Initial Diagnosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_recommended_evaluat/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gr_3ms.T.3m_syndrome_recommended_evaluat_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gr_3ms.T.3m_syndrome_recommended_evaluat_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_gr_3ms.T.3m_syndrome_recommended_evaluat_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_gr_3ms.T.3m_syndrome_recommended_evaluat_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_gr_3ms.T.3m_syndrome_recommended_evaluat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Musculoskeletal</b>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_evaluat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical exam to assess for joint hypermobility, kyphoscoliosis, & hip dysplasia/dislocation</td><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_evaluat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hip US in infancy or hip radiographs in older children may be helpful.</div></li><li class="half_rhythm"><div>Refer to orthopedist if hip dysplasia/dislocation or scoliosis is identified.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_evaluat_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Endocrine</b>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_evaluat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical exam to assess for hypospadias</td><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_evaluat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_evaluat_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Refer to pediatric endocrinologist to assess for:
|
|
<ul><li class="half_rhythm"><div>Gonadal function in pubertal males by physical exam & serum concentrations of FSH, LH, & testosterone;</div></li><li class="half_rhythm"><div>GH deficiency &/or GH insensitivity.</div></li></ul>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_evaluat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_evaluat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Genetic counseling</b>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_evaluat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_evaluat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of 3-M syndrome to facilitate medical & personal decision making</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">FSH = follicle-stimulating hormone; GH = growth hormone; LH = luteinizing hormone; MOI = mode of inheritance; US = ultrasound</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="gr_3ms.TF.3.1"><p class="no_margin">Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobgr3msT3msyndrometreatmentofmanife"><div id="gr_3ms.T.3m_syndrome_treatment_of_manife" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>3-M Syndrome: Treatment of Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_treatment_of_manife/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gr_3ms.T.3m_syndrome_treatment_of_manife_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_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_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Growth deficiency</b>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Refer to pediatric endocrinologist for consideration of GH treatment.</div></li><li class="half_rhythm"><div>A trial of GH, particularly in prepubertal children, w/close monitoring of growth velocity & measurement of IGF-1 is recommended. <sup>1</sup></div></li><li class="half_rhythm"><div>GH should be discontinued if there is reduction in growth velocity.</div></li></ul>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>GH treatment should be carried out in center w/experience in managing growth disorders.</div></li><li class="half_rhythm"><div>The use of GH for short stature in 3-M syndrome has been used w/varying effects; GH has yielded poor results in many w/3-M syndrome. However, there are reports of children responding well to GH, w/↑ growth velocity & marked ↑ in height SD.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Adaptive aids for people w/short stature</div></li><li class="half_rhythm"><div>Surgical bone lengthening may be an option for some.</div></li></ul>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PT, OT, & community child health services to ensure necessary adaptations for short stature are put in place to maximize access to person's environment</td></tr><tr><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Musculoskeletal manifestations</b>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Orthopedic eval & treatment for hip dysplasia/dislocation & kyphoscoliosis</div></li><li class="half_rhythm"><div>Significant joint laxity should prompt orthopedic eval & measures to control development of arthritis.</div></li></ul>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hypogonadism</b>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment per endocrinologist</td><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hypospadias</b>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment per urologist</td><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_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_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In neonates w/severe respiratory distress, neonatal/pediatric intensive care team input & follow up w/pediatric respiratory physician</td><td headers="hd_h_gr_3ms.T.3m_syndrome_treatment_of_manife_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">GH = growth hormone; IGF-1 = insulin-like growth factor 1; OT = occupational therapy; PT = physical therapy; SD = standard deviation</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="gr_3ms.TF.4.1"><p class="no_margin"><a class="bibr" href="#gr_3ms.REF.clayton.2012.335" rid="gr_3ms.REF.clayton.2012.335">Clayton et al [2012]</a>, <a class="bibr" href="#gr_3ms.REF.deeb.2015.150012" rid="gr_3ms.REF.deeb.2015.150012">Deeb et al [2015]</a>, <a class="bibr" href="#gr_3ms.REF.yang.2020.1609" rid="gr_3ms.REF.yang.2020.1609">Yang & Patni [2020]</a>, <a class="bibr" href="#gr_3ms.REF.karacan_k___kali.2023.104828" rid="gr_3ms.REF.karacan_k___kali.2023.104828">Karacan Küçükali et al [2023]</a>, <a class="bibr" href="#gr_3ms.REF.akal_n.2024.68" rid="gr_3ms.REF.akal_n.2024.68">Akalın et al [2024]</a></p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobgr3msT3msyndromerecommendedsurveil"><div id="gr_3ms.T.3m_syndrome_recommended_surveil" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>3-M Syndrome: Recommended Surveillance</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_recommended_surveil/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gr_3ms.T.3m_syndrome_recommended_surveil_lrgtbl__"><table><thead><tr><th id="hd_h_gr_3ms.T.3m_syndrome_recommended_surveil_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_gr_3ms.T.3m_syndrome_recommended_surveil_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_gr_3ms.T.3m_syndrome_recommended_surveil_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_gr_3ms.T.3m_syndrome_recommended_surveil_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Growth deficiency</b>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_surveil_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor growth on standard growth charts w/special attention to growth velocity.</td><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_surveil_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 6-12 mos</td></tr><tr><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_surveil_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Musculoskeletal</b>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_surveil_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assess for joint hypermobility.</div></li><li class="half_rhythm"><div>Examine back for kyphoscoliosis.</div></li></ul>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_surveil_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_surveil_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Assess for hip dislocation.</td><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_surveil_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit in infancy, esp if walking is delayed</td></tr><tr><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_surveil_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Cardiac</b>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_surveil_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram w/measurement of aortic root</td><td headers="hd_h_gr_3ms.T.3m_syndrome_recommended_surveil_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider in adolescence</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobgr3msmolgenTA"><div id="gr_3ms.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>3-M Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1481/table/gr_3ms.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gr_3ms.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_gr_3ms.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_gr_3ms.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_gr_3ms.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_gr_3ms.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_gr_3ms.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_gr_3ms.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="/gene/83987" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
|
<i>CCDC8</i>
|
|
</a>
|
|
</td><td headers="hd_b_gr_3ms.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=83987" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">19q13<wbr style="display:inline-block"></wbr>​.32</a>
|
|
</td><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/Q9H0W5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Coiled-coil domain-containing protein 8</a>
|
|
</td><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;"></td><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CCDC8" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CCDC8</a>
|
|
</td><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=CCDC8[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CCDC8</a>
|
|
</td></tr><tr><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="/gene/9820" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
|
<i>CUL7</i>
|
|
</a>
|
|
</td><td headers="hd_b_gr_3ms.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=9820" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">6p21<wbr style="display:inline-block"></wbr>​.1</a>
|
|
</td><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/Q14999" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Cullin-7</a>
|
|
</td><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://databases.lovd.nl/shared/genes/CUL7" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CUL7 database</a>
|
|
</td><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CUL7" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CUL7</a>
|
|
</td><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=CUL7[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CUL7</a>
|
|
</td></tr><tr><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="/gene/23363" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
|
<i>OBSL1</i>
|
|
</a>
|
|
</td><td headers="hd_b_gr_3ms.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=23363" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">2q35</a>
|
|
</td><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/O75147" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Obscurin-like protein 1</a>
|
|
</td><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://databases.lovd.nl/shared/genes/OBSL1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OBSL1 database</a>
|
|
</td><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=OBSL1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OBSL1</a>
|
|
</td><td headers="hd_b_gr_3ms.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=OBSL1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OBSL1</a>
|
|
</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="gr_3ms.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
|
|
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
|
chromosome locus from
|
|
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
|
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
|
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
|
<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobgr3msmolgenTB"><div id="gr_3ms.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for 3-M Syndrome (<a href="/omim/273750,609577,610991,612921,614145,614205" 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/NBK1481/table/gr_3ms.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gr_3ms.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/273750" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">273750</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THREE M SYNDROME 1; 3M1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/609577" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">609577</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CULLIN 7; CUL7</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/610991" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">610991</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OBSCURIN-LIKE 1; OBSL1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/612921" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">612921</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THREE M SYNDROME 2; 3M2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/614145" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">614145</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">COILED-COIL DOMAIN-CONTAINING PROTEIN 8; CCDC8</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/614205" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">614205</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THREE M SYNDROME 3; 3M3</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobgr3msT3msyndromegenespecificlabora"><div id="gr_3ms.T.3m_syndrome_genespecific_labora" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>3-M Syndrome: Gene-Specific Laboratory Considerations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1481/table/gr_3ms.T.3m_syndrome_genespecific_labora/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gr_3ms.T.3m_syndrome_genespecific_labora_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gr_3ms.T.3m_syndrome_genespecific_labora_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_gr_3ms.T.3m_syndrome_genespecific_labora_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Special Consideration</th></tr></thead><tbody><tr><td headers="hd_h_gr_3ms.T.3m_syndrome_genespecific_labora_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>CCDC8</i>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_genespecific_labora_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>CCDC8</i> comprises a single exon. Pathogenic variants lead to truncation w/subsequent loss of function [<a class="bibr" href="#gr_3ms.REF.holderespinasse.2014.22" rid="gr_3ms.REF.holderespinasse.2014.22">Holder-Espinasse et al 2014</a>].</td></tr><tr><td headers="hd_h_gr_3ms.T.3m_syndrome_genespecific_labora_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>CUL7</i>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_genespecific_labora_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">There is a predominance of null variants (nonsense & splice site but missense variants are also frequent). Fifty percent of <i>CUL7</i> pathogenic variants are located in the cullin domain critical for anchoring the ROC1 protein [<a class="bibr" href="#gr_3ms.REF.holderespinasse.2014.22" rid="gr_3ms.REF.holderespinasse.2014.22">Holder-Espinasse et al 2014</a>].</td></tr><tr><td headers="hd_h_gr_3ms.T.3m_syndrome_genespecific_labora_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>OBSL1</i>
|
|
</td><td headers="hd_h_gr_3ms.T.3m_syndrome_genespecific_labora_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Most reported pathogenic variants occur w/in 1st 8 exons affecting all known isoforms, w/predominance of loss of function [<a class="bibr" href="#gr_3ms.REF.holderespinasse.2014.22" rid="gr_3ms.REF.holderespinasse.2014.22">Holder-Espinasse et al 2014</a>].</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="gr_3ms.TF.6.1"><p class="no_margin">Genes from <a href="/books/NBK1481/table/gr_3ms.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobgr3msTmoleculargenetictestingused">Table 1</a> are in alphabetic order.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobgr3msTpathogenicvariantsreferenced"><div id="gr_3ms.T.pathogenic_variants_referenced" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Pathogenic Variants Referenced in This <i>GeneReview</i> by Gene</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1481/table/gr_3ms.T.pathogenic_variants_referenced/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gr_3ms.T.pathogenic_variants_referenced_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gr_3ms.T.pathogenic_variants_referenced_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_gr_3ms.T.pathogenic_variants_referenced_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change<br />(Alias <sup>2</sup>)</th><th id="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change<br />(Alias <sup>2</sup>)</th><th id="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>CUL7</i>
|
|
</td><td headers="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_014780.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_014780<wbr style="display:inline-block"></wbr>​.5</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_055595.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_055595<wbr style="display:inline-block"></wbr>​.2</a>
|
|
</td><td headers="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.4451_4452delTG</td><td headers="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Val1484GlyfsTer69</td><td headers="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Founder variant reported in Maghreb population in Tunisia [<a class="bibr" href="#gr_3ms.REF.khachnaouizaafrane.2022.104448" rid="gr_3ms.REF.khachnaouizaafrane.2022.104448">Khachnaoui-Zaafrane et al 2022</a>]</td></tr><tr><td headers="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.4581dupT<br />(4582_4583insT)</td><td headers="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg1528SerfsTer26<br />(Arg1528LeufsTer26)</td><td headers="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Founder variant reported in Yakut population [<a class="bibr" href="#gr_3ms.REF.maksimova.2007.772" rid="gr_3ms.REF.maksimova.2007.772">Maksimova et al 2007</a>] (See <a href="#gr_3ms.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>.)</td></tr><tr><td headers="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>OBSL1</i>
|
|
</td><td headers="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_015311.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_015311<wbr style="display:inline-block"></wbr>​.3</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_056126.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_056126<wbr style="display:inline-block"></wbr>​.1</a>
|
|
</td><td headers="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1273dupA</td><td headers="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Thr425AsnfsTer40</td><td headers="hd_h_gr_3ms.T.pathogenic_variants_referenced_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Emerging founder pathogenic variant in Turkish population [<a class="bibr" href="#gr_3ms.REF.akal_n.2024.68" rid="gr_3ms.REF.akal_n.2024.68">Akalın et al 2024</a>]</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the author. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>). See <a href="/books/n/gene/app3/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="gr_3ms.TF.7.1"><p class="no_margin">Genes from <a href="/books/NBK1481/table/gr_3ms.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobgr3msTmoleculargenetictestingused">Table 1</a> are in alphabetic order.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="gr_3ms.TF.7.2"><p class="no_margin">Variant designation that does not conform to current naming conventions</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.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></div></div>
|
|
|
|
|
|
|
|
|
|
<!-- Book content -->
|
|
|
|
<script type="text/javascript" src="/portal/portal3rc.fcgi/rlib/js/InstrumentNCBIBaseJS/InstrumentPageStarterJS.js"> </script>
|
|
|
|
|
|
<!-- CE8B5AF87C7FFCB1_0191SID /projects/books/PBooks@9.11 portal107 v4.1.r689238 Tue, Oct 22 2024 16:10:51 -->
|
|
<span id="portal-csrf-token" style="display:none" data-token="CE8B5AF87C7FFCB1_0191SID"></span>
|
|
|
|
<script type="text/javascript" src="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/js/3968615.js" snapshot="books"></script></body>
|
|
</html>
|