373 lines
199 KiB
Text
373 lines
199 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="NBK1127">
|
|
<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="/NBK1127/?report=reader">
|
|
<meta name="ncbi_pagename" content="CLCN7-Related Osteopetrosis - 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>CLCN7-Related Osteopetrosis - 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/clcn4-ndd/?report=reader">
|
|
<meta name="jr-next-unit" content="/books/n/gene/clpb-def/?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="CLCN7-Related Osteopetrosis">
|
|
<meta name="citation_publisher" content="University of Washington, Seattle">
|
|
<meta name="citation_date" content="2022/01/20">
|
|
<meta name="citation_author" content="Cristina Sobacchi">
|
|
<meta name="citation_author" content="Anna Villa">
|
|
<meta name="citation_author" content="Ansgar Schulz">
|
|
<meta name="citation_author" content="Uwe Kornak">
|
|
<meta name="citation_pmid" content="20301306">
|
|
<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1127/">
|
|
<meta name="citation_keywords" content="Autosomal Dominant Osteopetrosis Type II (ADOII)">
|
|
<meta name="citation_keywords" content="Autosomal Recessive Osteopetrosis (ARO)">
|
|
<meta name="citation_keywords" content="Intermediate Autosomal Osteopetrosis (IAO)">
|
|
<meta name="citation_keywords" content="H(+)/Cl(-) exchange transporter 7">
|
|
<meta name="citation_keywords" content="CLCN7">
|
|
<meta name="citation_keywords" content="CLCN7-Related Osteopetrosis">
|
|
<link rel="schema.DC" href="http://purl.org/DC/elements/1.0/">
|
|
<meta name="DC.Title" content="CLCN7-Related Osteopetrosis">
|
|
<meta name="DC.Type" content="Text">
|
|
<meta name="DC.Publisher" content="University of Washington, Seattle">
|
|
<meta name="DC.Contributor" content="Cristina Sobacchi">
|
|
<meta name="DC.Contributor" content="Anna Villa">
|
|
<meta name="DC.Contributor" content="Ansgar Schulz">
|
|
<meta name="DC.Contributor" content="Uwe Kornak">
|
|
<meta name="DC.Date" content="2022/01/20">
|
|
<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1127/">
|
|
<meta name="description" content="The spectrum of CLCN7-related osteopetrosis includes infantile malignant CLCN7-related autosomal recessive osteopetrosis (ARO), intermediate autosomal osteopetrosis (IAO), and autosomal dominant osteopetrosis type II (ADOII; Albers-Schönberg disease).">
|
|
<meta name="og:title" content="CLCN7-Related Osteopetrosis">
|
|
<meta name="og:type" content="book">
|
|
<meta name="og:description" content="The spectrum of CLCN7-related osteopetrosis includes infantile malignant CLCN7-related autosomal recessive osteopetrosis (ARO), intermediate autosomal osteopetrosis (IAO), and autosomal dominant osteopetrosis type II (ADOII; Albers-Schönberg disease).">
|
|
<meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK1127/">
|
|
<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/clcn7/?report=reader">
|
|
<link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK1127/">
|
|
<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="CE8D927B7C83C7F100000000004D003C.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/NBK1127/?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/clcn4-ndd/?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">CLCN7-Related Osteopetrosis</div><div class="j">GeneReviews® [Internet]</div></div><div class="tail"><a href="/books/n/gene/clpb-def/?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/NBK1127/"><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/NBK1127/&text=CLCN7-Related%20Osteopetrosis"><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/NBK1127/?report=classic">Switch to classic view</a><a href="/books/NBK1127/pdf/Bookshelf_NBK1127.pdf">PDF (643K)</a><a href="/books/NBK1127/?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%20NBK1127%20%2F%20sid%3ACE8B5AF87C7FFCB1_0191SID%20%2F%20phid%3ACE8D927B7C83C7F100000000004D003C.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="_NBK1127_"><span class="title" itemprop="name"><i>CLCN7</i>-Related Osteopetrosis</span></h1><p class="contribs">Sobacchi C, Villa A, Schulz A, et al.</p><p class="fm-aai"><a href="#_NBK1127_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 31 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="clcn7.Summary" itemprop="description"><h2 id="_clcn7_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>The spectrum of <i>CLCN7</i>-related osteopetrosis includes infantile malignant <i>CLCN7</i>-related autosomal recessive osteopetrosis (ARO), intermediate autosomal osteopetrosis (IAO), and autosomal dominant osteopetrosis type II (ADOII; Albers-Schönberg disease).</p><ul><li class="half_rhythm"><div><b>ARO.</b> Onset is at birth. Findings may include: fractures; reduced growth; sclerosis of the skull base (with or without choanal stenosis or hydrocephalus) resulting in optic nerve compression, facial palsy, and hearing loss; absence of the bone marrow cavity resulting in severe anemia and thrombocytopenia; dental abnormalities, odontomas, and risk for mandibular osteomyelitis; and hypocalcemia with tetanic seizures and secondary hyperparathyroidism. Without treatment maximal life span in ARO is ten years.</div></li><li class="half_rhythm"><div><b>IAO.</b> Onset is in childhood. Findings may include: fractures after minor trauma, characteristic skeletal radiographic changes found incidentally, mild anemia, and occasional visual impairment secondary to optic nerve compression. Life expectancy in IAO is usually normal.</div></li><li class="half_rhythm"><div><b>ADOII.</b> Onset is usually late childhood or adolescence. Findings may include: fractures (in any long bone and/or the posterior arch of a vertebra), scoliosis, hip osteoarthritis, and osteomyelitis of the mandible or septic osteitis or osteoarthritis elsewhere. Cranial nerve compression is rare.</div></li></ul></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of a <i>CLCN7</i>-related osteopetrosis is established in a proband with suggestive findings and biallelic pathogenic variants or a heterozygous pathogenic variant in <i>CLCN7</i> identified by molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p>
|
|
<i>Treatment of manifestations:</i>
|
|
</p><ul><li class="half_rhythm"><div><b>ARO.</b> Calcium supplementation for hypocalcemic convulsions; management of calcium homeostasis per individual needs; erythrocyte or platelet transfusions as needed; antibiotics for leukocytopenia; immunoglobulins for hypogammaglobulinemia. Newly diagnosed individuals should be transferred as soon as possible to a pediatric center experienced in allogeneic stem cell transplantation in this disease. The collaboration of pediatricians, pediatric neurologists, ophthalmologists, and psychologists is required to determine best treatment of neurologic and ophthalmic issues, which may include surgical decompression of the optic nerve and hearing aids. Treatment of fractures by an experienced orthopedist and dental care with attention to tooth eruption, ankylosis, abscesses, cysts, and fistulas.</div></li><li class="half_rhythm"><div><b>ADOII.</b> Orthopedic treatment for fractures and arthritis with attention to potential post-surgical complications (delayed union or non-union of fractures, infection); fractures near joints may require total joint arthroplasty. Medical treatment for arthritis with anti-inflammatory agents; transfusions for anemia and thrombocytopenia; surgical optic nerve decompression, hearing aids, and regular dental care and good oral hygiene.</div></li></ul><p><i>Prevention of primary manifestations:</i> In ARO, hematopoietic stem cell transplantation (HSCT) can be curative; however, cranial nerve dysfunction is usually irreversible, and progressive neurologic sequelae occur in children with the neuronopathic form even after successful HSCT.</p><p><i>Surveillance:</i> Complete blood count, ophthalmologic examination, and audiologic evaluation at least once a year; dental evaluation every 6-12 months or as directed. For ARO, follow up as directed by the transplantation center following HSCT.</p><p><i>Agents/circumstances to avoid:</i> In ADOII, activities with high fracture risk. Orthopedic surgery should only be performed when absolutely necessary.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>CLCN7</i>-related osteopetrosis is inherited in an autosomal recessive or autosomal dominant manner: ARO is inherited in an autosomal recessive manner; about 40% of IAO is inherited in an autosomal recessive manner and about 60% in an autosomal dominant manner; and ADOII is inherited in an autosomal dominant manner.</p><ul><li class="half_rhythm"><div><b>Autosomal recessive inheritance.</b> If both parents are known to be heterozygous for a <i>CLCN7</i> pathogenic variant associated with autosomal recessive osteopetrosis, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial <i>CLCN7</i> pathogenic variants. Carrier testing for at-risk relatives requires prior identification of the <i>CLCN7</i> pathogenic variants in the family.</div></li><li class="half_rhythm"><div><b>Autosomal dominant inheritance.</b> Most individuals diagnosed with autosomal dominant <i>CLCN7</i>-related osteopetrosis have an affected parent. Each child of an individual with autosomal dominant osteopetrosis has a 50% chance of inheriting the pathogenic variant.</div></li></ul><p>Once the <i>CLCN7</i> pathogenic variant(s) have been identified in an affected family member, prenatal testing and preimplantation genetic testing for <i>CLCN7</i>-related osteopetrosis are possible.</p></div></div><div id="clcn7.GeneReview_Scope"><h2 id="_clcn7_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><p><i>CLCN7</i>-Related Osteopetrosis: Included Phenotypes</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figclcn7Td"><a href="/books/NBK1127/table/clcn7.Td/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobclcn7Td"><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="clcn7.Td"><a href="/books/NBK1127/table/clcn7.Td/?report=objectonly" target="object" rid-ob="figobclcn7Td">Table</a></h4></div></div></div><div id="clcn7.Diagnosis"><h2 id="_clcn7_Diagnosis_">Diagnosis</h2><p>The spectrum of <i>CLCN7</i>-related osteopetrosis includes the following:</p><ul><li class="half_rhythm"><div>Autosomal recessive osteopetrosis (ARO; infantile malignant <i>CLCN7</i>-related autosomal recessive osteopetrosis)</div></li><li class="half_rhythm"><div>Intermediate autosomal osteopetrosis (IAO)</div></li><li class="half_rhythm"><div>Autosomal dominant osteopetrosis type II (ADOII; Albers-Schönberg disease)</div></li></ul><div id="clcn7.Suggestive_Findings"><h3>Suggestive Findings</h3><p>A <i>CLCN7</i>-related osteopetrosis <b>should be suspected</b> in individuals with osteosclerosis noted on radiographs, which may be accompanied by hypocalcemia and resulting convulsions, anemia, thrombocytopenia, visual impairment, and/or central nervous system involvement (<a href="/books/NBK1127/table/clcn7.T.diagnostic_features_of_the_subty/?report=objectonly" target="object" rid-ob="figobclcn7Tdiagnosticfeaturesofthesubty">Table 1</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figclcn7Tdiagnosticfeaturesofthesubty"><a href="/books/NBK1127/table/clcn7.T.diagnostic_features_of_the_subty/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobclcn7Tdiagnosticfeaturesofthesubty"><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="clcn7.T.diagnostic_features_of_the_subty"><a href="/books/NBK1127/table/clcn7.T.diagnostic_features_of_the_subty/?report=objectonly" target="object" rid-ob="figobclcn7Tdiagnosticfeaturesofthesubty">Table 1. </a></h4><p class="float-caption no_bottom_margin">Diagnostic Features of the Subtypes of <i>CLCN7</i>-Related Osteopetrosis </p></div></div></div><div id="clcn7.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of a <i>CLCN7</i>-related osteopetrosis <b>is established</b> in a proband with <a href="#clcn7.Suggestive_Findings">suggestive findings</a> and biallelic pathogenic variants or a heterozygous pathogenic variant in <i>CLCN7</i> identified by molecular genetic testing (see <a href="/books/NBK1127/table/clcn7.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobclcn7Tmoleculargenetictestingusedi">Table 2</a>).</p><p>Note: Identification of biallelic <i>CLCN7</i> variants of uncertain significance, of one known <i>CLCN7</i> pathogenic variant and one <i>CLCN7</i> variant of uncertain significance, or of a heterozygous <i>CLCN7</i> variant of uncertain significance does not establish or rule out a diagnosis of this disorder.</p><p>Because the phenotype of a <i>CLCN7</i>-related osteopetrosis may be indistinguishable from other inherited sclerosing bone dysplasias resulting from impaired osteoclast function, recommended molecular genetic testing approaches include use of a <b>multigene panel</b> or <b>comprehensive genomic testing</b>.</p><p>Note: Single-gene testing (sequence analysis of <i>CLCN7</i>, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.</p><p><b>An osteopetrosis</b>
|
|
<b>multigene panel</b> that includes <i>CLCN7</i> and other genes of interest (see <a href="#clcn7.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><b>Comprehensive genomic testing</b> does not require the clinician to determine which genes 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="figclcn7Tmoleculargenetictestingusedi"><a href="/books/NBK1127/table/clcn7.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobclcn7Tmoleculargenetictestingusedi"><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="clcn7.T.molecular_genetic_testing_used_i"><a href="/books/NBK1127/table/clcn7.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobclcn7Tmoleculargenetictestingusedi">Table 2. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in <i>CLCN7</i>-Related Osteopetrosis </p></div></div></div></div><div id="clcn7.Clinical_Characteristics"><h2 id="_clcn7_Clinical_Characteristics_">Clinical Characteristics</h2><div id="clcn7.Clinical_Description"><h3>Clinical Description</h3><p>To date, approximately 300 individuals have been identified with a pathogenic variant in <i>CLCN7</i> [<a class="bibr" href="#clcn7.REF.stenson.2020.1197" rid="clcn7.REF.stenson.2020.1197">Stenson et al 2020</a>]. The three different associated phenotypes are described in this section.</p><div id="clcn7.Infantile_Malignant_CLCN7Related_A"><h4>Infantile Malignant <i>CLCN7</i>-Related Autosomal Recessive Osteopetrosis (ARO)</h4><p>ARO is a systemic, life-threatening disorder. Onset of symptoms is at birth. Without treatment, life span is approximately ten years (although rare exceptions of far longer survival have occurred). Note: Many of the most complete clinical descriptions of ARO were published prior to the discovery of the causative gene.</p><p>Possible clinical manifestations of ARO include the following.</p><p>
|
|
<b>Skeletal findings</b>
|
|
</p><ul><li class="half_rhythm"><div><b>Fractures.</b> The near-complete absence of osteoclastic bone resorption leads to osteosclerosis of the whole skeleton within the first few months after birth (<a class="figpopup" href="/books/NBK1127/figure/clcn7.F1/?report=objectonly" target="object" rid-figpopup="figclcn7F1" rid-ob="figobclcn7F1">Figure 1</a>). Because of defective microarchitecture, the bones become brittle, resulting in recurrent fractures (usually of the long bones).</div></li><li class="half_rhythm"><div><b>Reduced growth.</b> Resorption of cartilage and bone at the growth plate is a prerequisite for longitudinal growth; its absence results in variable growth retardation. In severely affected children, body length at age 12 months is as much as 5 cm below the third centile.</div></li><li class="half_rhythm"><div><b>Skull.</b> In some severely affected children, macrocephaly and frontal bossing develop within the first year. This is not necessarily paralleled by sclerosis of the cranial vault. The sclerosis of the skull base often leads to choanal stenosis.</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col fig" id="figclcn7F1" co-legend-rid="figlgndclcn7F1"><a href="/books/NBK1127/figure/clcn7.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figclcn7F1" rid-ob="figobclcn7F1"><img class="small-thumb" src="/books/NBK1127/bin/clcn7-Image001.gif" src-large="/books/NBK1127/bin/clcn7-Image001.jpg" alt="Figure 1. " /></a><div class="icnblk_cntnt" id="figlgndclcn7F1"><h4 id="clcn7.F1"><a href="/books/NBK1127/figure/clcn7.F1/?report=objectonly" target="object" rid-ob="figobclcn7F1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">Autosomal recessive osteopetrosis radiographs </p></div></div><p>
|
|
<b>Calcium and blood cell findings</b>
|
|
</p><ul><li class="half_rhythm"><div><b>Hypocalcemia.</b> Hypocalcemia may result in tetanic seizures and secondary hyperparathyroidism.</div></li><li class="half_rhythm"><div><b>Anemia and thrombocytopenia.</b> The absence of the bone marrow cavity leads to extramedullary hematopoiesis, hepatosplenomegaly, anemia, and thrombocytopenia. The bleeding associated with thrombocytopenia can be severe and life threatening, especially in the central nervous system (CNS).</div></li><li class="half_rhythm"><div><b>Immune function.</b> Immune function may be impaired. Leukocytosis, present in the early stage of the disease, can become leukocytopenia. In conjunction with the frequently observed choanal stenosis, impaired immune function may lead to chronic rhinitis. Defective superoxide generation by granulocytes and monocytes has been reported in ARO [<a class="bibr" href="#clcn7.REF.wilson.2000.449" rid="clcn7.REF.wilson.2000.449">Wilson & Vellodi 2000</a>].</div></li></ul><p>
|
|
<b>CNS involvement</b>
|
|
</p><ul><li class="half_rhythm"><div>
|
|
<b>Neurologic complications</b>
|
|
</div><ul><li class="half_rhythm"><div>Visual impairment beginning shortly after birth is common. In most individuals it is caused by optic nerve compression within the osteosclerotic skull base.</div></li><li class="half_rhythm"><div>Skull changes may also cause hydrocephalus.</div></li><li class="half_rhythm"><div>A prominent and large anterior fontanelle is common and sometimes associated with hydrocephalus, possibly caused by obstruction of cerebral blood flow and cerebrospinal fluid circulation as a result of hyperostosis.</div></li><li class="half_rhythm"><div>Facial palsy caused by facial nerve entrapment is an uncommon manifestation.</div></li><li class="half_rhythm"><div>Seizures can result from hypocalcemia.</div></li></ul></li><li class="half_rhythm"><div><b>Neuronopathic form.</b> If seizures appear together with normal serum calcium concentration and developmental delay, a neuronopathic form must be considered. In these individuals the neuronal phenotype resembles neuronal ceroid-lipofuscinosis [<a class="bibr" href="#clcn7.REF.steward.2003.87" rid="clcn7.REF.steward.2003.87">Steward 2003</a>]. In this subset of very severely affected children, primary degeneration of the retina and CNS occurs. If the onset is very early brain development can be disturbed, resulting in structural brain anomalies and heterotopias [<a class="bibr" href="#clcn7.REF.r_ssler.2021.1621" rid="clcn7.REF.r_ssler.2021.1621">Rössler et al 2021</a>]. It is important to differentiate these rare primary neurologic manifestations of the neuronopathic form of ARO (which has a poor prognosis) from more common secondary lesions resulting from hyperostosis of the skull base. It is noteworthy that pathologic EEG changes with a characteristic pattern of very frequent multifocal spikes and sharp waves usually precede the clinical symptoms and brain MRI findings of neurodegeneration [A Schulz, unpublished results].</div></li></ul><p>
|
|
<b>Other</b>
|
|
</p><ul><li class="half_rhythm"><div><b>Otologic manifestations.</b> According to <a class="bibr" href="#clcn7.REF.dozier.2005.762" rid="clcn7.REF.dozier.2005.762">Dozier et al [2005]</a>, 78% of individuals with ARO showed variable hearing loss. Poor pneumatization of the mastoid bone and narrowing of the external auditory canal, eustachian tube, and internal auditory canal frequently lead to otitis media, conductive and sensorineural hearing loss, and facial nerve paralysis [<a class="bibr" href="#clcn7.REF.dozier.2005.762" rid="clcn7.REF.dozier.2005.762">Dozier et al 2005</a>].</div></li><li class="half_rhythm"><div><b>Dental.</b> Oral problems in ARO are delayed tooth eruption, hypodontia, malformed teeth, enamel hypoplasia, hypomineralization of enamel and dentin, the presence of odontomas, and severe mandibular osteomyelitis. Even if the primary dentition is impaired, the secondary dentition can be normal after successful stem cell transplantation [<a class="bibr" href="#clcn7.REF.kantaputra.2012.909" rid="clcn7.REF.kantaputra.2012.909">Kantaputra et al 2012</a>, <a class="bibr" href="#clcn7.REF.wang.2016.19971" rid="clcn7.REF.wang.2016.19971">Wang et al 2016</a>, <a class="bibr" href="#clcn7.REF.zhang.2019.1387" rid="clcn7.REF.zhang.2019.1387">Zhang et al 2019</a>].</div></li></ul></div><div id="clcn7.Intermediate_Autosomal_Osteopetros"><h4>Intermediate Autosomal Osteopetrosis (IAO)</h4><p>IAO is characterized by childhood onset with a milder course than ARO. Life expectancy is normal in most individuals. Children may present with fractures after minor trauma or characteristic changes on x-rays obtained for other clinical indications. Hematologic signs are milder than those in ARO and are usually restricted to anemia. Although CNS involvement is usually absent, visual impairment secondary to optic nerve encroachment can occur [<a class="bibr" href="#clcn7.REF.camposxavier.2003.186" rid="clcn7.REF.camposxavier.2003.186">Campos-Xavier et al 2003</a>, <a class="bibr" href="#clcn7.REF.frattini.2003.1740" rid="clcn7.REF.frattini.2003.1740">Frattini et al 2003</a>].</p></div><div id="clcn7.Autosomal_Dominant_Osteopetrosis_T"><h4>Autosomal Dominant Osteopetrosis Type II (ADOII)</h4><p>Although ADOII is sometimes called "benign osteopetrosis," as many as 60%-80% of individuals with radiologic signs of ADOII experience clinical problems (<a class="figpopup" href="/books/NBK1127/figure/clcn7.F2/?report=objectonly" target="object" rid-figpopup="figclcn7F2" rid-ob="figobclcn7F2">Figure 2</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figclcn7F2" co-legend-rid="figlgndclcn7F2"><a href="/books/NBK1127/figure/clcn7.F2/?report=objectonly" target="object" title="Figure 2. " class="img_link icnblk_img figpopup" rid-figpopup="figclcn7F2" rid-ob="figobclcn7F2"><img class="small-thumb" src="/books/NBK1127/bin/clcn7-Image002.gif" src-large="/books/NBK1127/bin/clcn7-Image002.jpg" alt="Figure 2. " /></a><div class="icnblk_cntnt" id="figlgndclcn7F2"><h4 id="clcn7.F2"><a href="/books/NBK1127/figure/clcn7.F2/?report=objectonly" target="object" rid-ob="figobclcn7F2">Figure 2. </a></h4><p class="float-caption no_bottom_margin">Autosomal dominant osteopetrosis type II radiographs Reprinted from Bénichou et al [2000] with permission from Elsevier</p></div></div><p>Onset of radiologic and clinical manifestations of ADOII is usually in late childhood or adolescence, although earlier occurrence has been reported. Osteosclerosis of the spine predominates, with a "sandwich vertebra" appearance, a diagnostic criterion for ADOII. Most affected individuals have a "bone-within-bone" appearance primarily in the iliac wings, but also in other bones. Transverse bands of sclerosis, perpendicular to the main axis, are often observed in long bones. Increase in the skull base density can be seen [<a class="bibr" href="#clcn7.REF.b_nichou.2000.87" rid="clcn7.REF.b_nichou.2000.87">Bénichou et al 2000</a>, <a class="bibr" href="#clcn7.REF.cleiren.2001.2861" rid="clcn7.REF.cleiren.2001.2861">Cleiren et al 2001</a>].</p><p>Clinical findings vary even within the same family [<a class="bibr" href="#clcn7.REF.waguespack.2007.771" rid="clcn7.REF.waguespack.2007.771">Waguespack et al 2007</a>]. In three families in which most affected individuals had mild ADOII, early-onset disease, anemia, and blindness caused by optic nerve compression were observed in some affected family members; this phenotype has been called "intermediate osteopetrosis" because of its overlap with mild ARO.</p><p>The main complications affect the skeleton:</p><ul><li class="half_rhythm"><div><b>Fractures</b> occur in 60%-80% of affected individuals, with a mean of three fractures per person [<a class="bibr" href="#clcn7.REF.b_nichou.2000.87" rid="clcn7.REF.b_nichou.2000.87">Bénichou et al 2000</a>, <a class="bibr" href="#clcn7.REF.waguespack.2007.771" rid="clcn7.REF.waguespack.2007.771">Waguespack et al 2007</a>]. Some individuals had more than ten fractures. The most frequently affected bone is the femur, but fractures occur in any long bone and in the posterior arch of the vertebrae, thereby inducing spondylolisthesis.</div></li><li class="half_rhythm"><div><b>Scoliosis</b> is seen in a number of individuals.</div></li><li class="half_rhythm"><div><b>Hip osteoarthritis</b> is common (up to 27%) and could be caused by the excessive toughness of the subchondral bone.</div></li><li class="half_rhythm"><div><b>Osteomyelitis</b> of the mandible is often associated with dental abscess or caries [<a class="bibr" href="#clcn7.REF.b_nichou.2000.87" rid="clcn7.REF.b_nichou.2000.87">Bénichou et al 2000</a>, <a class="bibr" href="#clcn7.REF.waguespack.2007.771" rid="clcn7.REF.waguespack.2007.771">Waguespack et al 2007</a>]. Septic osteitis or osteoarthritis at other localizations can also occur.</div></li></ul><p>Cranial nerve compression caused by osteosclerosis of the skull base is rare. Hearing loss and visual loss occurs in up to 19% of affected individuals.</p></div></div><div id="clcn7.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No genotype-phenotype correlations have been identified.</p></div><div id="clcn7.Penetrance"><h3>Penetrance</h3><p>Penetrance ranges from 60% to 90% in families with ADOII [<a class="bibr" href="#clcn7.REF.waguespack.2007.771" rid="clcn7.REF.waguespack.2007.771">Waguespack et al 2007</a>].</p></div><div id="clcn7.Prevalence"><h3>Prevalence</h3><p>The prevalence of ADOII has been estimated at up to 1:20,000 [<a class="bibr" href="#clcn7.REF.b_nichou.2000.87" rid="clcn7.REF.b_nichou.2000.87">Bénichou et al 2000</a>]. The disease is probably underdiagnosed in those with milder phenotypes.</p><p>ARO is less common, with an estimated prevalence of 1:250,000.</p></div></div><div id="clcn7.Genetically_Related_Allelic_Disord"><h2 id="_clcn7_Genetically_Related_Allelic_Disord_">Genetically Related (Allelic) Disorders</h2><p>Heterozygous germline pathogenic variants in <i>CLCN7</i> have been reported in children with hypopigmentation, organomegaly, and delayed myelination and development (OMIM <a href="https://omim.org/entry/618541" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">618541</a>). Osteopetrosis was not observed in the two affected children reported to date [<a class="bibr" href="#clcn7.REF.nicoli.2019.1127" rid="clcn7.REF.nicoli.2019.1127">Nicoli et al 2019</a>].</p></div><div id="clcn7.Differential_Diagnosis"><h2 id="_clcn7_Differential_Diagnosis_">Differential Diagnosis</h2><p>Pathogenic variants in <i>CLCN7</i> account for 13% of the infantile autosomal recessive osteopetrosis (ARO), 40% of the recessive intermediate autosomal osteopetrosis (IAO), 60% of the dominant IAO, and 99% of the autosomal dominant osteopetrosis type II (ADOII) [Authors, personal observation].</p><div id="clcn7.ARO"><h3>ARO</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figclcn7Tothertypesofautosomalrecessi"><a href="/books/NBK1127/table/clcn7.T.other_types_of_autosomal_recessi/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobclcn7Tothertypesofautosomalrecessi"><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="clcn7.T.other_types_of_autosomal_recessi"><a href="/books/NBK1127/table/clcn7.T.other_types_of_autosomal_recessi/?report=objectonly" target="object" rid-ob="figobclcn7Tothertypesofautosomalrecessi">Table 3. </a></h4><p class="float-caption no_bottom_margin">Other Types of Autosomal Recessive Osteopetrosis </p></div></div><p><b>A mild form of ARO</b> can be caused by deep intronic or splice site variants in <i>TCIRG1</i> (OMIM <a href="http://omim.org/entry/259700" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">259700</a>) [<a class="bibr" href="#clcn7.REF.sobacchi.2014.1646" rid="clcn7.REF.sobacchi.2014.1646">Sobacchi et al 2014</a>, <a class="bibr" href="#clcn7.REF.palagano.2015.1814" rid="clcn7.REF.palagano.2015.1814">Palagano et al 2015</a>]. This form can be very similar to <i>CLCN7</i>-related IAO or ADOII.</p></div><div id="clcn7.Autosomal_Dominant_Osteopetrosis_A"><h3>Autosomal Dominant Osteopetrosis (ADO)</h3><p>Heterozygous pathogenic variants in <i>LRP5</i> are associated with ADO type I (ADOI) (OMIM <a href="https://omim.org/entry/607634" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">607634</a>). In ADOI, osteosclerosis is most pronounced in the skull vault and does not lead to sandwich vertebrae. ADOI is not associated with an increased fracture rate. (Note: It is debated whether this disease entity should be called "endosteal hyperostosis" or "high bone mass disorder," as "osteopetrosis" should be reserved for osteoclast-related disorders.)</p></div><div id="clcn7.Other"><h3>Other</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figclcn7Totherdisorderstoconsiderint"><a href="/books/NBK1127/table/clcn7.T.other_disorders_to_consider_in_t/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobclcn7Totherdisorderstoconsiderint"><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="clcn7.T.other_disorders_to_consider_in_t"><a href="/books/NBK1127/table/clcn7.T.other_disorders_to_consider_in_t/?report=objectonly" target="object" rid-ob="figobclcn7Totherdisorderstoconsiderint">Table 4. </a></h4><p class="float-caption no_bottom_margin">Other Disorders to Consider in the Differential Diagnosis of <i>CLCN7</i>-Related Osteopetrosis </p></div></div></div></div><div id="clcn7.Management"><h2 id="_clcn7_Management_">Management</h2><p>General guidelines for diagnosis, therapy, and follow up are available for all forms of osteopetrosis; see <a href="#clcn7.Author_Information">Author Information</a>.</p><p>Due to the difference in severity, the evaluation, treatment, and surveillance recommendations for infantile malignant <i>CLCN7</i>-related autosomal recessive osteopetrosis (ARO) and <i>CLCN7</i>-related autosomal dominant osteopetrosis type II (ADOII) differ. The <i>CLCN7</i>-related intermediate autosomal osteopetrosis (IAO) phenotype lies between these two forms and has variable manifestations and prognosis. Therefore, management options for <i>CLCN7</i>-related IAO must be evaluated on an individual basis.</p><div id="clcn7.Evaluations_Following_Initial_Diag"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <b>ARO</b>, the evaluations summarized in <a href="/books/NBK1127/table/clcn7.T.recommended_evaluations_followin/?report=objectonly" target="object" rid-ob="figobclcn7Trecommendedevaluationsfollowin">Table 5</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="figclcn7Trecommendedevaluationsfollowin"><a href="/books/NBK1127/table/clcn7.T.recommended_evaluations_followin/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobclcn7Trecommendedevaluationsfollowin"><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="clcn7.T.recommended_evaluations_followin"><a href="/books/NBK1127/table/clcn7.T.recommended_evaluations_followin/?report=objectonly" target="object" rid-ob="figobclcn7Trecommendedevaluationsfollowin">Table 5. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with Infantile Malignant <i>CLCN7</i>-Related Autosomal Recessive Osteopetrosis (ARO) </p></div></div><p>To establish the extent of disease and needs in an individual diagnosed with <b>ADOII</b>, the evaluations summarized in <a href="/books/NBK1127/table/clcn7.T.recommended_evaluations_followin_1/?report=objectonly" target="object" rid-ob="figobclcn7Trecommendedevaluationsfollowin1">Table 6</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="figclcn7Trecommendedevaluationsfollowin1"><a href="/books/NBK1127/table/clcn7.T.recommended_evaluations_followin_1/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobclcn7Trecommendedevaluationsfollowin1"><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="clcn7.T.recommended_evaluations_followin_1"><a href="/books/NBK1127/table/clcn7.T.recommended_evaluations_followin_1/?report=objectonly" target="object" rid-ob="figobclcn7Trecommendedevaluationsfollowin1">Table 6. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with <i>CLCN7</i>-Related Autosomal Dominant Osteopetrosis Type II </p></div></div></div><div id="clcn7.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Due to the difference in severity, treatment strategies for ARO and ADOII differ. IAO lies between these two forms and has a variable prognosis. Therefore, treatment options must be evaluated on an individual basis.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figclcn7Ttreatmentofmanifestationsini"><a href="/books/NBK1127/table/clcn7.T.treatment_of_manifestations_in_i/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobclcn7Ttreatmentofmanifestationsini"><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="clcn7.T.treatment_of_manifestations_in_i"><a href="/books/NBK1127/table/clcn7.T.treatment_of_manifestations_in_i/?report=objectonly" target="object" rid-ob="figobclcn7Ttreatmentofmanifestationsini">Table 7. </a></h4><p class="float-caption no_bottom_margin">Treatment of Manifestations in Individuals with Infantile Malignant <i>CLCN7</i>-Related Autosomal Recessive Osteopetrosis (ARO) </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figclcn7Ttreatmentofmanifestationsini1"><a href="/books/NBK1127/table/clcn7.T.treatment_of_manifestations_in_i_1/?report=objectonly" target="object" title="Table 8. " class="img_link icnblk_img" rid-ob="figobclcn7Ttreatmentofmanifestationsini1"><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="clcn7.T.treatment_of_manifestations_in_i_1"><a href="/books/NBK1127/table/clcn7.T.treatment_of_manifestations_in_i_1/?report=objectonly" target="object" rid-ob="figobclcn7Ttreatmentofmanifestationsini1">Table 8. </a></h4><p class="float-caption no_bottom_margin">Treatment of Manifestations in Individuals with <i>CLCN7</i>-Related Autosomal Dominant Osteopetrosis Type II (ADOII) </p></div></div></div><div id="clcn7.Prevention_of_Primary_Manifestatio"><h3>Prevention of Primary Manifestations</h3><div id="clcn7.Infantile_Malignant_CLCN7Related_A_1"><h4>Infantile Malignant <i>CLCN7</i>-Related ARO</h4><p><b>Hematopoietic stem cell transplantation (HSCT).</b> Since the defective osteoclasts in osteopetrosis are of hematopoietic origin, allogeneic HSCT can be curative. Most manifestations (bone sclerosis, bone marrow failure, and extramedullary hematopoiesis) can be prevented or reversed by HSCT.</p><ul><li class="half_rhythm"><div class="half_rhythm">Restricted intake of calcium and vitamin D just before, during, and following HSCT to prevent hypercalcemia is recommended.</div></li><li class="half_rhythm"><div class="half_rhythm">Secondary neurosensory impairments caused by nerve compression may be prevented by early transplantation, but not reversed when they are already present.</div><div class="half_rhythm">Cranial nerve dysfunction (visual impairment caused by optic nerve atrophy) is irreversible in most individuals. In the authors' series including about 30 individuals, about two thirds of affected individuals were visually impaired after successful transplantation [A Schulz, unpublished results]. <a class="bibr" href="#clcn7.REF.evenor.2022.116229" rid="clcn7.REF.evenor.2022.116229">Even-Or et al [2022]</a> report blindness in 26% of a group with ARO associated with mutation of different genes.</div></li><li class="half_rhythm"><div class="half_rhythm">Primary neurologic problems and retinal degeneration developing in the neuronopathic form of ARO, however, are independent of the bone disease and therefore cannot be improved or prevented by HSCT. Persons with ARO resulting from <i>CLCN7</i> pathogenic variants who do not develop neurologic complications have been reported [<a class="bibr" href="#clcn7.REF.pangrazio.2010.e1071" rid="clcn7.REF.pangrazio.2010.e1071">Pangrazio et al 2010</a>; <a class="bibr" href="#clcn7.REF.gayt_nmorales.2021.225" rid="clcn7.REF.gayt_nmorales.2021.225">Gaytán-Morales et al 2021</a>; A Schulz & U Kornak, unpublished results].</div><div class="half_rhythm">It is highly important but difficult to exclude individuals with the neuronopathic form from this invasive treatment [<a class="bibr" href="#clcn7.REF.r_ssler.2021.1621" rid="clcn7.REF.r_ssler.2021.1621">Rössler et al 2021</a>]. On the other hand, HSCT should be performed as soon as possible in the majority of those without primary neurologic sequelae to prevent irreversible secondary complications, including visual impairment. The evaluation of affected individuals and treatment by HSCT should therefore be performed in experienced pediatric centers after multidisciplinary evaluation to assess the severity of the disease and individual prognostic factors.</div></li><li class="half_rhythm"><div class="half_rhythm">Progressive neurologic sequelae, developmental delay, and repeated seizures occur in a subset of individuals after successful HSCT [<a class="bibr" href="#clcn7.REF.steward.2003.87" rid="clcn7.REF.steward.2003.87">Steward 2003</a>]. Severe neurologic manifestations other than visual impairment following transplant have been seen in about 10% of individuals in the authors' series [A Schulz, unpublished results]. However, it must be stressed that individuals with ARO who do not have primary CNS involvement can be cured by HSCT [<a class="bibr" href="#clcn7.REF.gayt_nmorales.2021.225" rid="clcn7.REF.gayt_nmorales.2021.225">Gaytán-Morales et al 2021</a>].</div></li><li class="half_rhythm"><div class="half_rhythm">
|
|
<b>Reported outcomes of HSCT</b>
|
|
</div><ul><li class="half_rhythm"><div>The incidence of severe complications post-HSCT is high, particularly when alternative stem cell sources are used. Complications include rejection, delayed hematopoietic reconstitution, venous occlusive disease, pulmonary hypertension, and hypercalcemic crisis [<a class="bibr" href="#clcn7.REF.steward.2004.63" rid="clcn7.REF.steward.2004.63">Steward et al 2004</a>, <a class="bibr" href="#clcn7.REF.corbacioglu.2006.547" rid="clcn7.REF.corbacioglu.2006.547">Corbacioglu et al 2006</a>, <a class="bibr" href="#clcn7.REF.shroff.2012.1766" rid="clcn7.REF.shroff.2012.1766">Shroff et al 2012</a>].</div></li><li class="half_rhythm"><div>The outcome of HSCT in ARO has been analyzed in a retrospective survey of the European Society of Immunodeficiencies (ESID) and the European Group of Bone Marrow Transplantation (EBMT) [<a class="bibr" href="#clcn7.REF.sobacchi.2013.522" rid="clcn7.REF.sobacchi.2013.522">Sobacchi et al 2013</a>]. The five-year disease-free survival was estimated at 88% for HLA-identical donor transplants, 80% for HLA-matched unrelated donor transplants, and 66% for HLA-haplotype-mismatched related donor transplants [<a class="bibr" href="#clcn7.REF.sobacchi.2013.522" rid="clcn7.REF.sobacchi.2013.522">Sobacchi et al 2013</a>].</div></li><li class="half_rhythm"><div>In a published report of 193 individuals transplanted in various centers by a cyclophosphamide-based regimen, the five-year probabilities of survival were 62% after HLA-matched sib transplantation and 42% after alternative donor transplantation [<a class="bibr" href="#clcn7.REF.orchard.2015.270" rid="clcn7.REF.orchard.2015.270">Orchard et al 2015</a>].</div></li><li class="half_rhythm"><div>A further improved outcome was reported from three large transplant centers using a fludarabine-based conditioning regimen [<a class="bibr" href="#clcn7.REF.natsheh.2016.535" rid="clcn7.REF.natsheh.2016.535">Natsheh et al 2016</a>; Schulz & Moshous, personal communication].</div></li><li class="half_rhythm"><div>In HLA-haploidentical HSCT, the implementation of post-transplant cyclophosphamide according to a modified Baltimore protocol achieved promising results. Therefore, this protocol was included in the recently updated treatment guidelines of the EBMT/ESID inborn errors working party [<a class="bibr" href="#clcn7.REF.lankester.2021.2052" rid="clcn7.REF.lankester.2021.2052">Lankester et al 2021</a>].</div></li></ul></li></ul><p>Note: Because <i>TCIRG1</i> pathogenic variants are more often the cause of ARO than are <i>CLCN7</i> pathogenic variants, the majority of HSCTs have been performed in infants with <i>TCIRG1</i> rather than <i>CLCN7</i> pathogenic variants. However, there appears to be no significant difference in treatment outcome between individuals with <i>TCIRG1</i> and <i>CLCN7</i> pathogenic variants [A Schulz et al, unpublished results].</p></div></div><div id="clcn7.Surveillance"><h3>Surveillance</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figclcn7Trecommendedsurveillanceforind"><a href="/books/NBK1127/table/clcn7.T.recommended_surveillance_for_ind/?report=objectonly" target="object" title="Table 9. " class="img_link icnblk_img" rid-ob="figobclcn7Trecommendedsurveillanceforind"><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="clcn7.T.recommended_surveillance_for_ind"><a href="/books/NBK1127/table/clcn7.T.recommended_surveillance_for_ind/?report=objectonly" target="object" rid-ob="figobclcn7Trecommendedsurveillanceforind">Table 9. </a></h4><p class="float-caption no_bottom_margin">Recommended Surveillance for Individuals with Infantile Malignant <i>CLCN7</i>-Related Autosomal Recessive Osteopetrosis (ARO) </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figclcn7Trecommendedsurveillanceforind1"><a href="/books/NBK1127/table/clcn7.T.recommended_surveillance_for_ind_1/?report=objectonly" target="object" title="Table 10. " class="img_link icnblk_img" rid-ob="figobclcn7Trecommendedsurveillanceforind1"><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="clcn7.T.recommended_surveillance_for_ind_1"><a href="/books/NBK1127/table/clcn7.T.recommended_surveillance_for_ind_1/?report=objectonly" target="object" rid-ob="figobclcn7Trecommendedsurveillanceforind1">Table 10. </a></h4><p class="float-caption no_bottom_margin">Recommended Surveillance for Individuals with <i>CLCN7</i>-Related Autosomal Dominant Osteopetrosis Type II (ADOII) </p></div></div></div><div id="clcn7.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>
|
|
<b>ADOII</b>
|
|
</p><ul><li class="half_rhythm"><div>Activities with high fracture risk should be avoided.</div></li><li class="half_rhythm"><div>Orthopedic surgery should only be performed when absolutely necessary and the surgeon should be aware of potential complications and difficulties in handling osteopetrotic bone.</div></li></ul></div><div id="clcn7.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing of the <i>CLCN7</i> pathogenic variant(s) in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.</p><p><b>For hematopoietic stem cell donation (relatives of a proband with <i>CLCN7</i>-related ARO).</b> Any relative considering stem cell donation should undergo molecular genetic testing to clarify their genetic status. Whenever possible, related donors who do not have a familial <i>CLCN7</i> pathogenic variant are preferred.</p><p>See <a href="#clcn7.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="clcn7.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="clcn7.Genetic_Counseling"><h2 id="_clcn7_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="clcn7.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>CLCN7</i>-related osteopetrosis is inherited in an autosomal recessive or autosomal dominant manner:</p><ul><li class="half_rhythm"><div>Infantile malignant <i>CLCN7</i>-related autosomal recessive osteopetrosis (ARO) is inherited in an autosomal recessive manner.</div></li><li class="half_rhythm"><div>About 40% of <i>CLCN7</i>-related intermediate autosomal osteopetrosis (IAO) is inherited in an autosomal recessive manner and about 60% in an autosomal dominant manner.</div></li><li class="half_rhythm"><div><i>CLCN7</i>-related autosomal dominant osteopetrosis type II (ADOII) is inherited in an autosomal dominant manner.</div></li></ul></div><div id="clcn7.Autosomal_Recessive_Inheritance__R"><h3>Autosomal Recessive Inheritance – 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 <i>CLCN7</i> pathogenic variant.</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a <i>CLCN7</i> pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>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="#clcn7.REF.j_nsson.2017.519" rid="clcn7.REF.j_nsson.2017.519">Jónsson et al 2017</a>].</div></li><li class="half_rhythm"><div>Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.</div></li></ul></li><li class="half_rhythm"><div>Individuals who are heterozygous for a <i>CLCN7</i> pathogenic variant associated with ARO are asymptomatic; however, no systematic studies have been performed to evaluate for subtle changes in bone mass.</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>CLCN7</i> pathogenic variant associated with autosomal recessive osteopetrosis, each sib of an affected individual has at conception a 25% chance of inheriting biallelic <i>CLCN7</i> pathogenic variants and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial <i>CLCN7</i> pathogenic variants.</div></li><li class="half_rhythm"><div>The limited data available suggest that in the presence of ARO, a similar presentation of the disorder is expected in individuals with biallelic <i>CLCN7</i> pathogenic variants in the same family; in particular, if the neuronopathic form of the disorder is present in the proband, a primary central nervous system involvement is likely to be present in other affected sibs [Sobacchi, unpublished observation].</div></li><li class="half_rhythm"><div>Individuals who are heterozygous for a <i>CLCN7</i> pathogenic variant associated with autosomal recessive osteopetrosis are asymptomatic; however, no systematic studies have been performed to evaluate for subtle changes in bone mass.</div></li></ul><p>
|
|
<b>Offspring of a proband</b>
|
|
</p><ul><li class="half_rhythm"><div>The offspring of an individual with autosomal recessive <i>CLCN7</i>-related osteopetrosis are obligate heterozygotes (carriers) for a pathogenic variant in <i>CLCN7</i>.</div></li><li class="half_rhythm"><div>In general, individuals with ARO reproduce only if successfully treated by hematopoietic stem cell transplantation.</div></li></ul><p><b>Other family members.</b> Each sib of the proband's parents is at a 50% risk of being a carrier of a <i>CLCN7</i> pathogenic variant.</p><div id="clcn7.Carrier_Detection"><h4>Carrier Detection</h4><p>Carrier testing for at-risk relatives requires prior identification of the <i>CLCN7</i> pathogenic variants in the family.</p></div></div><div id="clcn7.Autosomal_Dominant_Inheritance__Ri"><h3>Autosomal Dominant Inheritance – Risk to Family Members</h3><p>
|
|
<b>Parents of a proband</b>
|
|
</p><ul><li class="half_rhythm"><div>Most individuals diagnosed with autosomal dominant <i>CLCN7</i>-related osteopetrosis have an affected parent.</div></li><li class="half_rhythm"><div>A proband with autosomal dominant <i>CLCN7</i>-related osteopetrosis may have the disorder as the result of a <i>de novo</i> pathogenic variant. The proportion of individuals with <i>CLCN7</i>-related osteopetrosis caused by a <i>de novo</i> pathogenic variant is unknown.</div></li><li class="half_rhythm"><div>If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of parents include x-ray investigation of the skeleton and molecular genetic testing for the pathogenic variant identified in the proband. Evaluation of the parents is used to confirm their genetic status and to allow reliable recurrence risk counseling.</div></li><li class="half_rhythm"><div>If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The proband has a <i>de novo</i> pathogenic variant.</div></li><li class="half_rhythm"><div>The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.</div></li></ul></li><li class="half_rhythm"><div>Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of reduced penetrance, failure by health care professionals to recognize the syndrome, and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).</div></li></ul><p><b>Sibs of a proband.</b> The risk to the sibs of the proband depends on the genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of the proband is affected and/or is known to have the <i>CLCN7</i> pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because ADOII is associated with both intrafamilial clinical variability and reduced penetrance (see <a href="#clcn7.Penetrance">Penetrance</a>), a sib who inherits a <i>CLCN7</i> pathogenic variant associated with autosomal dominant <i>CLCN7</i>-related osteopetrosis may be more or less severely affected than the proband.</div></li><li class="half_rhythm"><div>If the proband has a known <i>CLCN7</i> pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [<a class="bibr" href="#clcn7.REF.rahbari.2016.126" rid="clcn7.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>If the parents have not been tested for the <i>CLCN7</i> pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for <i>CLCN7</i>-related osteopetrosis because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.</div></li></ul><p><b>Offspring of a proband.</b> Each child of an individual with autosomal dominant <i>CLCN7</i>-related osteopetrosis has a 50% chance of inheriting the pathogenic variant.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the proband's parents. If a parent has the <i>CLCN7</i> pathogenic variant, his or her family members may be at risk.</p></div><div id="clcn7.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#clcn7.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p>
|
|
<b>Family planning</b>
|
|
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 at risk of being carriers.</div></li></ul></div><div id="clcn7.Prenatal_Testing_and_Preimplantati"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>CLCN7</i> pathogenic variant(s) have been identified in an affected family member, prenatal testing and preimplantation genetic testing for <i>CLCN7</i>-related osteopetrosis are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="clcn7.Resources"><h2 id="_clcn7_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>The OsteoPETrosis Society (OPETS)</b>
|
|
</div><div><b>Email:</b> osteopetrosispatient@gmail.com; janecastello.opets@gmail.com</div><div>
|
|
<a href="http://www.osteopetrosis.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">osteopetrosis.org</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>MedlinePlus</b>
|
|
</div><div>
|
|
<a href="https://medlineplus.gov/genetics/condition/osteopetrosis/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Osteopetrosis</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>National Institute of Arthritis and Musculoskeletal and Skin Diseases</b>
|
|
</div><div><b>Phone:</b> 877-226-4267</div><div><b>Email:</b> niamsinfo@mail.nih.gov</div><div>
|
|
<a href="http://www.niams.nih.gov" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">niams.nih.gov</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>Network for Rare Osteopathies (NetsOs)</b>
|
|
</div><div>CeSER</div><div>Alexandrinenstraße 5</div><div>Germany</div><div><b>Phone:</b> 49 (0)234 509-2601</div><div><b>Fax:</b> 49 (0)234 509-2688</div><div><b>Email:</b> ceser@klinikum-bochum.de</div><div>
|
|
<a href="https://centrum-seltene-erkrankungen-ruhr.de/versorgungsnetze/netsos/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Netzwerks für Seltene Osteopathien</a>
|
|
</div></li><li class="half_rhythm"><div>
|
|
<b>European Society for Immunodeficiencies (ESID) Registry</b>
|
|
</div><div><b>Email:</b> esid-registry@uniklinik-freiburg.de</div><div>
|
|
<a href="https://esid.org/Working-Parties/Registry-Working-Party/ESID-Registry" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ESID Registry</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="clcn7.Molecular_Genetics"><h2 id="_clcn7_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="figclcn7molgenTA"><a href="/books/NBK1127/table/clcn7.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobclcn7molgenTA"><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="clcn7.molgen.TA"><a href="/books/NBK1127/table/clcn7.molgen.TA/?report=objectonly" target="object" rid-ob="figobclcn7molgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">CLCN7-Related Osteopetrosis: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figclcn7molgenTB"><a href="/books/NBK1127/table/clcn7.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobclcn7molgenTB"><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="clcn7.molgen.TB"><a href="/books/NBK1127/table/clcn7.molgen.TB/?report=objectonly" target="object" rid-ob="figobclcn7molgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for CLCN7-Related Osteopetrosis (View All in OMIM) </p></div></div><div id="clcn7.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>CLCN7</i>-related osteopetrosis is caused by osteoclast dysfunction. The osteoclast is a highly specialized cell with the unique ability to resorb large amounts of mineralized bone tissue. After attaching to the bone surface, a sealing zone that isolates the resorption lacuna from the extracellular environment is formed. Large quantities of acidic vesicles then fuse with the plasma membrane juxtaposed to the bone surface to create the ruffled membrane. This structure is exclusively found in osteoclasts and secretes large amounts of acid into the resorption lacuna, which therefore is also referred to as an "extracellular lysosome" [<a class="bibr" href="#clcn7.REF.sobacchi.2013.522" rid="clcn7.REF.sobacchi.2013.522">Sobacchi et al 2013</a>]. The low pH is required to dissolve the bone mineral and for the optimal activity of acid hydrolases that degrade the bone matrix.</p><p><i>CLCN7</i> encodes the ClC-7 chloride channel, which resides in lysosomal vesicles and in the ruffled membrane and acts as a 2Cl<sup>-</sup>/1H<sup>+</sup> exchanger transporting negative charges into the resorption lacuna in parallel to the protons pumped in this extracellular space by the ruffled membrane v-type H<sup>+</sup>-ATPase [<a class="bibr" href="#clcn7.REF.kornak.2001.205" rid="clcn7.REF.kornak.2001.205">Kornak et al 2001</a>, <a class="bibr" href="#clcn7.REF.leisle.2011.2140" rid="clcn7.REF.leisle.2011.2140">Leisle et al 2011</a>].</p><p><b>Mechanism of disease causation.</b> Pathogenic variants in <i>CLCN7</i> lead to a loss of chloride channel function of varying degree. In the most severe autosomal recessive osteopetrosis phenotype, the ClC-7 chloride channel is absent, while the autosomal dominant osteopetrosis type II phenotype-causing pathogenic variants do not necessarily impair chloride currents, but do result in abnormal gating behavior of the channel [<a class="bibr" href="#clcn7.REF.leisle.2011.2140" rid="clcn7.REF.leisle.2011.2140">Leisle et al 2011</a>].</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figclcn7Tnotableclcn7pathogenicvariant"><a href="/books/NBK1127/table/clcn7.T.notable_clcn7_pathogenic_variant/?report=objectonly" target="object" title="Table 11. " class="img_link icnblk_img" rid-ob="figobclcn7Tnotableclcn7pathogenicvariant"><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="clcn7.T.notable_clcn7_pathogenic_variant"><a href="/books/NBK1127/table/clcn7.T.notable_clcn7_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobclcn7Tnotableclcn7pathogenicvariant">Table 11. </a></h4><p class="float-caption no_bottom_margin">Notable <i>CLCN7</i> Pathogenic Variants </p></div></div></div></div><div id="clcn7.Chapter_Notes"><h2 id="_clcn7_Chapter_Notes_">Chapter Notes</h2><div id="clcn7.Author_Information"><h3>Author Information</h3><p>Guidelines for diagnosis, therapy, and follow up for this disorder are available <a href="https://esid.org/content/download/15294/420706/file/00_OP_Guidelines_V3.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">online</a> (pdf) and from author Ansgar Schulz, MD, at <a href="mailto:dev@null" data-email="ed.mlu-kinilkinu@zluhcs.ragsna" class="oemail">ed.mlu-kinilkinu@zluhcs.ragsna</a>.</p></div><div id="clcn7.Author_History"><h3>Author History</h3><p>Marie-Christine de Vernejoul, MD, PhD; Hôpital Lariboisière (2007-2016)<br />Uwe Kornak, MD, PhD (2007-present)<br />Ansgar Schulz, MD (2007-present)<br />Cristina Sobacchi, MS (2016-present)<br />Anna Villa, MD, PhD (2016-present)</p></div><div id="clcn7.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>20 January 2022 (ha) Comprehensive update posted live</div></li><li class="half_rhythm"><div>9 June 2016 (ha) Comprehensive update posted live</div></li><li class="half_rhythm"><div>20 June 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>14 October 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>12 February 2007 (me) Review posted live</div></li><li class="half_rhythm"><div>8 September 2006 (uk) Original submission</div></li></ul></div></div><div id="clcn7.References"><h2 id="_clcn7_References_">References</h2><div id="clcn7.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.aker.2012.221">Aker M, Rouvinski A, Hashavia S, Ta-Shma A, Shaag A, Zenvirt S, Israel S, Weintraub M, Taraboulos A, Bar-Shavit Z, Elpeleg O. An SNX10 mutation causes malignant osteopetrosis of infancy. <span><span class="ref-journal">J Med Genet. </span>2012;<span class="ref-vol">49</span>:221–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22499339" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22499339</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.b_nichou.2000.87">Bénichou OD, Laredo JD, de Vernejoul MC. Type II autosomal dominant osteopetrosis (Albers-Schönberg disease): clinical and radiological manifestations in 42 patients. <span><span class="ref-journal">Bone. </span>2000;<span class="ref-vol">26</span>:87–93.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10617161" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10617161</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.bo.2016.1979">Bo T, Yan F, Guo J, Lin X, Zhang H, Guan Q, Wang H, Fang L, Gao L, Zhao J, Xu C. Characterization of a relatively malignant form of osteopetrosis caused by a novel mutation in the PLEKHM1 gene. <span><span class="ref-journal">J Bone Miner Res. </span>2016;<span class="ref-vol">31</span>:1979–87.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27291868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27291868</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.brance.2020.115550">Brance ML, Brun LR, Cóccaro NM, Aravena A, Duan S, Mumm S, Whyte MP. High bone mass from mutation of low-density lipoprotein receptor-related protein 6 (LRP6). <span><span class="ref-journal">Bone. </span>2020;<span class="ref-vol">141</span>:115550. </span> [<a href="https://pubmed.ncbi.nlm.nih.gov/32730923" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32730923</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.camposxavier.2003.186">Campos-Xavier AB, Saraiva JM, Ribeiro LM, Munnich A, Cormier-Daire V. Chloride channel 7 (CLCN7) gene mutations in intermediate autosomal recessive osteopetrosis. <span><span class="ref-journal">Hum Genet. </span>2003;<span class="ref-vol">112</span>:186–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12522560" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12522560</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.chorin.2020.e1405">Chorin O, Yachelevich N, Mohamed K, Moscatelli I, Pappas J, Henriksen K, Evrony GD. Transcriptome sequencing identifies a noncoding, deep intronic variant in CLCN7 causing autosomal recessive osteopetrosis. <span><span class="ref-journal">Mol Genet Genomic Med. </span>2020;<span class="ref-vol">8</span>:e1405. </span> [<a href="/pmc/articles/PMC7549584/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7549584</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32691986" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32691986</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.cleiren.2001.2861">Cleiren E, Bénichou O, Van Hul E, Gram J, Bollerslev J, Singer FR, Beaverson K, Aledo A, Whyte MP, Yoneyama T, deVernejoul MC, Van Hul W. Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. <span><span class="ref-journal">Hum Mol Genet. </span>2001;<span class="ref-vol">10</span>:2861–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11741829" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11741829</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.corbacioglu.2006.547">Corbacioglu S, Hönig M, Lahr G, Stöhr S, Berry G, Friedrich W, Schulz AS. Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide. <span><span class="ref-journal">Bone Marrow Transplant. </span>2006;<span class="ref-vol">38</span>:547–53.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16953210" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16953210</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.crazzolara.2015.1677">Crazzolara R, Maurer K, Schulze H, Zieger B, Zustin J, Schulz AS. A new mutation in the KINDLIN-3 gene ablates integrin-dependent leukocyte, platelet, and osteoclast function in a patient with leukocyte adhesion deficiency-III. <span><span class="ref-journal">Pediatr Blood Cancer. </span>2015;<span class="ref-vol">62</span>:1677–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25854317" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25854317</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.dozier.2005.762">Dozier TS, Duncan IM, Klein AJ, Lambert PR, Key LL Jr. Otologic manifestations of malignant osteopetrosis. <span><span class="ref-journal">Otol Neurotol. </span>2005;<span class="ref-vol">26</span>:762–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16015181" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16015181</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.evenor.2022.116229">Even-Or E, Schiesel G, Simanovsky N. NaserEddin A, Zaidman I, Elpeleg O, Mor-Shaked H, Stepensky P. Clinical presentation and analysis of genotype-phenotype correlations in patients with malignant infantile osteopetrosis. <span><span class="ref-journal">Bone. </span>2022;<span class="ref-vol">154</span>:116229. </span> [<a href="https://pubmed.ncbi.nlm.nih.gov/34624559" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34624559</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.frattini.2000.343">Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Andersson AK, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. <span><span class="ref-journal">Nat Genet. </span>2000;<span class="ref-vol">25</span>:343–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10888887" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10888887</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.frattini.2003.1740">Frattini A, Pangrazio A, Susani L, Sobacchi C, Mirolo M, Abinun M, Andolina M, Flanagan A, Horwitz EM, Mihci E, Notarangelo LD, Ramenghi U, Teti A, Van Hove J, Vujic D, Young T, Albertini A, Orchard PJ, Vezzoni P, Villa A. Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis. <span><span class="ref-journal">J Bone Miner Res. </span>2003;<span class="ref-vol">18</span>:1740–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14584882" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14584882</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.gayt_nmorales.2021.225">Gaytán-Morales JF, Castorena-Villa I, Mendoza-Camargo FO, Cortés-Flores DC, Gómez-Domíguez YA, Montenegro-Chahar PD, García-Maldonado P, Parra-Ortega I. Hematopoietic stem cell transplantation in a patient with osteopetrosis and mutation in CLCN7: long-term follow-up. <span><span class="ref-journal">Bol Med Hosp Infant Mex. </span>2021;<span class="ref-vol">78</span>:225–33.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/33651788" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33651788</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.guerrini.2008.64">Guerrini MM, Sobacchi C, Cassani B, Abinun M, Kilic SS, Pangrazio A, Moratto D, Mazzolari E, Clayton-Smith J, Orchard P, Coxon FP, Helfrich MH, Crockett JC, Mellis D, Vellodi A, Tezcan I, Notarangelo J, Rogers MJ, Vezzoni P, Villa A, Frattini A. Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. <span><span class="ref-journal">Am J Hum Genet. </span>2008;<span class="ref-vol">83</span>:64–76.</span> [<a href="/pmc/articles/PMC2443850/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2443850</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18606301" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18606301</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.howaldt.2019.495">Howaldt A, Nampoothiri S, Quell LM, Ozden A, Fischer-Zirnsak B, Collet C, de Vernejoul MC, Doneray H, Kayserili H, Kornak U. Sclerosing bone dysplasias with hallmarks of dysosteosclerosis in four patients carrying mutations in SLC29A3 and TCIRG1. <span><span class="ref-journal">Bone. </span>2019;<span class="ref-vol">120</span>:495–503.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30537558" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30537558</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.howaldt.2020.1322">Howaldt A, Hennig AF, Rolvien T, Rössler U, Stelzer N, Knaus A, Böttger S, Zustin J, Geißler S, Oheim R, Amling M, Howaldt HP, Kornak U. Adult osteosclerotic metaphyseal dysplasia with progressive osteonecrosis of the jaws and abnormal bone resorption pattern due to a LRRK1 splice site mutation. <span><span class="ref-journal">J Bone Miner Res. </span>2020;<span class="ref-vol">35</span>:1322–32.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/32119750" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32119750</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.hu.2013.e73576">Hu Y, Chen IP, de Almeida S, Tiziani V, Do Amaral CM, Gowrishankar K, Passos-Bueno MR, Reichenberger EJ. A novel autosomal recessive GJA1 missense mutation linked to Craniometaphyseal dysplasia. <span><span class="ref-journal">PLoS One. </span>2013;<span class="ref-vol">8</span>:e73576. </span> [<a href="/pmc/articles/PMC3741164/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3741164</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23951358" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23951358</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.hwang.2000.328">Hwang JM, Kim IO, Wang KC. Complete visual recovery in osteopetrosis by early optic nerve decompression. <span><span class="ref-journal">Pediatr Neurosurg. </span>2000;<span class="ref-vol">33</span>:328–32.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11182645" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11182645</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.jacquemin.1998.662">Jacquemin C, Mullaney P, Svedberg E. Marble brain syndrome: osteopetrosis, renal acidosis and calcification of the brain. <span><span class="ref-journal">Neuroradiology. </span>1998;<span class="ref-vol">40</span>:662–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9833897" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9833897</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.j_nsson.2017.519">Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. <span><span class="ref-journal">Nature. </span>2017;<span class="ref-vol">549</span>:519–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28959963" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28959963</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.kantaputra.2012.909">Kantaputra PN, Thawanaphong S, Issarangporn W, Klangsinsirikul P, Ohazama A, Sharpe P, Supanchart C. Long-term survival in infantile malignant autosomal recessive osteopetrosis secondary to homozygous p.Arg526Gln mutation in CLCN7. <span><span class="ref-journal">Am J Med Genet A. </span>2012;<span class="ref-vol">158A</span>:909–16.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22419446" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22419446</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.kornak.2001.205">Kornak U, Kasper D, Bosl MR, Kaiser E, Schweizer M, Schulz A, Friedrich W, Delling G, Jentsch TJ. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. <span><span class="ref-journal">Cell. </span>2001;<span class="ref-vol">104</span>:205–15.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11207362" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11207362</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.kornak.2000.2059">Kornak U, Schulz A, Friedrich W, Uhlhaas S, Kremens B, Voit T, Hasan C, Bode U, Jentsch TJ, Kubisch C. Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. <span><span class="ref-journal">Hum Mol Genet. </span>2000;<span class="ref-vol">9</span>:2059–63.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10942435" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10942435</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.lankester.2021.2052">Lankester AC, Albert MH, Booth C, Gennery AR, Güngör T, Hönig M, Morris EC, Moshous D, Neven B, Schulz A, Slatter M, Veys P, et al. EBMT/ESID inborn errors working party guidelines for hematopoietic stem cell transplantation for inborn errors of immunity. <span><span class="ref-journal">Bone Marrow Transplant. </span>2021;<span class="ref-vol">56</span>:2052–62.</span> [<a href="/pmc/articles/PMC8410590/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8410590</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34226669" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34226669</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.leisle.2011.2140">Leisle L, Ludwig CF, Wagner FA, Jentsch TJ, Stauber T. ClC-7 is a slowly voltage-gated 2Cl(-)/1H(+)-exchanger and requires Ostm1 for transport activity. <span><span class="ref-journal">EMBO J. </span>2011;<span class="ref-vol">30</span>:2140–52.</span> [<a href="/pmc/articles/PMC3117652/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3117652</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21527911" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21527911</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.natsheh.2016.535">Natsheh J, Drozdinsky G, Simanovsky N, Lamdan R, Erlich O, Gorelik N, Or R, Weintraub M, Stepensky P. Improved outcomes of hematopoietic stem cell transplantation in patients with infantile malignant osteopetrosis using fludarabine-based conditioning. <span><span class="ref-journal">Pediatr Blood Cancer. </span>2016;<span class="ref-vol">63</span>:535–40.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/26485304" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26485304</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.nicoli.2019.1127">Nicoli ER, Weston MR, Hackbarth M, Becerril A, Larson A, Zein WM, Baker PR 2nd, Burke JD, Dorward H, Davids M, Huang Y, Adams DR, Zerfas PM, Chen D, Markello TC, Toro C, Wood T, Elliott G, Vu M. Undiagnosed Diseases Network, Zheng W, Garrett LJ, Tifft CJ, Gahl WA, Day-Salvatore DL, Mindell JA, Malicdan MCV. Lysosomal storage and albinism due to effects of a de novo CLCN7 variant on lysosomal acidification. <span><span class="ref-journal">Am J Hum Genet. </span>2019;<span class="ref-vol">104</span>:1127–38.</span> [<a href="/pmc/articles/PMC6562152/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6562152</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31155284" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31155284</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.orchard.2015.270">Orchard PJ, Fasth AL, Le Rademacher J, He W, Boelens JJ, Horwitz EM, Al-Seraihy A, Ayas M, Bonfim CM, Boulad F, Lund T, Buchbinder DK, Kapoor N, O'Brien TA, Perez MA, Veys PA, Eapen M. Hematopoietic stem cell transplantation for infantile osteopetrosis. <span><span class="ref-journal">Blood. </span>2015;<span class="ref-vol">126</span>:270–6.</span> [<a href="/pmc/articles/PMC4497967/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4497967</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26012570" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26012570</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.palagano.2015.1814">Palagano E, Blair HC, Pangrazio A, Tourkova I, Strina D, Angius A, Cuccuru G, Oppo M, Uva P, Van Hul W, Boudin E, Superti-Furga A, Faletra F, Nocerino A, Ferrari MC, Grappiolo G, Monari M, Montanelli A, Vezzoni P, Villa A, Sobacchi C. Buried in the middle but guilty: intronic mutations in the TCIRG1 gene cause human autosomal recessive osteopetrosis. <span><span class="ref-journal">J Bone Miner Res. </span>2015;<span class="ref-vol">30</span>:1814–21.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25829125" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25829125</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.pangrazio.2013.1041">Pangrazio A, Fasth A, Sbardellati A, Orchard PJ, Kasow KA, Raza J, Albayrak C, Albayrak D, Vanakker OM, De Moerloose B, Vellodi A, Notarangelo LD, Schlack C, Strauss G, Kühl JS, Caldana E, Iacono NL, Susani L, Kornak U, Schulz A, Vezzoni P, Villa A, Sobacchi C. SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity. <span><span class="ref-journal">J Bone Miner Res. </span>2013;<span class="ref-vol">28</span>:1041–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23280965" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23280965</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.r_ssler.2021.1621">Rössler U, Hennig AF, Stelzer N, Bose S, Kopp J, Søe K, Cyganek L, Zifarelli G, Ali S, von der Hagen M, Strässler ET, Hahn G, Pusch M, Stauber T, Izsvák Z, Gossen M, Stachelscheid H, Kornak U. Efficient generation of osteoclasts from human induced pluripotent stem cells and functional investigations of lethal CLCN7-related osteopetrosis. <span><span class="ref-journal">J Bone Miner Res. </span>2021;<span class="ref-vol">36</span>:1621–35.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/33905594" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33905594</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.pangrazio.2012.250">Pangrazio A, Frattini A, Valli R, Maserati E, Susani L, Vezzoni P, Villa A, Al-Herz W, Sobacchi C. A homozygous contiguous gene deletion in chromosome 16p13.3 leads to autosomal recessive osteopetrosis in a Jordanian patient. <span><span class="ref-journal">Calcif Tissue Int. </span>2012;<span class="ref-vol">91</span>:250–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22847576" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22847576</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.pangrazio.2006.1098">Pangrazio A, Poliani PL, Megarbane A, Lefranc G, Lanino E, Di Rocco M, Rucci F, Lucchini F, Ravanini M, Facchetti F, Abinun M, Vezzoni P, Villa A, Frattini A. Mutations in OSTM1 (grey lethal) define a particularly severe form of autosomal recessive osteopetrosis with neural involvement. <span><span class="ref-journal">J Bone Miner Res. </span>2006;<span class="ref-vol">21</span>:1098–105.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16813530" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16813530</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.pangrazio.2010.e1071">Pangrazio A, Pusch M, Caldana E, Frattini A, Lanino E, Tamhankar PM, Phadke S, Lopez AG, Orchard P, Mihci E, Abinun M, Wright M, Vettenranta K, Bariae I, Melis D, Tezcan I, Baumann C, Locatelli F, Zecca M, Horwitz E, Mansour LS, Van Roij M, Vezzoni P, Villa A, Sobacchi C. Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations. <span><span class="ref-journal">Hum Mutat. </span>2010;<span class="ref-vol">31</span>:E1071–80.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19953639" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19953639</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.pangrazio.2014.122">Pangrazio A, Puddu A, Oppo M, Valentini M, Zammataro L, Vellodi A, Gener B, Llano-Rivas I, Raza J, Atta I, Vezzoni P, Superti-Furga A, Villa A, Sobacchi C. Exome sequencing identifies CTSK mutations in patients originally diagnosed as intermediate osteopetrosis. <span><span class="ref-journal">Bone. </span>2014;<span class="ref-vol">59</span>:122–6.</span> [<a href="/pmc/articles/PMC3885796/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3885796</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24269275" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24269275</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.rahbari.2016.126">Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. <span><span class="ref-journal">Nat Genet. </span>2016;<span class="ref-vol">48</span>:126–33.</span> [<a href="/pmc/articles/PMC4731925/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4731925</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26656846" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26656846</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.shroff.2012.1766">Shroff R, Beringer O, Rao K, Hofbauer L, Schulz A. Denosumab for post-transplantation hypercalcemia in osteopetrosis. <span><span class="ref-journal">N Engl J Med. </span>2012;<span class="ref-vol">367</span>:1766–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23113501" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23113501</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.sobacchi.2007.960">Sobacchi C, Frattini A, Guerrini MM, Abinun M, Pangrazio A, Susani L, Bredius R, Mancini G, Cant A, Bishop N, Grabowski P, Del Fattore A, Messina C, Errigo G, Coxon FP, Scott DI, Teti A, Rogers MJ, Vezzoni P, Villa A Helfrich MH. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. <span><span class="ref-journal">Nat Genet. </span>2007;<span class="ref-vol">39</span>:960–2.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17632511" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17632511</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.sobacchi.2014.1646">Sobacchi C, Pangrazio A, Lopez AG, Gomez DP, Caldana ME, Susani L, Vezzoni P, Villa A. As little as needed: the extraordinary case of a mild recessive osteopetrosis owing to a novel splicing hypomorphic mutation in the TCIRG1 gene. <span><span class="ref-journal">J Bone Miner Res. </span>2014;<span class="ref-vol">29</span>:1646–50.</span> [<a href="/pmc/articles/PMC4258090/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4258090</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24535816" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24535816</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.sobacchi.2013.522">Sobacchi C, Schulz A, Coxon FP, Helfrich MH. Osteopetrosis: genetics, treatment and new insights into osteoclast function. <span><span class="ref-journal">Nat Rev Endocrinol. </span>2013;<span class="ref-vol">9</span>:522–36.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23877423" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23877423</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.stenson.2020.1197">Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. <span><span class="ref-journal">Hum Genet. </span>2020;<span class="ref-vol">139</span>:1197–207.</span> [<a href="/pmc/articles/PMC7497289/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7497289</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32596782" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32596782</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.steward.2003.87">Steward CG. Neurological aspects of osteopetrosis. <span><span class="ref-journal">Neuropathol Appl Neurobiol. </span>2003;<span class="ref-vol">29</span>:87–97.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12662317" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12662317</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.steward.2004.63">Steward CG, Pellier I, Mahajan A, Ashworth MT, Stuart AG, Fasth A, Lang D, Fischer A, Friedrich W, Schulz AS. Severe pulmonary hypertension: a frequent complication of stem cell transplantation for malignant infantile osteopetrosis. <span><span class="ref-journal">Br J Haematol. </span>2004;<span class="ref-vol">124</span>:63–71.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14675409" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14675409</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.strickland.2005.815">Strickland JP, Berry DJ. Total joint arthroplasty in patients with osteopetrosis: a report of 5 cases and review of the literature. <span><span class="ref-journal">J Arthroplasty. </span>2005;<span class="ref-vol">20</span>:815–20.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16139724" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16139724</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.van_wesenbeeck.2007.919">Van Wesenbeeck L, Odgren PR, Coxon FP, Frattini A, Moens P, Perdu B, MacKay CA, Van Hul E, Timmermans JP, Vanhoenacker F, Jacobs R, Peruzzi B, Teti A, Helfrich MH, Rogers MJ, Villa A, Van Hul W. Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans. <span><span class="ref-journal">J Clin Invest. </span>2007;<span class="ref-vol">117</span>:919–30.</span> [<a href="/pmc/articles/PMC1838941/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1838941</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17404618" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17404618</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.waguespack.2007.771">Waguespack SG, Hui SL, Dimeglio LA, Econs MJ. Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation. <span><span class="ref-journal">J Clin Endocrinol Metab. </span>2007;<span class="ref-vol">92</span>:771–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17164308" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17164308</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.wang.2016.19971">Wang H, Pan M, Ni J, Zhang Y, Zhang Y, Gao S, Liu J, Wang Z, Zhang R, He H, Wu B, Duan X. ClC-7 deficiency impairs tooth development and eruption. <span><span class="ref-journal">Sci Rep. </span>2016;<span class="ref-vol">6</span>:19971.</span> [<a href="/pmc/articles/PMC4734291/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4734291</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26829236" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26829236</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.wilson.2000.449">Wilson CJ, Vellodi A. Autosomal recessive osteopetrosis: diagnosis, management, and outcome. <span><span class="ref-journal">Arch Dis Child. </span>2000;<span class="ref-vol">83</span>:449–52.</span> [<a href="/pmc/articles/PMC1718540/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1718540</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11040159" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11040159</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="clcn7.REF.zhang.2019.1387">Zhang Y, Ji D, Li L, Yang S, Zhang H. Duan. ClC-7 regulates the pattern and early development of craniofacial bone and tooth. <span><span class="ref-journal">Theranostics. </span>2019;<span class="ref-vol">9</span>:1387–400.</span> [<a href="/pmc/articles/PMC6401512/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6401512</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30867839" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30867839</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1127_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Cristina Sobacchi</span>, MS<div class="affiliation small">CNR-IRGB, Milan Unit
|
|
Humanitas Clinical and Research Center
|
|
Rozzano, Italy<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ti.hcraesersatinamuh@ihccabos.anitsirc" class="oemail">ti.hcraesersatinamuh@ihccabos.anitsirc</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Anna Villa</span>, MD, PhD<div class="affiliation small">CNR-IRGB, Milan Unit
|
|
Humanitas Clinical and Research Center
|
|
Rozzano, Italy<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ti.hcraesersatinamuh@alliv.anna" class="oemail">ti.hcraesersatinamuh@alliv.anna</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Ansgar Schulz</span>, MD<div class="affiliation small">Universitätsklinik für Kinder- und Jugendmedizin
|
|
Ulm, Germany<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ed.mlu-kinilkinu@zluhcs.ragsna" class="oemail">ed.mlu-kinilkinu@zluhcs.ragsna</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Uwe Kornak</span>, MD, PhD<div class="affiliation small">Institut für Humangenetik
|
|
Universitätsmedizin Göttingen, Germany<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ed.negnitteog-inu.dem@kanrok.ewu" class="oemail">ed.negnitteog-inu.dem@kanrok.ewu</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">February 12, 2007</span>; Last Update: <span itemprop="dateModified">January 20, 2022</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>Sobacchi C, Villa A, Schulz A, et al. CLCN7-Related Osteopetrosis. 2007 Feb 12 [Updated 2022 Jan 20]. 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/clcn4-ndd/?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/clpb-def/?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="figobclcn7Td"><div id="clcn7.Td" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1127/table/clcn7.Td/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__clcn7.Td_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_clcn7.Td_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Phenotype <sup>1</sup></th><th id="hd_h_clcn7.Td_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Synonym</th></tr></thead><tbody><tr><td headers="hd_h_clcn7.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Autosomal recessive osteopetrosis (ARO)</td><td headers="hd_h_clcn7.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Infantile malignant <i>CLCN7</i>-related autosomal recessive osteopetrosis</td></tr><tr><td headers="hd_h_clcn7.Td_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intermediate autosomal osteopetrosis (IAO)</td><td headers="hd_h_clcn7.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.Td_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Autosomal dominant osteopetrosis type II (ADOII)</td><td headers="hd_h_clcn7.Td_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Albers-Schönberg disease</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="clcn7.TF.d.1"><p class="no_margin">For other genetic causes of these phenotypes see <a href="#clcn7.Differential_Diagnosis">Differential Diagnosis</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobclcn7Tdiagnosticfeaturesofthesubty"><div id="clcn7.T.diagnostic_features_of_the_subty" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Diagnostic Features of the Subtypes of <i>CLCN7</i>-Related Osteopetrosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1127/table/clcn7.T.diagnostic_features_of_the_subty/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__clcn7.T.diagnostic_features_of_the_subty_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_1" style="text-align:left;vertical-align:middle;">Finding</th><th id="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2" colspan="3" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Subtype of <i>CLCN7</i>-Related Osteopetrosis</th></tr><tr><th headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2" id="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">ARO</th><th headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2" id="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">IAO</th><th headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2" id="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ADOII</th></tr></thead><tbody><tr><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Radiographic changes</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pathognomonic <sup>1</sup></td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Characteristic <sup>2</sup></td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Characteristic <sup>3</sup></td></tr><tr><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypocalcemia</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe to absent</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td></tr><tr><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Anemia</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe to moderate</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mild to absent</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td></tr><tr><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Thrombocytopenia</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe to absent</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td></tr><tr><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Visual impairment</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequent</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Very rare</td></tr><tr><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CNS involvement</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe to absent <sup>4</sup></td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td></tr><tr><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Age of onset of symptoms</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Birth</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">First 2 years</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">First 10 yrs</td></tr><tr><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Inheritance</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR or AD</td><td headers="hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_1_2 hd_h_clcn7.T.diagnostic_features_of_the_subty_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</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">ADOII = autosomal dominant osteopetrosis type II; ARO = infantile malignant <i>CLCN7</i>-related autosomal recessive osteopetrosis; CNS = central nervous system; IAO = intermediate autosomal osteopetrosis</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="clcn7.TF.1.1"><p class="no_margin">Generalized osteosclerosis, club-shaped long bones, sclerosis of the skull base, bone-within-bone appearance; these signs are observed in all types of ARO.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="clcn7.TF.1.2"><p class="no_margin">Findings similar to ARO, already present in early childhood, but less severe</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="clcn7.TF.1.3"><p class="no_margin">Findings: <br /> • Osteosclerosis of the spine ("sandwich vertebrae") <br /> • Bone-within-bone appearance, mainly in iliac wings <br /> • Erlenmeyer-shaped femoral metaphysis <br /> • Mild osteosclerosis of the skull base <br /> • Transverse bands of osteosclerosis in long bones</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="clcn7.TF.1.4"><p class="no_margin">Typical signs of CNS involvement:<br /> • Delayed psychomotor development<br /> • Loss of abilities<br /> • Seizures (can be also due to hypocalcemia)<br /> • On MRI: global brain atrophy, cortical abnormalities, and in rare individuals, heterotopias</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobclcn7Tmoleculargenetictestingusedi"><div id="clcn7.T.molecular_genetic_testing_used_i" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>CLCN7</i>-Related Osteopetrosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1127/table/clcn7.T.molecular_genetic_testing_used_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__clcn7.T.molecular_genetic_testing_used_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_clcn7.T.molecular_genetic_testing_used_i_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_clcn7.T.molecular_genetic_testing_used_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_clcn7.T.molecular_genetic_testing_used_i_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_clcn7.T.molecular_genetic_testing_used_i_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>CLCN7</i>
|
|
</td><td headers="hd_h_clcn7.T.molecular_genetic_testing_used_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_clcn7.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~99% <sup>4, 5</sup></td></tr><tr><td headers="hd_h_clcn7.T.molecular_genetic_testing_used_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>6</sup></td><td headers="hd_h_clcn7.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare <sup>7</sup></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="clcn7.TF.2.1"><p class="no_margin">See <a href="/books/NBK1127/?report=reader#clcn7.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="clcn7.TF.2.2"><p class="no_margin">See <a href="#clcn7.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="clcn7.TF.2.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="https://www.ncbi.nlm.nih.gov/books/NBK6851/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="clcn7.TF.2.4"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bibr" href="#clcn7.REF.stenson.2020.1197" rid="clcn7.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="clcn7.TF.2.5"><p class="no_margin">A noncoding deep intronic variant in <i>CLCN7</i> causing autosomal recessive osteopetrosis was reported to have been missed on genome sequencing [<a class="bibr" href="#clcn7.REF.chorin.2020.e1405" rid="clcn7.REF.chorin.2020.e1405">Chorin et al 2020</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="clcn7.TF.2.6"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include 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>7. </dt><dd><div id="clcn7.TF.2.7"><p class="no_margin">A homozygous 101-kb contiguous gene deletion including exons 7-25 of <i>CLCN7</i> has been reported [<a class="bibr" href="#clcn7.REF.pangrazio.2012.250" rid="clcn7.REF.pangrazio.2012.250">Pangrazio et al 2012</a>].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobclcn7Tothertypesofautosomalrecessi"><div id="clcn7.T.other_types_of_autosomal_recessi" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Other Types of Autosomal Recessive Osteopetrosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1127/table/clcn7.T.other_types_of_autosomal_recessi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__clcn7.T.other_types_of_autosomal_recessi_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Characteristics</th><th id="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Features Distinguishing this Disorder from <i>CLCN7</i>-Related ARO</th></tr></thead><tbody><tr><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>CA2</i>
|
|
</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ARO w/renal tubular acidosis (RTA) (OMIM <a href="https://omim.org/entry/259730" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">259730</a>)</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Generalized osteosclerosis. Cerebral calcifications are typical & may be assoc w/ID. <sup>1</sup></td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Onset of ARO w/RTA is usually later than in infantile malignant form of ARO & disease course is milder.</td></tr><tr><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>OSTM1</i>
|
|
</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>OSTM1</i>-related ARO (OMIM <a href="https://omim.org/entry/259720" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">259720</a>)</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~4% of ARO is caused by pathogenic variants in <i>OSTM1</i>. Extremely severe form of ARO w/CNS involvement <sup>2</sup> that is indistinguishable from most severe forms of <i>CLCN7</i>-related ARO.</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>OSTM1</i>-related ARO is frequently assoc w/structural brain anomalies.</td></tr><tr><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>PLEKHM1</i>
|
|
</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PLEKHM1</i>-related ARO (OMIM <a href="https://omim.org/entry/611497" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">611497</a>)</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Very rare, can look like ADOII</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PLEKHM1</i>-related ARO appears to be very mild & can regress w/↑ age. <sup>3</sup> One person w/<i>PLEKHM1</i>-related ARO caused by a heterozygous pathogenic variant has been described. <sup>4</sup></td></tr><tr><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>SNX10</i>
|
|
</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>SNX10</i>-related ARO (OMIM <a href="https://omim.org/entry/615085" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615085</a>)</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~4% of ARO is caused by pathogenic variants in <i>SNX10</i>; in particular<i>,</i> "Västerbottenian osteopetrosis" is caused by <i>SNX10</i> pathogenic variants. Loss of vision, anemia, & bone fragility are frequently observed, warranting use of HSCT. <sup>5</sup></td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>SNX10</i>-related ARO appears to be slightly less severe than <i>CLCN7</i>-related ARO.</td></tr><tr><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>TCIRG1</i>
|
|
</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>TCIRG1</i>-related ARO (OMIM <a href="https://omim.org/entry/259700" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">259700</a>)</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>50% of ARO is caused by pathogenic variants in <i>TCIRG1</i>.</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Higher frequency of neurodevelopmental delay & seizures in <i>CLCN7</i>-related ARO than in <i>TCIRG1</i>-related ARO. <sup>6</sup> Noncoding <i>TCIRG1</i> variants can cause milder phenotype that resembles ADOII.</td></tr><tr><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>TNFRSF11A</i>
|
|
</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Osteoclast-poor ARO (OMIM <a href="https://omim.org/entry/612301" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">612301</a>)</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Characterized by onset w/in 1st yr of life & typical ARO manifestations. Investigation of bone biopsy is prerequisite for reliable diagnosis.</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_4" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;"><i>TNFSF11</i> pathogenic variants cause a slight T-cell defect & <i>TNFRSF11A</i> pathogenic variants can lead to hypogammaglobulinemia similar to a common variable immune deficiency. <sup>7</sup> It is crucial to rule out <i>TNFSF11</i>- & <i>TNFRSF11A</i>-related ARO, as HSCT is not successful in these persons.</td></tr><tr><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>TNFSF11</i>
|
|
</td><td headers="hd_h_clcn7.T.other_types_of_autosomal_recessi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Osteoclast-poor ARO (OMIM <a href="https://omim.org/entry/259710" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">259710</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">ADOII = autosomal dominant osteopetrosis type II; ARO = autosomal recessive osteopetrosis; CNS = central nervous system; ID = intellectual disability; HSCT = hematopoietic stem cell transplantation</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="clcn7.TF.3.1"><p class="no_margin">
|
|
<a class="bibr" href="#clcn7.REF.jacquemin.1998.662" rid="clcn7.REF.jacquemin.1998.662">Jacquemin et al [1998]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="clcn7.TF.3.2"><p class="no_margin">
|
|
<a class="bibr" href="#clcn7.REF.pangrazio.2006.1098" rid="clcn7.REF.pangrazio.2006.1098">Pangrazio et al [2006]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="clcn7.TF.3.3"><p class="no_margin">
|
|
<a class="bibr" href="#clcn7.REF.van_wesenbeeck.2007.919" rid="clcn7.REF.van_wesenbeeck.2007.919">Van Wesenbeeck et al [2007]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="clcn7.TF.3.4"><p class="no_margin">
|
|
<a class="bibr" href="#clcn7.REF.bo.2016.1979" rid="clcn7.REF.bo.2016.1979">Bo et al [2016]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="clcn7.TF.3.5"><p class="no_margin"><a class="bibr" href="#clcn7.REF.aker.2012.221" rid="clcn7.REF.aker.2012.221">Aker et al [2012]</a>, <a class="bibr" href="#clcn7.REF.pangrazio.2013.1041" rid="clcn7.REF.pangrazio.2013.1041">Pangrazio et al [2013]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="clcn7.TF.3.6"><p class="no_margin"><a class="bibr" href="#clcn7.REF.frattini.2000.343" rid="clcn7.REF.frattini.2000.343">Frattini et al [2000]</a>, <a class="bibr" href="#clcn7.REF.kornak.2000.2059" rid="clcn7.REF.kornak.2000.2059">Kornak et al [2000]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="clcn7.TF.3.7"><p class="no_margin"><a class="bibr" href="#clcn7.REF.sobacchi.2007.960" rid="clcn7.REF.sobacchi.2007.960">Sobacchi et al [2007]</a>, <a class="bibr" href="#clcn7.REF.guerrini.2008.64" rid="clcn7.REF.guerrini.2008.64">Guerrini et al [2008]</a></p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobclcn7Totherdisorderstoconsiderint"><div id="clcn7.T.other_disorders_to_consider_in_t" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Other Disorders to Consider in the Differential Diagnosis of <i>CLCN7</i>-Related Osteopetrosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1127/table/clcn7.T.other_disorders_to_consider_in_t/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__clcn7.T.other_disorders_to_consider_in_t_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder/Phenotype</th><th id="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>ANKH</i>
|
|
</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/cranio-md/?report=reader">AD craniometaphyseal dysplasia</a>
|
|
</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Clinical hallmark is skull hyperostosis → deep-set eyes & paranasal bossing. Facial nerve palsy is common & more frequent than optic nerve compression.</div></li><li class="half_rhythm"><div>The femur shows a modeling defect, but no osteosclerosis. Susceptibility to fractures is not ↑.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>CSF1R</i>
|
|
</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Brain anomalies, neurodegeneration, & dysosteosclerosis (BANDDOS) (OMIM <a href="https://omim.org/entry/618476" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">618476</a>)</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Characterized by structural brain anomalies & a primary neurodegenerative phenotype. Like other forms of dysosteosclerosis, affected persons have platyspondyly.</td></tr><tr><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>CTSK</i>
|
|
</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="/books/n/gene/pycnodys/?report=reader">Pycnodysostosis</a>
|
|
</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Short-limbed short stature, typical facial appearance (convex nasal ridge & small jaw w/obtuse mandibular angle), osteosclerosis w/↑ bone fragility, acroosteolysis of distal phalanges, delayed closure of cranial sutures, & dysplasia of clavicle</div></li><li class="half_rhythm"><div>In some affected persons clinical presentation can resemble IAO. <sup>1</sup></div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>FERMT3</i>
|
|
</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Leukocyte adhesion deficiency type III (OMIM <a href="https://omim.org/entry/612840" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">612840</a>)</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Affected persons present w/recurrent infections & bleeding diathesis regardless of platelet or leukocyte count. In some, high bone density can be found, since fermitin family homolog 3 signaling is required for osteoclast-mediated bone resorption. <sup>2</sup></td></tr><tr><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>GJA1</i>
|
|
</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR craniometaphyseal dysplasia (OMIM <a href="https://omim.org/entry/218400" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">218400</a>)</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Typical features of craniometaphyseal dysplasia (macrocephaly, hearing loss, skull hyperostosis w/paranasal bossing, metaphyseal widening) but less pronounced calvarial thickening <sup>3</sup></div></li><li class="half_rhythm"><div>Due to diaphyseal osteosclerosis; can occasionally resemble mild forms of osteopetrosis</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>LRP6</i>
|
|
</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">High bone mass phenotype <sup>4</sup></td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Endosteal hyperostosis similar to ADOI but w/hypodontia</td></tr><tr><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>LRRK1</i>
|
|
</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Osteosclerotic metaphyseal dysplasia (OSMD) <sup>5</sup></td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>While the disorder name differs, <i>LRRK1</i>-related OSMD is a typical recessive osteopetrosis w/dysfunctional osteoclasts. No neurologic complications.</div></li><li class="half_rhythm"><div><i>LRRK1</i>-related OSMD is milder than <i>CLCN7</i>-related ARO & can be best compared to IAO.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>SLC29A3</i>
|
|
</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dysosteosclerosis <sup>6</sup></td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assoc w/platyspondyly (a distinguishing feature). Disorder appears to be osteoclast-poor. No neurologic complications.</div></li><li class="half_rhythm"><div><i>SLC39A3</i>-related dysosteosclerosis is milder than <i>CLCN7</i>-related ARO & is best compared to IAO.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>SOST</i>
|
|
</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/sost/?report=reader"><i>SOST</i>-related sclerosing bone dysplasias</a>, incl van Buchem disease & sclerosteosis</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_clcn7.T.other_disorders_to_consider_in_t_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Moderate-to-gross skull hyperostosis → cranial nerve dysfunction, mandibular enlargement, & generalized osteosclerosis. Sclerosteosis also comprises syndactyly & tall stature & can be lethal as a result of ↑ intracranial pressure.</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; ADO = autosomal dominant osteopetrosis; AR = autosomal recessive; ARO = autosomal recessive osteopetrosis; IAO = intermediate autosomal osteopetrosis; MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="clcn7.TF.4.1"><p class="no_margin">
|
|
<a class="bibr" href="#clcn7.REF.pangrazio.2014.122" rid="clcn7.REF.pangrazio.2014.122">Pangrazio et al [2014]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="clcn7.TF.4.2"><p class="no_margin">
|
|
<a class="bibr" href="#clcn7.REF.crazzolara.2015.1677" rid="clcn7.REF.crazzolara.2015.1677">Crazzolara et al [2015]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="clcn7.TF.4.3"><p class="no_margin">
|
|
<a class="bibr" href="#clcn7.REF.hu.2013.e73576" rid="clcn7.REF.hu.2013.e73576">Hu et al [2013]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="clcn7.TF.4.4"><p class="no_margin">
|
|
<a class="bibr" href="#clcn7.REF.brance.2020.115550" rid="clcn7.REF.brance.2020.115550">Brance et al [2020]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="clcn7.TF.4.5"><p class="no_margin">
|
|
<a class="bibr" href="#clcn7.REF.howaldt.2020.1322" rid="clcn7.REF.howaldt.2020.1322">Howaldt et al [2020]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="clcn7.TF.4.6"><p class="no_margin">
|
|
<a class="bibr" href="#clcn7.REF.howaldt.2019.495" rid="clcn7.REF.howaldt.2019.495">Howaldt et al [2019]</a>
|
|
</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobclcn7Trecommendedevaluationsfollowin"><div id="clcn7.T.recommended_evaluations_followin" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Infantile Malignant <i>CLCN7</i>-Related Autosomal Recessive Osteopetrosis (ARO)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1127/table/clcn7.T.recommended_evaluations_followin/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__clcn7.T.recommended_evaluations_followin_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_clcn7.T.recommended_evaluations_followin_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_clcn7.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Osteosclerosis</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Baseline radiographic skeletal survey</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Choanal stenosis</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Otorhinolaryngologic exam to evaluate for choanal stenosis assoc w/sclerosis of skull base</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hypocalcemia &</b>
|
|
<br />
|
|
<b>secondary hyper-</b>
|
|
<br />
|
|
<b>parathyroidism</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Calcium concentrations in blood & urine</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Anemia &</b>
|
|
<br />
|
|
<b>thrombocytopenia</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CBC w/reticulocyte count</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Abdominal ultrasound</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluate for hepatosplenomegaly assoc w/extrameduallry hematopoeisis.</td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurologic</b>
|
|
<br />
|
|
<b>complications</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MRI &/or CT of neurocranium to evaluate for narrowed neuroforamina, hydrocephalus, & brain abnormalities in neuronopathic form of osteopetrosis</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">EEG</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluate for evidence of neurodegeneration.</td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Baseline neurodevelopmental assessment</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Visual impairment</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic exam incl VEPs to evaluate for optic nerve atrophy assoc w/optic nerve compression w/in skull base</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hearing loss</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Baseline audiologic assessment</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Genetic</b>
|
|
<br />
|
|
<b>counseling</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_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_clcn7.T.recommended_evaluations_followin_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & their families re nature, MOI, & implications of <i>CLCN7</i>-related ARO to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Family support</b>
|
|
<br />
|
|
<b>& resources</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for:
|
|
<ul><li class="half_rhythm"><div>Community or <a href="#clcn7.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Social work involvement for parental support;</div></li><li class="half_rhythm"><div>Home nursing referral.</div></li></ul>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_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">ARO = autosomal recessive osteopetrosis; MOI = mode of inheritance; VEP = visual evoked potential</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="clcn7.TF.5.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobclcn7Trecommendedevaluationsfollowin1"><div id="clcn7.T.recommended_evaluations_followin_1" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with <i>CLCN7</i>-Related Autosomal Dominant Osteopetrosis Type II</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1127/table/clcn7.T.recommended_evaluations_followin_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__clcn7.T.recommended_evaluations_followin_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_clcn7.T.recommended_evaluations_followin_1_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_clcn7.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Osteosclerosis</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Baseline radiographic skeletal survey</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Anemia & thrombocytopenia</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CBC w/reticulocyte count</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurologic complications</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MRI &/or CT of neurocranium to evaluate for narrowed neuroforamina</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Visual impairment</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic exam incl VEPs to evaluate for optic nerve atrophy assoc w/optic nerve compression w/in skull base</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hearing loss</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Baseline audiologic assessment</td><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.recommended_evaluations_followin_1_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_clcn7.T.recommended_evaluations_followin_1_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_clcn7.T.recommended_evaluations_followin_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & their families re nature, MOI, & implications of <i>CLCN7</i>-related ADOII 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">ADOII = autosomal dominant osteopetrosis type II; MOI = mode of inheritance; VEP = visual evoked potential</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="clcn7.TF.6.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobclcn7Ttreatmentofmanifestationsini"><div id="clcn7.T.treatment_of_manifestations_in_i" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Infantile Malignant <i>CLCN7</i>-Related Autosomal Recessive Osteopetrosis (ARO)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1127/table/clcn7.T.treatment_of_manifestations_in_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__clcn7.T.treatment_of_manifestations_in_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/<br />Concern</th><th id="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_clcn7.T.treatment_of_manifestations_in_i_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_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hypocalcemic</b>
|
|
<br />
|
|
<b>convulsions</b>
|
|
</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Calcium supplementation <sup>1</sup></td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Bone marrow</b>
|
|
<br />
|
|
<b>failure</b>
|
|
</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Erythrocyte or platelet transfusions (irradiated products) as needed</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In case of leukocytopenia &/or hypogammaglobulinemia, which may develop in a subset of persons, antibiotics & immunoglobulins may be given in a prophylactic or therapeutic manner.</td></tr><tr><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Newly diagnosed persons should be transferred as soon as possible to pediatric center experienced in allogeneic HSCT in this disease.</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#clcn7.Prevention_of_Primary_Manifestatio">Prevention of Primary Manifestations</a>.</td></tr><tr><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurologic</b>
|
|
<br />
|
|
<b>issues</b>
|
|
</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The collaboration of pediatricians, pediatric neurologists, ophthalmologists, & psychologists is required to determine best treatment.</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Visual</b>
|
|
<br />
|
|
<b>impairment</b>
|
|
</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Surgical decompression of optic nerve, a difficult procedure, has been performed w/some success to prevent vision loss in those w/ARO in general [<a class="bibr" href="#clcn7.REF.hwang.2000.328" rid="clcn7.REF.hwang.2000.328">Hwang et al 2000</a>].</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hearing loss</b>
|
|
</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing aids</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Fractures</b>
|
|
</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment by orthopedist w/experience w/ARO in collaboration w/treating pediatrician</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Dental issues</b>
|
|
</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment as needed by dentist</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Oral surgery may be needed for defective tooth eruption, ankylosis, abscesses, & formation of cysts & fistulas.</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">ARO = autosomal recessive osteopetrosis; HSCT = hematopoietic stem cell transplantation</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="clcn7.TF.7.1"><p class="no_margin">The management of calcium homeostasis may be difficult and recommendations are conflicting: whereas physiologic doses of calcium and vitamin D have been used to treat children with osteopetrosis who have rickets, restriction of calcium and vitamin D has been used to prevent progression of disease and hypercalcemic crisis following HSCT. Treatment needs to take into account the particular situation of the affected individual.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobclcn7Ttreatmentofmanifestationsini1"><div id="clcn7.T.treatment_of_manifestations_in_i_1" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with <i>CLCN7</i>-Related Autosomal Dominant Osteopetrosis Type II (ADOII)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1127/table/clcn7.T.treatment_of_manifestations_in_i_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__clcn7.T.treatment_of_manifestations_in_i_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_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_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Fractures</b>
|
|
</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment by orthopedist w/experience w/ADOII</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fractures near joints may require total joint arthroplasty [<a class="bibr" href="#clcn7.REF.strickland.2005.815" rid="clcn7.REF.strickland.2005.815">Strickland & Berry 2005</a>].</td></tr><tr><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Arthritis</b>
|
|
</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Medical treatment w/anti-inflammatory agents</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Anemia & thrombocytopenia</b>
|
|
</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Transfusions</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Visual impairment</b>
|
|
</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Surgical optic nerve decompression</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hearing loss</b>
|
|
</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing aids</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Dental issues</b>
|
|
</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Regular dental care & good oral hygiene</td><td headers="hd_h_clcn7.T.treatment_of_manifestations_in_i_1_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">ADOII = autosomal dominant osteopetrosis type II</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobclcn7Trecommendedsurveillanceforind"><div id="clcn7.T.recommended_surveillance_for_ind" class="table"><h3><span class="label">Table 9. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Infantile Malignant <i>CLCN7</i>-Related Autosomal Recessive Osteopetrosis (ARO)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1127/table/clcn7.T.recommended_surveillance_for_ind/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__clcn7.T.recommended_surveillance_for_ind_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_clcn7.T.recommended_surveillance_for_ind_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_clcn7.T.recommended_surveillance_for_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Bone marrow failure</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CBC</td><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Annually at a minimum</td></tr><tr><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Visual loss</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmic exam</td></tr><tr><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hearing loss</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologic eval</td></tr><tr><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Dental issues</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dental eval</td><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 6-12 mos or as directed</td></tr><tr><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Potential for graft failure after HSCT</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Transplant center surveillance</td><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As directed by specialists</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">CBC = complete blood count; HSCT = hematopoietic stem cell transplantation</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobclcn7Trecommendedsurveillanceforind1"><div id="clcn7.T.recommended_surveillance_for_ind_1" class="table"><h3><span class="label">Table 10. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with <i>CLCN7</i>-Related Autosomal Dominant Osteopetrosis Type II (ADOII)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1127/table/clcn7.T.recommended_surveillance_for_ind_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__clcn7.T.recommended_surveillance_for_ind_1_lrgtbl__"><table><thead><tr><th id="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_clcn7.T.recommended_surveillance_for_ind_1_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_clcn7.T.recommended_surveillance_for_ind_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Anemia & thrombocytopenia</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CBC</td><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">At least annually</td></tr><tr><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Visual loss</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmic exam</td></tr><tr><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hearing loss</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologic eval</td></tr><tr><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Dental issues</b>
|
|
</td><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dental eval</td><td headers="hd_h_clcn7.T.recommended_surveillance_for_ind_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 6-12 mos or as directed</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobclcn7molgenTA"><div id="clcn7.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>CLCN7-Related Osteopetrosis: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1127/table/clcn7.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__clcn7.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_clcn7.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_clcn7.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_clcn7.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_clcn7.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_clcn7.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_clcn7.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_clcn7.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="/gene/1186" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
|
<i>CLCN7</i>
|
|
</a>
|
|
</td><td headers="hd_b_clcn7.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=1186" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">16p13<wbr style="display:inline-block"></wbr>​.3</a>
|
|
</td><td headers="hd_b_clcn7.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/P51798" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">H(+)/Cl(-) exchange transporter 7</a>
|
|
</td><td headers="hd_b_clcn7.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://databases.lovd.nl/shared/genes/CLCN7" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CLCN7 database</a>
|
|
</td><td headers="hd_b_clcn7.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=CLCN7" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CLCN7</a>
|
|
</td><td headers="hd_b_clcn7.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=CLCN7[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CLCN7</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="clcn7.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="figobclcn7molgenTB"><div id="clcn7.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for CLCN7-Related Osteopetrosis (<a href="/omim/166600,602727,611490" 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/NBK1127/table/clcn7.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__clcn7.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/166600" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">166600</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OSTEOPETROSIS, AUTOSOMAL DOMINANT 2; OPTA2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/602727" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">602727</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CHLORIDE CHANNEL 7; CLCN7</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/611490" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">611490</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OSTEOPETROSIS, AUTOSOMAL RECESSIVE 4; OPTB4</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobclcn7Tnotableclcn7pathogenicvariant"><div id="clcn7.T.notable_clcn7_pathogenic_variant" class="table"><h3><span class="label">Table 11. </span></h3><div class="caption"><p>Notable <i>CLCN7</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1127/table/clcn7.T.notable_clcn7_pathogenic_variant/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__clcn7.T.notable_clcn7_pathogenic_variant_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_clcn7.T.notable_clcn7_pathogenic_variant_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_clcn7.T.notable_clcn7_pathogenic_variant_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_clcn7.T.notable_clcn7_pathogenic_variant_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_clcn7.T.notable_clcn7_pathogenic_variant_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_clcn7.T.notable_clcn7_pathogenic_variant_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001287.6" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_001287<wbr style="display:inline-block"></wbr>​.6</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_001278.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_001278<wbr style="display:inline-block"></wbr>​.1</a>
|
|
</td><td headers="hd_h_clcn7.T.notable_clcn7_pathogenic_variant_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.643G>A</td><td headers="hd_h_clcn7.T.notable_clcn7_pathogenic_variant_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly215Arg</td><td headers="hd_h_clcn7.T.notable_clcn7_pathogenic_variant_1_1_1_4" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent pathogenic variants assoc w/ADOII [<a class="bibr" href="#clcn7.REF.cleiren.2001.2861" rid="clcn7.REF.cleiren.2001.2861">Cleiren et al 2001</a>]</td></tr><tr><td headers="hd_h_clcn7.T.notable_clcn7_pathogenic_variant_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.856C>T</td><td headers="hd_h_clcn7.T.notable_clcn7_pathogenic_variant_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg286Trp</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">ADOII = autosomal dominant osteopetrosis type II</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></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></div></div></div></article><article data-type="fig" id="figobclcn7F1"><div id="clcn7.F1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK1127/bin/clcn7-Image001.jpg" alt="Figure 1. " /></div><h3><span class="label">Figure 1. </span></h3><div class="caption"><p>Autosomal recessive osteopetrosis radiographs</p></div></div></article><article data-type="fig" id="figobclcn7F2"><div id="clcn7.F2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK1127/bin/clcn7-Image002.jpg" alt="Figure 2. " /></div><h3><span class="label">Figure 2. </span></h3><div class="caption"><p>Autosomal dominant osteopetrosis type II radiographs</p><p>Reprinted from <a class="bibr" href="#clcn7.REF.b_nichou.2000.87" rid="clcn7.REF.b_nichou.2000.87">Bénichou et al [2000]</a> with permission from Elsevier</p></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 portal106 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>
|