582 lines
No EOL
154 KiB
HTML
582 lines
No EOL
154 KiB
HTML
<?xml version="1.0" encoding="utf-8"?>
|
||
<!DOCTYPE html PUBLIC "-//W3C//DTD XHTML 1.0 Transitional//EN" "http://www.w3.org/TR/xhtml1/DTD/xhtml1-transitional.dtd">
|
||
<html xmlns="http://www.w3.org/1999/xhtml" xml:lang="en" lang="en">
|
||
|
||
<head><meta http-equiv="Content-Type" content="text/html; charset=utf-8" />
|
||
<!-- AppResources meta begin -->
|
||
<meta name="paf-app-resources" content="" />
|
||
<script type="text/javascript">var ncbi_startTime = new Date();</script>
|
||
|
||
<!-- AppResources meta end -->
|
||
|
||
<!-- TemplateResources meta begin -->
|
||
<meta name="paf_template" content="" />
|
||
|
||
<!-- TemplateResources meta end -->
|
||
|
||
<!-- Logger begin -->
|
||
<meta name="ncbi_db" content="books" /><meta name="ncbi_pdid" content="book-part" /><meta name="ncbi_acc" content="NBK476671" /><meta name="ncbi_domain" content="gene" /><meta name="ncbi_report" content="record" /><meta name="ncbi_type" content="fulltext" /><meta name="ncbi_objectid" content="" /><meta name="ncbi_pcid" content="/NBK476671/" /><meta name="ncbi_pagename" content="X-Linked Acrogigantism - GeneReviews® - NCBI Bookshelf" /><meta name="ncbi_bookparttype" content="chapter" /><meta name="ncbi_app" content="bookshelf" />
|
||
<!-- Logger end -->
|
||
|
||
<title>X-Linked Acrogigantism - GeneReviews® - NCBI Bookshelf</title>
|
||
|
||
<!-- AppResources external_resources begin -->
|
||
<link rel="stylesheet" href="/core/jig/1.15.2/css/jig.min.css" /><script type="text/javascript" src="/core/jig/1.15.2/js/jig.min.js"></script>
|
||
|
||
<!-- AppResources external_resources end -->
|
||
|
||
<!-- Page meta begin -->
|
||
<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="X-Linked Acrogigantism" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2018/02/01" /><meta name="citation_author" content="Donato Iacovazzo" /><meta name="citation_author" content="Márta Korbonits" /><meta name="citation_pmid" content="29389097" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK476671/" /><meta name="citation_keywords" content="Chromosome Xq26.3 Duplication Syndrome" /><meta name="citation_keywords" content="X-LAG" /><meta name="citation_keywords" content="XLAG" /><meta name="citation_keywords" content="XLAG" /><meta name="citation_keywords" content="X-LAG" /><meta name="citation_keywords" content="Chromosome Xq26.3 Duplication Syndrome" /><meta name="citation_keywords" content="Probable G-protein coupled receptor 101" /><meta name="citation_keywords" content="GPR101" /><meta name="citation_keywords" content="X-Linked Acrogigantism" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="X-Linked Acrogigantism" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Donato Iacovazzo" /><meta name="DC.Contributor" content="Márta Korbonits" /><meta name="DC.Date" content="2018/02/01" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK476671/" /><meta name="description" content="X-linked acrogigantism is the occurrence of pituitary gigantism in an individual heterozygous or hemizygous for a germline or somatic duplication of GPR101. X-linked acrogigantism is characterized by acceleration of linear growth in early childhood – in most cases during the first two years of life – due to growth hormone (GH) excess. Most individuals with X-linked acrogigantism present with associated hyperprolactinemia due to a mixed GH- and prolactin-secreting pituitary adenoma with or without associated hyperplasia; less commonly they develop diffuse hyperplasia of the GH- and prolactin-secreting pituitary cells without a pituitary adenoma. Most affected individuals are females. Growth acceleration is the main presenting feature; other frequently observed clinical features include enlargement of hands and feet, coarsening of the facial features, and increased appetite. Neurologic signs or symptoms are rarely present. Untreated X-linked acrogigantism can lead to markedly increased stature, with obvious severe physical and psychological sequelae." /><meta name="og:title" content="X-Linked Acrogigantism" /><meta name="og:type" content="book" /><meta name="og:description" content="X-linked acrogigantism is the occurrence of pituitary gigantism in an individual heterozygous or hemizygous for a germline or somatic duplication of GPR101. X-linked acrogigantism is characterized by acceleration of linear growth in early childhood – in most cases during the first two years of life – due to growth hormone (GH) excess. Most individuals with X-linked acrogigantism present with associated hyperprolactinemia due to a mixed GH- and prolactin-secreting pituitary adenoma with or without associated hyperplasia; less commonly they develop diffuse hyperplasia of the GH- and prolactin-secreting pituitary cells without a pituitary adenoma. Most affected individuals are females. Growth acceleration is the main presenting feature; other frequently observed clinical features include enlargement of hands and feet, coarsening of the facial features, and increased appetite. Neurologic signs or symptoms are rarely present. Untreated X-linked acrogigantism can lead to markedly increased stature, with obvious severe physical and psychological sequelae." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK476671/" /><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/x-ag/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK476671/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script><meta name="book-collection" content="NONE" />
|
||
|
||
<!-- Page meta end -->
|
||
<link rel="shortcut icon" href="//www.ncbi.nlm.nih.gov/favicon.ico" /><meta name="ncbi_phid" content="CE8CF8357D2AD411000000000049003E.m_13" />
|
||
<meta name='referrer' content='origin-when-cross-origin'/><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3852956/3985586/3808861/4121862/3974050/3917732/251717/4216701/14534/45193/4113719/3849091/3984811/3751656/4033350/3840896/3577051/3852958/4008682/4207974/4206132/4062871/12930/3964959/3854974/36029/4128070/9685/3549676/3609192/3609193/3609213/3395586.css" /><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3411343/3882866.css" media="print" /></head>
|
||
<body class="book-part">
|
||
<div class="grid">
|
||
<div class="col twelve_col nomargin shadow">
|
||
<!-- System messages like service outage or JS required; this is handled by the TemplateResources portlet -->
|
||
<div class="sysmessages">
|
||
<noscript>
|
||
<p class="nojs">
|
||
<strong>Warning:</strong>
|
||
The NCBI web site requires JavaScript to function.
|
||
<a href="/guide/browsers/#enablejs" title="Learn how to enable JavaScript" target="_blank">more...</a>
|
||
</p>
|
||
</noscript>
|
||
</div>
|
||
<!--/.sysmessage-->
|
||
<div class="wrap">
|
||
<div class="page">
|
||
<div class="top">
|
||
<div id="universal_header">
|
||
<section class="usa-banner">
|
||
<div class="usa-accordion">
|
||
<header class="usa-banner-header">
|
||
<div class="usa-grid usa-banner-inner">
|
||
<img src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/favicons/favicon-57.png" alt="U.S. flag" />
|
||
<p>An official website of the United States government</p>
|
||
<button class="non-usa-accordion-button usa-banner-button" aria-expanded="false" aria-controls="gov-banner-top" type="button">
|
||
<span class="usa-banner-button-text">Here's how you know</span>
|
||
</button>
|
||
</div>
|
||
</header>
|
||
<div class="usa-banner-content usa-grid usa-accordion-content" id="gov-banner-top" aria-hidden="true">
|
||
<div class="usa-banner-guidance-gov usa-width-one-half">
|
||
<img class="usa-banner-icon usa-media_block-img" src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/icon-dot-gov.svg" alt="Dot gov" />
|
||
<div class="usa-media_block-body">
|
||
<p>
|
||
<strong>The .gov means it's official.</strong>
|
||
<br />
|
||
Federal government websites often end in .gov or .mil. Before
|
||
sharing sensitive information, make sure you're on a federal
|
||
government site.
|
||
</p>
|
||
</div>
|
||
</div>
|
||
<div class="usa-banner-guidance-ssl usa-width-one-half">
|
||
<img class="usa-banner-icon usa-media_block-img" src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/icon-https.svg" alt="Https" />
|
||
<div class="usa-media_block-body">
|
||
<p>
|
||
<strong>The site is secure.</strong>
|
||
<br />
|
||
The <strong>https://</strong> ensures that you are connecting to the
|
||
official website and that any information you provide is encrypted
|
||
and transmitted securely.
|
||
</p>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
</section>
|
||
<div class="usa-overlay"></div>
|
||
<header class="ncbi-header" role="banner" data-section="Header">
|
||
|
||
<div class="usa-grid">
|
||
<div class="usa-width-one-whole">
|
||
|
||
<div class="ncbi-header__logo">
|
||
<a href="/" class="logo" aria-label="NCBI Logo" data-ga-action="click_image" data-ga-label="NIH NLM Logo">
|
||
<img src="https://www.ncbi.nlm.nih.gov/coreutils/nwds/img/logos/AgencyLogo.svg" alt="NIH NLM Logo" />
|
||
</a>
|
||
</div>
|
||
|
||
<div class="ncbi-header__account">
|
||
<a id="account_login" href="https://account.ncbi.nlm.nih.gov" class="usa-button header-button" style="display:none" data-ga-action="open_menu" data-ga-label="account_menu">Log in</a>
|
||
<button id="account_info" class="header-button" style="display:none" aria-controls="account_popup" type="button">
|
||
<span class="fa fa-user" aria-hidden="true">
|
||
<svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 24 24" width="20px" height="20px">
|
||
<g style="fill: #fff">
|
||
<ellipse cx="12" cy="8" rx="5" ry="6"></ellipse>
|
||
<path d="M21.8,19.1c-0.9-1.8-2.6-3.3-4.8-4.2c-0.6-0.2-1.3-0.2-1.8,0.1c-1,0.6-2,0.9-3.2,0.9s-2.2-0.3-3.2-0.9 C8.3,14.8,7.6,14.7,7,15c-2.2,0.9-3.9,2.4-4.8,4.2C1.5,20.5,2.6,22,4.1,22h15.8C21.4,22,22.5,20.5,21.8,19.1z"></path>
|
||
</g>
|
||
</svg>
|
||
</span>
|
||
<span class="username desktop-only" aria-hidden="true" id="uname_short"></span>
|
||
<span class="sr-only">Show account info</span>
|
||
</button>
|
||
</div>
|
||
|
||
<div class="ncbi-popup-anchor">
|
||
<div class="ncbi-popup account-popup" id="account_popup" aria-hidden="true">
|
||
<div class="ncbi-popup-head">
|
||
<button class="ncbi-close-button" data-ga-action="close_menu" data-ga-label="account_menu" type="button">
|
||
<span class="fa fa-times">
|
||
<svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 48 48" width="24px" height="24px">
|
||
<path d="M38 12.83l-2.83-2.83-11.17 11.17-11.17-11.17-2.83 2.83 11.17 11.17-11.17 11.17 2.83 2.83 11.17-11.17 11.17 11.17 2.83-2.83-11.17-11.17z"></path>
|
||
</svg>
|
||
</span>
|
||
<span class="usa-sr-only">Close</span></button>
|
||
<h4>Account</h4>
|
||
</div>
|
||
<div class="account-user-info">
|
||
Logged in as:<br />
|
||
<b><span class="username" id="uname_long">username</span></b>
|
||
</div>
|
||
<div class="account-links">
|
||
<ul class="usa-unstyled-list">
|
||
<li><a id="account_myncbi" href="/myncbi/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_myncbi">Dashboard</a></li>
|
||
<li><a id="account_pubs" href="/myncbi/collections/bibliography/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_pubs">Publications</a></li>
|
||
<li><a id="account_settings" href="/account/settings/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_settings">Account settings</a></li>
|
||
<li><a id="account_logout" href="/account/signout/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_logout">Log out</a></li>
|
||
</ul>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
</div>
|
||
</div>
|
||
</header>
|
||
<div role="navigation" aria-label="access keys">
|
||
<a id="nws_header_accesskey_0" href="https://www.ncbi.nlm.nih.gov/guide/browsers/#ncbi_accesskeys" class="usa-sr-only" accesskey="0" tabindex="-1">Access keys</a>
|
||
<a id="nws_header_accesskey_1" href="https://www.ncbi.nlm.nih.gov" class="usa-sr-only" accesskey="1" tabindex="-1">NCBI Homepage</a>
|
||
<a id="nws_header_accesskey_2" href="/myncbi/" class="set-base-url usa-sr-only" accesskey="2" tabindex="-1">MyNCBI Homepage</a>
|
||
<a id="nws_header_accesskey_3" href="#maincontent" class="usa-sr-only" accesskey="3" tabindex="-1">Main Content</a>
|
||
<a id="nws_header_accesskey_4" href="#" class="usa-sr-only" accesskey="4" tabindex="-1">Main Navigation</a>
|
||
</div>
|
||
<section data-section="Alerts">
|
||
<div class="ncbi-alerts-placeholder"></div>
|
||
</section>
|
||
</div>
|
||
<div class="header">
|
||
<div class="res_logo"><h1 class="res_name"><a href="/books/" title="Bookshelf home">Bookshelf</a></h1><h2 class="res_tagline"></h2></div>
|
||
<div class="search"><form method="get" action="/books/"><div class="search_form"><label for="database" class="offscreen_noflow">Search database</label><select id="database"><optgroup label="Recent"><option value="books" selected="selected" data-ac_dict="bookshelf-search">Books</option><option value="pubmed">PubMed</option><option value="clinvar">ClinVar</option><option value="medgen" class="last">MedGen</option></optgroup><optgroup label="All"><option value="gquery">All Databases</option><option value="assembly">Assembly</option><option value="biocollections">Biocollections</option><option value="bioproject">BioProject</option><option value="biosample">BioSample</option><option value="books" data-ac_dict="bookshelf-search">Books</option><option value="clinvar">ClinVar</option><option value="cdd">Conserved Domains</option><option value="gap">dbGaP</option><option value="dbvar">dbVar</option><option value="gene">Gene</option><option value="genome">Genome</option><option value="gds">GEO DataSets</option><option value="geoprofiles">GEO Profiles</option><option value="gtr">GTR</option><option value="ipg">Identical Protein Groups</option><option value="medgen">MedGen</option><option value="mesh">MeSH</option><option value="nlmcatalog">NLM Catalog</option><option value="nuccore">Nucleotide</option><option value="omim">OMIM</option><option value="pmc">PMC</option><option value="protein">Protein</option><option value="proteinclusters">Protein Clusters</option><option value="protfam">Protein Family Models</option><option value="pcassay">PubChem BioAssay</option><option value="pccompound">PubChem Compound</option><option value="pcsubstance">PubChem Substance</option><option value="pubmed">PubMed</option><option value="snp">SNP</option><option value="sra">SRA</option><option value="structure">Structure</option><option value="taxonomy">Taxonomy</option><option value="toolkit">ToolKit</option><option value="toolkitall">ToolKitAll</option><option value="toolkitbookgh">ToolKitBookgh</option></optgroup></select><div class="nowrap"><label for="term" class="offscreen_noflow" accesskey="/">Search term</label><div class="nowrap"><input type="text" name="term" id="term" title="Search Books. Use up and down arrows to choose an item from the autocomplete." value="" class="jig-ncbiclearbutton jig-ncbiautocomplete" data-jigconfig="dictionary:'bookshelf-search',disableUrl:'NcbiSearchBarAutoComplCtrl'" autocomplete="off" data-sbconfig="ds:'no',pjs:'no',afs:'no'" /></div><button id="search" type="submit" class="button_search nowrap" cmd="go">Search</button></div></div></form><ul class="searchlinks inline_list"><li>
|
||
<a href="/books/browse/">Browse Titles</a>
|
||
</li><li>
|
||
<a href="/books/advanced/">Advanced</a>
|
||
</li><li class="help">
|
||
<a href="/books/NBK3833/">Help</a>
|
||
</li><li class="disclaimer">
|
||
<a target="_blank" data-ga-category="literature_resources" data-ga-action="link_click" data-ga-label="disclaimer_link" href="https://www.ncbi.nlm.nih.gov/books/about/disclaimer/">Disclaimer</a>
|
||
</li></ul></div>
|
||
</div>
|
||
|
||
|
||
|
||
<!--<component id="Page" label="headcontent"/>-->
|
||
|
||
</div>
|
||
<div class="content">
|
||
<!-- site messages -->
|
||
<!-- Custom content 1 -->
|
||
<div class="col1">
|
||
|
||
</div>
|
||
|
||
<div class="container">
|
||
<div id="maincontent" class="content eight_col col">
|
||
<!-- Custom content in the left column above book nav -->
|
||
<div class="col2">
|
||
|
||
</div>
|
||
|
||
<!-- Book content -->
|
||
|
||
|
||
<!-- Custom content between navigation and content -->
|
||
<div class="col3">
|
||
|
||
</div>
|
||
|
||
<div class="document">
|
||
<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK476671_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK476671_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/wss/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/x-ald/" title="Next page in this title">Next ></a></div></div></div></div></div>
|
||
<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK476671_"><span class="title" itemprop="name">X-Linked Acrogigantism</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Chromosome Xq26.3 Duplication Syndrome, X-LAG, XLAG</div><p class="contrib-group"><span itemprop="author">Donato Iacovazzo</span>, MD and <span itemprop="author">Márta Korbonits</span>, MD, PhD.</p><a data-jig="ncbitoggler" href="#__NBK476671_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK476671_ai__"><div class="contrib half_rhythm"><span itemprop="author">Donato Iacovazzo</span>, MD<div class="affiliation small">Department of Endocrinology
|
||
William Harvey Research Institute
|
||
Barts and the London School of Medicine
|
||
Queen Mary University of London
|
||
London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.ca.lumq@ozzavocai.d" class="oemail">ku.ca.lumq@ozzavocai.d</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Márta Korbonits</span>, MD, PhD<div class="affiliation small">Department of Endocrinology
|
||
William Harvey Research Institute
|
||
Barts and the London School of Medicine
|
||
Queen Mary University of London
|
||
London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.ca.lumq@stinobrok.m" class="oemail">ku.ca.lumq@stinobrok.m</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">February 1, 2018</span>.</p><p><em>Estimated reading time: 22 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="x-ag.Summary" itemprop="description"><h2 id="_x-ag_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism is the occurrence of pituitary gigantism in an individual <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> or <a class="def" href="/books/n/gene/glossary/def-item/hemizygous/">hemizygous</a> for a <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> or somatic <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> of <i>GPR101.</i> X-linked acrogigantism is characterized by acceleration of linear growth in early childhood – in most cases during the first two years of life – due to growth hormone (GH) excess. Most individuals with X-linked acrogigantism present with associated hyperprolactinemia due to a mixed GH- and prolactin-secreting pituitary adenoma with or without associated hyperplasia; less commonly they develop diffuse hyperplasia of the GH- and prolactin-secreting pituitary cells without a pituitary adenoma. Most affected individuals are females. Growth acceleration is the main presenting feature; other frequently observed clinical features include enlargement of hands and feet, coarsening of the facial features, and increased appetite. Neurologic signs or symptoms are rarely present. Untreated X-linked acrogigantism can lead to markedly increased stature, with obvious severe physical and psychological sequelae.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism is established in an individual with pituitary gigantism and a <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> or somatic <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> of <i>GPR101</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations</i>:</p><ul><li class="half_rhythm"><div>In patients with radiologic evidence of a pituitary adenoma: transsphenoidal surgery should be considered as first-line treatment as it can provide long-term control of the disease (although often at the cost of permanent hypopituitarism) and prevent excessive tumor growth; in those with persistent disease, GH receptor antagonist treatment should be promptly initiated and tailored to growth velocity and IGF-1 levels.</div></li><li class="half_rhythm"><div>In patients with radiologic evidence of hyperplasia without a pituitary tumor: first-line treatment with GH receptor antagonist should be considered as surgery (which is not usually recommended) can lead to disease remission only by means of a total hypophysectomy, invariably resulting in the need for lifelong pituitary hormone replacement treatment.</div></li><li class="half_rhythm"><div>In patients with associated hyperprolactinemia: a dopamine agonist should be employed.</div></li></ul><p><i>Surveillance:</i> Intensive monitoring of height, growth velocity, and pituitary function tests. Repeat pituitary MRI (with frequency based on presence of hyperplasia/tumor, previous extent of the tumor, treatment modality, clinical status, and disease activity). Routine surveillance for complications of GH excess (based on recommendations for patients with acromegaly).</p></div><div><h4 class="inline">Genetic counseling.</h4><p><a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism is inherited in an X-linked manner. The majority of affected individuals represent <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases (i.e., a single occurrence in a family) resulting from a <i>de novo GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a>; of note, all males who are simplex cases have had a somatic mosaic <i>GPR101</i> duplication. In the three reported instances of <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> X-linked acrogigantism, affected males inherited the <i>GPR101</i> duplication from their affected mothers. Females with X-linked acrogigantism have a 50% chance of transmitting the <i>GPR101</i> duplication in each pregnancy. While a male with a somatic mosaic <i>GPR101</i> duplication that involves germ cells could theoretically transmit the duplication to his daughters, and a male with a <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <i>GPR101</i> duplication will transmit the duplication to all of his daughters, to date male-to-female transmission has not been described. A male will not transmit the duplication to his sons. Offspring of either sex who inherit the <i>GPR101</i> duplication will be affected. Once the <i>GPR101</i> duplication has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p></div></div><div id="x-ag.Diagnosis"><h2 id="_x-ag_Diagnosis_">Diagnosis</h2><div id="x-ag.Suggestive_Findings"><h3>Suggestive Findings</h3><p><a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism <b>should be suspected</b> in an individual with early-onset pituitary gigantism, defined as acceleration of linear growth due to growth hormone (GH) excess. All individuals with X-linked acrogigantism reported to date have manifested the first signs of the disorder before age four years, with most manifesting the disease during the first two years of life.</p><p>
|
||
<b>Clinical findings</b>
|
||
</p><ul><li class="half_rhythm"><div>Accelerated growth velocity (>+2 SD) and/or abnormally tall stature (>+2 SD, adjusted for parental height). Note: When available, country-specific growth curves should be employed.</div></li><li class="half_rhythm"><div>Other frequently observed clinical features of GH excess: acral enlargement, coarse facial features, and increased appetite (~1/3 of cases)</div></li></ul><p>
|
||
<b>Laboratory findings</b>
|
||
</p><ul><li class="half_rhythm"><div>GH excess as demonstrated by:</div><ul><li class="half_rhythm"><div>Elevated levels of GH that do not suppress during an oral glucose tolerance test (OGTT) (1.75 g/kg of anhydrous glucose; maximum 75 g)</div></li><li class="half_rhythm"><div>Increased circulating age-adjusted IGF-1 levels</div></li></ul></li><li class="half_rhythm"><div>Hyperprolactinemia (seen in 26/28 reported individuals for whom data were available)</div></li></ul><p><b>Imaging findings</b> consistent with either of the following:</p><ul><li class="half_rhythm"><div>Pituitary macroadenoma (>10 mm in diameter) with or without associated hyperplasia (in 24 of 30 reported individuals with available data)</div></li><li class="half_rhythm"><div>Diffusely (even slightly) enlarged pituitary gland secondary to pituitary hyperplasia without an adenoma (in 6 of 30 reported individuals with available data)</div></li></ul><p>Note: Although none of the reported individuals presented with a microadenoma, this presentation is theoretically possible.</p><p><b>Histopathologic findings.</b> Pituitary adenomas observed in <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism have a peculiar sinusoidal and lobular architecture with frequent calcifications and follicle-like structures. Sparsely and densely granulated GH-secreting cells are admixed with cells secreting prolactin. Mitotic activity and the proliferation index Ki-67 are generally low [<a class="bk_pop" href="#x-ag.REF.beckers.2015.353">Beckers et al 2015</a>, <a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>].</p></div><div id="x-ag.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism is established in an individual with pituitary gigantism and a <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> or somatic <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> of <i>GPR101</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK476671/table/x-ag.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobxagTmoleculargenetictestingusedin">Table 1</a>) [<a class="bk_pop" href="#x-ag.REF.trivellin.2014.2363">Trivellin et al 2014</a>, <a class="bk_pop" href="#x-ag.REF.daly.2016b.221">Daly et al 2016b</a>, <a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>]. Although most (not all) individuals with X-linked acrogigantism have duplications of <i>GPR101</i> as well as <i>ARHGEF6</i>, <i>CD40LG</i>, and <i>RBMX</i>, to date it is unclear whether duplication of these other genes or the number of copies of <i>GPR101</i> influence diagnosis and/or prognosis.</p><p>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>:</p><ul><li class="half_rhythm"><div>Is female and a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case (i.e., a single occurrence in a family), the <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> is usually <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> (i.e., constitutional).</div></li><li class="half_rhythm"><div>Is male and a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case, the <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> is usually somatic with variable levels of <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a>. Although to date no males who are simplex cases have been identified with a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <i>GPR101</i> duplication, this remains a possibility.</div></li><li class="half_rhythm"><div>Has a family history consistent with an <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> pattern of early-onset pituitary gigantism, the <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> is likely to be <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a>.</div></li></ul><p>Molecular testing approaches used to identify <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> and somatic duplications can include <b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> testing</b> or <b><a class="def" href="/books/n/gene/glossary/def-item/chromosomal-microarray/">chromosomal microarray</a> analysis (CMA)</b>. Note: Sequence analysis of <i>GPR101</i> is not recommended as no pathogenic sequence variants have been identified to date in individuals with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> analysis of <i>GPR101</i> should be performed first on leukocyte DNA. If a <i>GPR101</i> duplication is not found on testing of leukocyte DNA, testing of DNA derived from other sources (e.g., pituitary tissue [if available], saliva, skin, tissue from previous surgery) is recommended – especially in <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> males whose <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> suggests <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism – as such testing may detect a somatic mosaic <i>GPR101</i> duplication not present in leukocyte DNA [<a class="bk_pop" href="#x-ag.REF.rodd.2016.1927">Rodd et al 2016</a>]. Note: Copy number variation droplet digital <a class="def" href="/books/n/gene/glossary/def-item/pcr/">PCR</a> is recommended as this technique can identify <i>GPR101</i> duplications and low-level <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a> with high <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> [<a class="bk_pop" href="#x-ag.REF.daly.2016b.221">Daly et al 2016b</a>, <a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>].</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Chromosomal microarray analysis (CMA)</b> may be used to detect genome-wide duplications (including <i>GPR101</i> duplications). However, standard <a class="def" href="/books/n/gene/glossary/def-item/cytogenetic/">cytogenetic</a> CMA may not correctly identify the <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> in all individuals with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism:</div><ul><li class="half_rhythm"><div>In one individual with a molecularly confirmed diagnosis of <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism, the length of the <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> was below the <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the standard genome-wide array employed [<a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>].</div></li><li class="half_rhythm"><div>Low-level <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a> may not be identified.</div></li></ul><div class="half_rhythm">Targeted CMA with a higher density of probes in the Xq26.3 region – if available – can overcome such limitations [<a class="bk_pop" href="#x-ag.REF.trivellin.2014.2363">Trivellin et al 2014</a>, <a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>].</div></li></ul><div id="x-ag.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in X-Linked Acrogigantism</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK476671/table/x-ag.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ag.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ag.T.molecular_genetic_testing_used_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_x-ag.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_x-ag.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands <sup>2</sup> with a Pathogenic Variant <sup>3</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_x-ag.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>GPR101</i>
|
||
</td><td headers="hd_h_x-ag.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> analysis <sup>4, 5</sup></td><td headers="hd_h_x-ag.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">33/33 <sup>6, 7</sup></td></tr><tr><td headers="hd_h_x-ag.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Standard <a class="def" href="/books/n/gene/glossary/def-item/cytogenetic/">cytogenetic</a> <a class="def" href="/books/n/gene/glossary/def-item/chromosomal-microarray/">chromosomal microarray</a> analysis</td><td headers="hd_h_x-ag.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">31/33 <sup>6, 8</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="x-ag.TF.1.1"><p class="no_margin">See <a href="/books/NBK476671/#x-ag.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="x-ag.TF.1.2"><p class="no_margin">Thirty-three affected individuals have been described to date. Not all 33 were tested using both techniques; the authors have calculated the number of probands whose <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> would have been identified using both techniques.</p></div></dd><dt>3. </dt><dd><div id="x-ag.TF.1.3"><p class="no_margin">See <a href="#x-ag.Molecular_Genetics">Molecular Genetics</a> for information on allelic variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>4. </dt><dd><div id="x-ag.TF.1.4"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd><dt>5. </dt><dd><div id="x-ag.TF.1.5"><p class="no_margin">These methods will detect from single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> to whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions or duplications; however, breakpoints of large deletions/duplications and/or <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a>/<a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> of adjacent genes may not be detected by these methods. (Note: <i>GPR101</i> has a single coding exon).</p></div></dd><dt>6. </dt><dd><div id="x-ag.TF.1.6"><p class="no_margin"><a class="bk_pop" href="#x-ag.REF.trivellin.2014.2363">Trivellin et al [2014]</a>, <a class="bk_pop" href="#x-ag.REF.beckers.2015.353">Beckers et al [2015]</a>, <a class="bk_pop" href="#x-ag.REF.daly.2016a.161">Daly et al [2016a]</a>, <a class="bk_pop" href="#x-ag.REF.daly.2016b.221">Daly et al [2016b]</a>, <a class="bk_pop" href="#x-ag.REF.naves.2016.236">Naves et al [2016]</a>, <a class="bk_pop" href="#x-ag.REF.gordon.2016.560">Gordon et al [2016]</a>, <a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al [2016]</a>, <a class="bk_pop" href="#x-ag.REF.rodd.2016.1927">Rodd et al [2016]</a>, <a class="bk_pop" href="#x-ag.REF.beckers.2017.l17">Beckers et al [2017]</a>. Note: The 26 individuals tested using both <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> analysis and standard CMA are represented in both rows of the table.</p></div></dd><dt>7. </dt><dd><div id="x-ag.TF.1.7"><p class="no_margin">In one male with <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a>, the <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> was not detected in leukocyte DNA but was detected in other tissues, including the pituitary [<a class="bk_pop" href="#x-ag.REF.rodd.2016.1927">Rodd et al 2016</a>].</p></div></dd><dt>8. </dt><dd><div id="x-ag.TF.1.8"><p class="no_margin">In two individuals, standard CMA did not identify the <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> (because of either its small size or low-level <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a>) [<a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>]. The duplications in these individuals were correctly identified using targeted CMA with higher density of probes in the Xq26.3 region.</p></div></dd></dl></div></div></div></div></div><div id="x-ag.Clinical_Characteristics"><h2 id="_x-ag_Clinical_Characteristics_">Clinical Characteristics</h2><div id="x-ag.Clinical_Description"><h3>Clinical Description</h3><p><a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism is characterized by marked growth acceleration due to growth hormone (GH) excess starting at an early age (see <a class="figpopup" href="/books/NBK476671/figure/x-ag.F1/?report=objectonly" target="object" rid-figpopup="figxagF1" rid-ob="figobxagF1">Figure 1</a>, <a class="figpopup" href="/books/NBK476671/figure/x-ag.F2/?report=objectonly" target="object" rid-figpopup="figxagF2" rid-ob="figobxagF2">Figure 2</a>, and <a class="figpopup" href="/books/NBK476671/figure/x-ag.F3/?report=objectonly" target="object" rid-figpopup="figxagF3" rid-ob="figobxagF3">Figure 3</a>). Most reported affected individuals (24/33) are females; clinical data are available for 30 individuals. In most individuals with X-linked acrogigantism GH excess results from a mixed GH- and prolactin-secreting pituitary macroadenoma (i.e., >10 mm). Less commonly, GH excess is caused by hyperplasia of the GH- and prolactin-secreting pituitary cells [<a class="bk_pop" href="#x-ag.REF.trivellin.2014.2363">Trivellin et al 2014</a>]; six of 30 individuals with available data had pituitary hyperplasia in the absence of a pituitary adenoma.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figxagF1" co-legend-rid="figlgndxagF1"><a href="/books/NBK476671/figure/x-ag.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figxagF1" rid-ob="figobxagF1"><img class="small-thumb" src="/books/NBK476671/bin/x-ag-Image001.gif" src-large="/books/NBK476671/bin/x-ag-Image001.jpg" alt="Figure 1. . Growth curve of a female patient with molecularly confirmed X-linked acrogigantism who presented at age five years with abnormally tall stature." /></a><div class="icnblk_cntnt" id="figlgndxagF1"><h4 id="x-ag.F1"><a href="/books/NBK476671/figure/x-ag.F1/?report=objectonly" target="object" rid-ob="figobxagF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">Growth curve of a female patient with molecularly confirmed X-linked acrogigantism who presented at age five years with abnormally tall stature. Her growth proceeded at a rapid pace despite treatment with somatostatin analogs (SSA) and dopamine agonists <a href="/books/NBK476671/figure/x-ag.F1/?report=objectonly" target="object" rid-ob="figobxagF1">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figxagF2" co-legend-rid="figlgndxagF2"><a href="/books/NBK476671/figure/x-ag.F2/?report=objectonly" target="object" title="Figure 2. " class="img_link icnblk_img figpopup" rid-figpopup="figxagF2" rid-ob="figobxagF2"><img class="small-thumb" src="/books/NBK476671/bin/x-ag-Image002.gif" src-large="/books/NBK476671/bin/x-ag-Image002.jpg" alt="Figure 2. " /></a><div class="icnblk_cntnt" id="figlgndxagF2"><h4 id="x-ag.F2"><a href="/books/NBK476671/figure/x-ag.F2/?report=objectonly" target="object" rid-ob="figobxagF2">Figure 2. </a></h4><p class="float-caption no_bottom_margin">Clinical and radiologic features of individuals with molecularly confirmed X-linked acrogigantism A-D. Girl (same patient as in Figure 1) age five years who presented with abnormally tall stature and no significant coarsening of the facial features</p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figxagF3" co-legend-rid="figlgndxagF3"><a href="/books/NBK476671/figure/x-ag.F3/?report=objectonly" target="object" title="Figure 3. " class="img_link icnblk_img figpopup" rid-figpopup="figxagF3" rid-ob="figobxagF3"><img class="small-thumb" src="/books/NBK476671/bin/x-ag-Image003.gif" src-large="/books/NBK476671/bin/x-ag-Image003.jpg" alt="Figure 3. . Patient age three years (right) at initial presentation, with her unaffected sister, age six years (left)." /></a><div class="icnblk_cntnt" id="figlgndxagF3"><h4 id="x-ag.F3"><a href="/books/NBK476671/figure/x-ag.F3/?report=objectonly" target="object" rid-ob="figobxagF3">Figure 3. </a></h4><p class="float-caption no_bottom_margin">Patient age three years (right) at initial presentation, with her unaffected sister, age six years (left). The diagnosis of X-linked acrogigantism was made at age 28 years [Iacovazzo et al 2016]. From Moran et al [1990]; republished with permission of <a href="/books/NBK476671/figure/x-ag.F3/?report=objectonly" target="object" rid-ob="figobxagF3">(more...)</a></p></div></div><p>The presenting feature in all affected individuals is growth acceleration, which can manifest as early as age two months [<a class="bk_pop" href="#x-ag.REF.trivellin.2014.2363">Trivellin et al 2014</a>, <a class="bk_pop" href="#x-ag.REF.beckers.2015.353">Beckers et al 2015</a>, <a class="bk_pop" href="#x-ag.REF.daly.2016a.161">Daly et al 2016a</a>, <a class="bk_pop" href="#x-ag.REF.daly.2016b.221">Daly et al 2016b</a>, <a class="bk_pop" href="#x-ag.REF.gordon.2016.560">Gordon et al 2016</a>, <a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>, <a class="bk_pop" href="#x-ag.REF.naves.2016.236">Naves et al 2016</a>, <a class="bk_pop" href="#x-ag.REF.rodd.2016.1927">Rodd et al 2016</a>, <a class="bk_pop" href="#x-ag.REF.beckers.2017.l17">Beckers et al 2017</a>]. All individuals with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism have manifested the first signs of the disorder before age four years, with most manifesting during the first two years of life. There is no difference in the clinical presentation between males and females.</p><p>Other manifestations – in order of frequency – include enlargement of hands and feet, coarsening of the facial features, and increased appetite [<a class="bk_pop" href="#x-ag.REF.beckers.2015.353">Beckers et al 2015</a>, <a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>]. Body mass index is also frequently increased at the time of diagnosis. Less frequently described findings are acanthosis nigricans, sleep apnea/snoring, excessive perspiration, diastema, abdominal distension, and skin thickening. Neurologic signs or symptoms are rarely present; intellectual disability has been reported in one affected individual only and was not clearly related to the <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> [<a class="bk_pop" href="#x-ag.REF.naves.2016.236">Naves et al 2016</a>]. While all individuals with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism are prepubertal at the time of presentation, untreated older individuals with hyperprolactinemia would be expected to develop signs of hypogonadism and/or delayed puberty.</p><p>Untreated <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism can lead to markedly increased stature with obvious severe physical and psychological sequelae. Moreover – as occurs in individuals with gigantism or acromegaly secondary to other causes – uncontrolled GH excess is associated with a significantly increased risk of cardiovascular, cerebrovascular, metabolic, neurologic, and orthopedic complications as well as decreased life expectancy [<a class="bk_pop" href="#x-ag.REF.tagliafico.2008.369">Tagliafico et al 2008</a>, <a class="bk_pop" href="#x-ag.REF.killinger.2010.713">Killinger et al 2010</a>, <a class="bk_pop" href="#x-ag.REF.jayasena.2011.220">Jayasena et al 2011</a>, <a class="bk_pop" href="#x-ag.REF.ritvonen.2016.469">Ritvonen et al 2016</a>].</p></div><div id="x-ag.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>To date, no <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a> are evident as the clinical phenotype of the single individual harboring a smaller <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> (encompassing <i>GPR101</i> only) was identical to the phenotype of other individuals whose duplications encompass <i>GPR101</i> and the neighboring genes on Xq26.3 [<a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>].</p><p>While a limited number of <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> males with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism have been reported to date, no differences have been observed between individuals with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> duplications and those with somatic mosaic duplications [<a class="bk_pop" href="#x-ag.REF.daly.2016b.221">Daly et al 2016b</a>, <a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>].</p></div><div id="x-ag.Penetrance"><h3>Penetrance</h3><p>All <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> females and <a class="def" href="/books/n/gene/glossary/def-item/hemizygous/">hemizygous</a> males described to date were affected.</p><p>In females who are <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases, the <i>GPR101</i> duplications arose <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> as demonstrated by the normal dosage of <i>GPR101</i> in samples from the unaffected parents. Moreover, in the three families described, all males who inherited the <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> from their affected mother were affected. Thus, based on currently available data the <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> for <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism appears to be 100%.</p></div><div id="x-ag.Nomenclature"><h3>Nomenclature</h3><p>The abbreviation X-LAG has traditionally been used in the medical literature as an abbreviation for <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism and the abbreviation XLAG for X-linked lissencephaly with ambiguous genitalia.</p></div><div id="x-ag.Prevalence"><h3>Prevalence</h3><p><a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism is extremely rare. To date, 33 individuals with a molecularly confirmed diagnosis have been reported [<a class="bk_pop" href="#x-ag.REF.trivellin.2014.2363">Trivellin et al 2014</a>, <a class="bk_pop" href="#x-ag.REF.beckers.2015.353">Beckers et al 2015</a>, <a class="bk_pop" href="#x-ag.REF.daly.2016a.161">Daly et al 2016a</a>, <a class="bk_pop" href="#x-ag.REF.naves.2016.236">Naves et al 2016</a>, <a class="bk_pop" href="#x-ag.REF.daly.2016b.221">Daly et al 2016b</a>, <a class="bk_pop" href="#x-ag.REF.gordon.2016.560">Gordon et al 2016</a>, <a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>, <a class="bk_pop" href="#x-ag.REF.rodd.2016.1927">Rodd et al 2016</a>, <a class="bk_pop" href="#x-ag.REF.beckers.2017.l17">Beckers et al 2017</a>].</p><p>In two series of individuals with pituitary gigantism who underwent genetic testing, <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism accounted for 10% of 143 affected individuals [<a class="bk_pop" href="#x-ag.REF.rostomyan.2015.745">Rostomyan et al 2015</a>] and 8% of 153 affected individuals [<a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>].</p><p><a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism accounts for approximately 20% of females with pituitary gigantism [<a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>] and approximately 65% of individuals whose symptoms appeared at or before age five years [Korbonits, unpublished data].</p></div></div><div id="x-ag.Genetically_Related_Allelic_Disorde"><h2 id="_x-ag_Genetically_Related_Allelic_Disorde_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> of <i>GPR101</i>.</p></div><div id="x-ag.Differential_Diagnosis"><h2 id="_x-ag_Differential_Diagnosis_">Differential Diagnosis</h2><p>Pituitary gigantism can be nonsyndromic or can be associated with other manifestations as part of a syndrome (<a class="figpopup" href="/books/NBK476671/figure/x-ag.F4/?report=objectonly" target="object" rid-figpopup="figxagF4" rid-ob="figobxagF4">Figure 4</a>) [<a class="bk_pop" href="#x-ag.REF.caimari.2016.5030">Caimari & Korbonits 2016</a>].</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figxagF4" co-legend-rid="figlgndxagF4"><a href="/books/NBK476671/figure/x-ag.F4/?report=objectonly" target="object" title="Figure 4. " class="img_link icnblk_img figpopup" rid-figpopup="figxagF4" rid-ob="figobxagF4"><img class="small-thumb" src="/books/NBK476671/bin/x-ag-Image004.gif" src-large="/books/NBK476671/bin/x-ag-Image004.jpg" alt="Figure 4. " /></a><div class="icnblk_cntnt" id="figlgndxagF4"><h4 id="x-ag.F4"><a href="/books/NBK476671/figure/x-ag.F4/?report=objectonly" target="object" rid-ob="figobxagF4">Figure 4. </a></h4><p class="float-caption no_bottom_margin">Syndromic and nonsyndromic genetic causes of pituitary gigantism </p></div></div><p>Approximately 50% of all individuals with pituitary gigantism have a known predisposing genetic variant [<a class="bk_pop" href="#x-ag.REF.rostomyan.2015.745">Rostomyan et al 2015</a>, <a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>].</p><p>The very young age at disease onset, female preponderance, and the absence of extrapituitary manifestations can help with the differential diagnosis of <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism (<a href="/books/NBK476671/table/x-ag.T.disorders_to_consider_in_the_diff/?report=objectonly" target="object" rid-ob="figobxagTdisorderstoconsiderinthediff">Table 2</a>).</p><div id="x-ag.T.disorders_to_consider_in_the_diff" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Disorders to Consider in the Differential Diagnosis of Pituitary Gigantism</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK476671/table/x-ag.T.disorders_to_consider_in_the_diff/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ag.T.disorders_to_consider_in_the_diff_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disease Name</th><th id="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Prevalence of<br />Pituitary<br />Disease by Sex</th><th id="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Age of Onset<br />of GH Excess</th><th id="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinically<br />Evident GH<br />Excess (%<br />of Affected<br />Persons)</th><th id="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_6" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pituitary Findings</th><th id="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_7" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Extrapituitary Manifestations</th></tr></thead><tbody><tr><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/mccune-albright/">McCune-Albright syndrome</a> <sup>1</sup></td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>GNAS</i> <sup>2</sup></td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Equal</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variable (~30% diagnosed < age 16 yrs)</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~20% <sup>3</sup></td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">GH-secreting pituitary adenoma or mixed GH- & prolactin-secreting pituitary adenoma &/or hyperplasia of GH- & prolactin-secreting pituitary cells</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Polyostotic fibrous dysplasia, café au lait spots, precocious puberty, other manifestations</td></tr><tr><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/men1/">Multiple endocrine neoplasia type 1</a> <sup>1</sup></td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>MEN1</i>
|
||
</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↑ Female <sup>4</sup></td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Typically adult-onset; gigantism is rare</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2%-5%</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">GH-secreting pituitary adenoma, mixed GH- & prolactin-secreting pituitary adenoma; pituitary hyperplasia secondary to a GHRH-secreting neuroendocrine tumor; other pituitary adenoma subtypes can occur: prolactinoma, NFPA, corticotropinoma.</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Primary hyperparathyroidism, pancreatic neuroendocrine tumors, other manifestations</td></tr><tr><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/carney/">Carney complex</a> <sup>1</sup></td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PRKAR1A</i>
|
||
<sup>5</sup></td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Equal</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Typically adult-onset, but gigantism can occur</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~10% <sup>6</sup></td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">GH-secreting pituitary adenoma or mixed GH- & prolactin-secreting pituitary adenoma &/or hyperplasia of GH- & prolactin-secreting pituitary cells; corticotropinomas described in 2 persons <sup>7</sup></td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Skin hyperpigmentation, myxomas, PPNAD, other manifestations</td></tr><tr><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/ipa/"><i>AIP</i>-related familial isolated pituitary adenoma</a> <sup>8</sup></td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>AIP</i>
|
||
</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↑ Male</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Typically 2nd decade of life</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~80%</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">GH- or mixed GH- & prolactin-secreting pituitary adenoma; pituitary hyperplasia rare; characteristically, can present w/pituitary apoplexy <sup>9</sup>; other pituitary adenoma subtypes can occur: prolactinoma, NFPA, corticotropinoma, thyrotropinoma</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No</td></tr><tr><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism <sup>8</sup></td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>GPR101</i>
|
||
</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↑ Female</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Early onset (in all cases < age 4 yrs)</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mixed GH- & prolactin-secreting pituitary adenoma &/or hyperplasia of GH- & prolactin-secreting pituitary cells; pituitary apoplexy not described</td><td headers="hd_h_x-ag.T.disorders_to_consider_in_the_diff_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">GH = growth hormone; GHRH = growth hormone-releasing hormone; NFPA = nonfunctioning pituitary adenoma; PPNAD = primary pigmented nodular adrenal disease</p></div></dd><dt>1. </dt><dd><div id="x-ag.TF.2.1"><p class="no_margin">Syndromic</p></div></dd><dt>2. </dt><dd><div id="x-ag.TF.2.2"><p class="no_margin">McCune-Albright syndrome is caused by early embryonic <a class="def" href="/books/n/gene/glossary/def-item/postzygotic/">postzygotic</a> somatic activating mutation of <i>GNAS</i></p></div></dd><dt>3. </dt><dd><div id="x-ag.TF.2.3"><p class="no_margin">Subclinical growth hormone excess has been described.</p></div></dd><dt>4. </dt><dd><div id="x-ag.TF.2.4"><p class="no_margin"><a class="bk_pop" href="#x-ag.REF.verg_s.2002.457">Vergès et al [2002]</a>, <a class="bk_pop" href="#x-ag.REF.de_laat.2016.182">de Laat et al [2016]</a></p></div></dd><dt>5. </dt><dd><div id="x-ag.TF.2.5"><p class="no_margin">Approximately 20% of families with Carney complex have been linked to 2p16. One individual with Carney complex (<1% of families with Carney complex) had a <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> rearrangement resulting in four copies of <i>PRKACB</i> [<a class="bk_pop" href="#x-ag.REF.forlino.2014.1065">Forlino et al 2014</a>]; the authors propose that this is a Carney complex-causing <a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a> variant.</p></div></dd><dt>6. </dt><dd><div id="x-ag.TF.2.6"><p class="no_margin">Most patients have subclinical GH excess.</p></div></dd><dt>7. </dt><dd><div id="x-ag.TF.2.7"><p class="no_margin"><a class="bk_pop" href="#x-ag.REF.hern_ndezram_rez.2017.918">Hernández-Ramírez et al [2017]</a>, <a class="bk_pop" href="#x-ag.REF.kiefer.2017.k7">Kiefer et al [2017]</a></p></div></dd><dt>8. </dt><dd><div id="x-ag.TF.2.8"><p class="no_margin">Nonsyndromic</p></div></dd><dt>9. </dt><dd><div id="x-ag.TF.2.9"><p class="no_margin">
|
||
<a class="bk_pop" href="#x-ag.REF.xekouki.2013.l11">Xekouki et al [2013]</a>
|
||
</p></div></dd></dl></div></div></div></div><div id="x-ag.Management"><h2 id="_x-ag_Management_">Management</h2><div id="x-ag.Evaluations_Following_Initial_Diagn"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and further management needs in an individual diagnosed with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism, the following evaluations are recommended:</p><ul><li class="half_rhythm"><div>Consultation with a specialist in pediatric endocrinology or endocrinology</div><ul><li class="half_rhythm"><div>Clinical assessment with special attention to signs and symptoms of growth hormone (GH) excess and hyperprolactinemia.</div></li><li class="half_rhythm"><div>Endocrine tests including spot GH (with dilution if above detection limit of the assay), IGF-1, and prolactin to assess for disease activity. LH, FSH, estradiol/testosterone, TSH, fT4, and 9 a.m. cortisol (and if needed dynamic testing) should also be checked in order to detect associated hypopituitarism.</div></li></ul></li><li class="half_rhythm"><div>Visual field evaluation to assess for mass effects due to an expanding pituitary tumor. Young children may need informal testing (e.g., observing eye movements toward small objects in different areas of the visual field).</div></li><li class="half_rhythm"><div>Pituitary MRI for evidence of pituitary hyperplasia or a pituitary tumor. In case of a pituitary tumor, extrasellar extension should be evaluated.</div></li><li class="half_rhythm"><div>Consultation with a clinical geneticist and/or genetic counselor</div></li></ul></div><div id="x-ag.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div id="x-ag.GH_Hypersecretion"><h4>GH Hypersecretion</h4><p>Pituitary gigantism secondary to <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism can be treated medically, surgically, and/or with radiotherapy.</p><p><b>Pituitary adenoma.</b> When MRI findings suggest the presence of a pituitary adenoma in patients with molecularly confirmed <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism, either transsphenoidal surgery or GH receptor antagonist therapy could be a first-line treatment option.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Transsphenoidal surgery</b> may provide long-term control of GH hypersecretion [<a class="bk_pop" href="#x-ag.REF.beckers.2015.353">Beckers et al 2015</a>, <a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>], although frequently at the cost of post-surgical hypopituitarism.</div><div class="half_rhythm">In case of persistent GH excess following surgery, the following are options:</div><ul><li class="half_rhythm"><div>Prompt initiation of GH receptor antagonist treatment with doses tailored to linear growth and IGF-1 levels. In most instances this treatment effectively controls GH excess and accelerated growth [<a class="bk_pop" href="#x-ag.REF.beckers.2015.353">Beckers et al 2015</a>, <a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>]. Of note, the combination of the GH receptor antagonist with a somatostatin analog could allow use of lower doses of the GH receptor antagonist.</div></li><li class="half_rhythm"><div>Repeat surgery or radiotherapy (conventional or radiosurgery). Note that because the effects of radiotherapy are often not immediately apparent, GH receptor antagonist therapy should be used while waiting to assess the efficacy of radiotherapy.</div></li></ul></li><li class="half_rhythm"><div class="half_rhythm"><b>GH receptor antagonist therapy</b> (with or without somatostatin analogs) could be considered as first-line treatment in selected patients (those with adenomas that do not reach or compress the optic chiasm), followed by close monitoring of the pituitary tumor by serial MRI. Transsphenoidal surgery should be performed in the event of tumor growth.</div></li></ul><p><b>Pituitary hyperplasia.</b> When imaging shows pituitary hyperplasia (i.e., a diffusely enlarged pituitary gland without clear evidence of a pituitary tumor), GH receptor antagonist therapy (with or without somatostatin analogs) can effectively control the disease [<a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>, <a class="bk_pop" href="#x-ag.REF.rodd.2016.1927">Rodd et al 2016</a>] and should be considered as first-line treatment. Note that surgery is not currently recommended because treatment requires total hypophysectomy with resulting lifelong pituitary hormone replacement therapy.</p></div><div id="x-ag.Hyperprolactinemia"><h4>Hyperprolactinemia</h4><p>Dopamine agonists (in appropriate dosages) can significantly reduce or normalize the prolactin levels and should be employed in patients with associated hyperprolactinemia [<a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>].</p></div></div><div id="x-ag.Surveillance"><h3>Surveillance</h3><p>Patients with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism require the following:</p><ul><li class="half_rhythm"><div>Intensive monitoring of height and growth velocity, and frequent clinical assessment for other manifestations of GH excess (including enlargement of the extremities, hyperhydrosis, headache, joint pain) and/or enlargement of a pituitary adenoma (visual field deficits)</div></li><li class="half_rhythm"><div>Intensive monitoring of pituitary function tests (spot GH, IGF-1, prolactin) to determine disease activity and response to treatment. Note: Frequency depends on control of GH excess, clinical status, compliance with treatment, treatment modality, and presence of comorbidities.</div></li><li class="half_rhythm"><div>Periodic evaluation of basal hormone tests (9 a.m. cortisol, TSH, fT4, LH, FSH, estradiol/testosterone), and, if necessary, dynamic testing (e.g., growth hormone stimulation tests, ACTH stimulation test) to evaluate for hypopituitarism. Note: Patients treated with radical neurosurgery and/or radiotherapy may develop GH deficiency and should receive GH replacement treatment as appropriate.</div></li><li class="half_rhythm"><div>Repeat pituitary MRI. Note: Frequency depends on previous extent of the tumor, treatment modality, clinical status, and disease activity.</div></li></ul><p>The established guidelines regarding surveillance for associated comorbidities and risk of secondary neoplasms for patients with acromegaly [<a class="bk_pop" href="#x-ag.REF.melmed.2013.294">Melmed et al 2013</a>] should be applied to patients with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism. These include the following:</p><ul><li class="half_rhythm"><div>Evaluation for associated comorbidities of GH excess (including hypertension, diabetes mellitus, sleep apnea, cardiovascular disease, osteoarthritis).</div></li><li class="half_rhythm"><div>Although this complication has not been reported in <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism, adults with active acromegaly (increased GH and age-adjusted IGF-1 levels) are at higher risk of developing colonic neoplasms. Thus, colonoscopy at age 40 years is advised with further surveillance at three- to ten-year intervals depending on the presence/absence of abnormalities in the initial colonoscopy and levels of GH and IGF-1 [<a class="bk_pop" href="#x-ag.REF.cairns.2010.666">Cairns et al 2010</a>].</div></li></ul></div><div id="x-ag.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#x-ag.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="x-ag.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Considering the need for multimodal treatment and the associated high frequency of hypopituitarism, women with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism may need specific fertility treatment in order to conceive.</p><p>As medical treatment does not result in significant tumor shrinkage in patients with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism, the authors recommend that women with macroadenomas undergo surgery to reduce the adenoma size prior to consideration of pregnancy.</p><p>Women with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism who have a pituitary macroadenoma may experience clinically significant enlargement of the adenoma during pregnancy. Thus, they should be questioned about symptoms that could indicate tumor growth (increased frequency of headaches, visual changes) and monitored clinically with serial visual field testing. In the presence of symptoms or new visual field abnormalities, an MRI should be performed.</p></div><div id="x-ag.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="http://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="x-ag.Genetic_Counseling"><h2 id="_x-ag_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="x-ag.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism is inherited in an X-linked manner; however, most individuals with X-linked acrogigantism have a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> genetic alteration not inherited from a parent.</p></div><div id="x-ag.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a female <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>All female probands reported to date have a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
|
||
<i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a>; vertical transmission of a <i>GPR101</i> duplication from an affected parent to a daughter has not been reported.</div></li><li class="half_rhythm"><div>Recommendations for the evaluation of parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with an apparent <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
|
||
<i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> include clinical evaluation and <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</div></li></ul><p>
|
||
<b>Parents of a male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>If a male is the only affected family member (i.e., a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case), the affected male most likely has <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a> for a <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> and his mother is not <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for the duplication. To date, all reported males who are simplex cases have a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> somatic mosaic <i>GPR101</i> duplication.</div></li><li class="half_rhythm"><div>If a male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has an affected sib, his mother is most likely <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for the <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a>. In the three reported instances of <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism, affected males inherited the <i>GPR101</i> duplication from affected mothers [<a class="bk_pop" href="#x-ag.REF.trivellin.2014.2363">Trivellin et al 2014</a>, <a class="bk_pop" href="#x-ag.REF.gordon.2016.560">Gordon et al 2016</a>]. Note: If the <i>GPR101</i> duplication cannot be detected in the leukocyte DNA of a mother with more than one affected child (one of whom is male), she most likely has <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> (maternal germline mosaicism has not been reported in X-linked acrogigantism but is a theoretic possibility).</div></li><li class="half_rhythm"><div>Clinical evaluation of the mother and review of the family history may help distinguish male probands with a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> somatic mosaic <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> from those with an inherited <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <i>GPR101</i> duplication. Molecular genetic testing of maternal leukocyte DNA can determine if the mother is <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for the <i>GPR101</i> duplication.</div></li><li class="half_rhythm"><div>The father of an affected male will not have the disorder nor will he be <a class="def" href="/books/n/gene/glossary/def-item/hemizygous/">hemizygous</a> for the <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a>; therefore, he does not require further evaluation/testing.</div></li></ul><p>
|
||
<b>Sibs of a female <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>Risk to sibs depends on the genetic status of the parents.</div></li><li class="half_rhythm"><div>All females reported to date have had a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
|
||
<i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a>, suggesting a low risk to sibs; however, risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> in one of the parents.</div></li></ul><p><b>Sibs of a male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Risk to sibs depends on the genetic status of the mother:</p><ul><li class="half_rhythm"><div>If the mother of a male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is not affected and the proband represents a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case (i.e., a single occurrence in a family), sibs are presumed to be at low risk as all simplex males reported to date have a somatic mosaic <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a>. However, risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of maternal <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>.</div></li><li class="half_rhythm"><div>If the mother of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is affected/has the <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a>, the chance of transmitting it in each pregnancy is 50%. Female and male sibs who inherit the <i>GPR101</i> duplication will be affected (see <a href="#x-ag.Penetrance">Penetrance</a>).</div></li></ul><p><b>Offspring of a female <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Each child of a female with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism has a 50% chance of inheriting the <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a>.</p><p>
|
||
<b>Offspring of a male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>If a male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a somatic mosaic <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> that involves germ cells, he could theoretically transmit the duplication to his daughters (who would be affected).</div></li><li class="half_rhythm"><div>A male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with a <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> will transmit the duplication to all of his daughters (who will be affected).</div></li><li class="half_rhythm"><div>A male <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> will not transmit the <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> to his sons.</div></li></ul><p><b>Other family members.</b> Given that most probands with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism reported to date have the disorder as a result of a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
|
||
<i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a>, the risk to other family members is presumed to be low.</p></div><div id="x-ag.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.</div></li></ul></div><div id="x-ag.Prenatal_Testing_and_Preimplantatio"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="x-ag.Resources"><h2 id="_x-ag_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>Familial Isolated Pituitary Adenoma (FIPA) Patients</b>
|
||
</div><div>United Kingdom</div><div><b>Email:</b> info@fipapatients.org</div><div>
|
||
<a href="https://www.qmul.ac.uk/fipa-patients/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">qmul.ac.uk/fipa-patients</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>AMEND Research Registry </b>
|
||
</div><div>Association for Multiple Endocrine Neoplasia Disorders</div><div>United Kingdom</div><div>
|
||
<a href="https://www.amend.org.uk/patients/research-opportunities/uk-national-men1-and-pnet-research-registry/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">amend.org.uk</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>FIPA Consortium Registry</b>
|
||
</div><div>
|
||
<i>Patients with <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> pituitary adenoma or childhood onset pituitary disease and their families are encouraged to contact the registry.</i>
|
||
</div><div><b>Email:</b> info@fipapatients.org</div><div>
|
||
<a href="https://www.qmul.ac.uk/fipa-patients/about-us/contact-us/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">fipapatients.org/contact</a>
|
||
</div></li></ul>
|
||
</div><div id="x-ag.Molecular_Genetics"><h2 id="_x-ag_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="x-ag.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>X-Linked Acrogigantism: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK476671/table/x-ag.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ag.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_x-ag.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_x-ag.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_x-ag.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_x-ag.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_x-ag.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_x-ag.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_x-ag.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/83550" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>GPR101</i>
|
||
</a>
|
||
</td><td headers="hd_b_x-ag.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=83550" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Xq26<wbr style="display:inline-block"></wbr>.3</a>
|
||
</td><td headers="hd_b_x-ag.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q96P66" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Probable G-protein coupled receptor 101</a>
|
||
</td><td headers="hd_b_x-ag.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.LOVD.nl/GPR101" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GPR101 @ LOVD</a>
|
||
</td><td headers="hd_b_x-ag.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=GPR101" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GPR101</a>
|
||
</td><td headers="hd_b_x-ag.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=GPR101[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GPR101</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="x-ag.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="x-ag.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for X-Linked Acrogigantism (<a href="/omim/300393,300942" 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/NBK476671/table/x-ag.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__x-ag.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/300393" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">300393</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">G PROTEIN-COUPLED RECEPTOR 101; GPR101</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/300942" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">300942</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CHROMOSOME Xq26.3 DUPLICATION SYNDROME</td></tr></tbody></table></div></div><div id="x-ag.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>The individuals originally described with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism harbored duplications of <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> Xq26.3 with a smallest region of overlap (SRO) encompassing four genes (<i>ARHGEF6</i>, <i>CD40LG</i>, <i>GPR101</i>, and <i>RBMX</i>) [<a class="bk_pop" href="#x-ag.REF.trivellin.2014.2363">Trivellin et al 2014</a>]. Of these genes, only <i>GPR101</i> was significantly overexpressed in the pituitary samples of affected individuals.</p><p>More recently, an individual with a typical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> and a complex <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> rearrangement was described [<a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>]. In this individual, high-density <a class="def" href="/books/n/gene/glossary/def-item/chromosomal-microarray/">chromosomal microarray</a> analysis revealed a proximal <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> followed by a normal copy segment and a distal duplication. The distal duplication allowed the definition of a novel SRO encompassing <i>GPR101</i> only, and not the neighboring genes on Xq26.3, thus proving the pathogenic role of <i>GPR101</i>.</p><p>Microhomologies, small insertions, or complex <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> rearrangements were identified at the breakpoint junctions in most individuals with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism. These mutational signatures suggest fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) as the causative mechanism [<a class="bk_pop" href="#x-ag.REF.trivellin.2014.2363">Trivellin et al 2014</a>, <a class="bk_pop" href="#x-ag.REF.daly.2016b.221">Daly et al 2016b</a>]. In one individual, the <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> was generated via an <i>Alu</i>-<i>Alu</i> mediated rearrangement [<a class="bk_pop" href="#x-ag.REF.iacovazzo.2016.56">Iacovazzo et al 2016</a>].</p><div id="x-ag.GPR101"><h4>
|
||
<i>GPR101</i>
|
||
</h4><p><b>Gene structure.</b>
|
||
<i>GPR101</i> comprises a single coding <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> (<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_054021.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_054021.1</a>) and encodes an orphan G-protein coupled receptor that is 508 amino acids long (<a href="https://www.ncbi.nlm.nih.gov/protein/NP_473362.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_473362.1</a>). Four <i>GPR101</i> <a class="def" href="/books/n/gene/glossary/def-item/isoforms/">isoforms</a> were identified, characterized by different 5' untranslated regions (UTRs) and a common 3'UTR [<a class="bk_pop" href="#x-ag.REF.trivellin.2016.97">Trivellin et al 2016</a>]. Based on <i>in silico</i> analyses, the putative <i>GPR101</i> promoter is localized within 2 kb upstream of the transcription start site [<a class="bk_pop" href="#x-ag.REF.trivellin.2016.97">Trivellin et al 2016</a>]. For a summary of <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> information, see <a href="/books/NBK476671/#x-ag.molgen.TA">Table A</a>.</p><p><b>Pathogenic variants.</b> All individuals with <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism harbor duplications of Xq26.3 (size ~500 kb). Such duplications are unique and have variable boundaries in individuals who represent <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases, while they are identical when transmitted within a family. Although in most cases the <a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> affects four genes (<i>ARHGEF6</i>, <i>CD40LG</i>, <i>GPR101</i>, and <i>RBMX</i>), the SRO among all individuals reported with X-linked acrogigantism encompasses <i>GPR101</i> only.</p><p><b>Normal <a class="def" href="/books/n/gene/glossary/def-item/gene-product/">gene product</a>.</b>
|
||
<i>GPR101</i> encodes a 508-amino acid protein. For a summary of protein information, see <a href="/books/NBK476671/#x-ag.molgen.TA">Table A</a>.</p><p>For information on <i>GPR101</i> variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, click <a href="/books/NBK476671/bin/x-ag-var_uncertain.pdf">here</a> (pdf).</p></div></div></div><div id="x-ag.References"><h2 id="_x-ag_References_">References</h2><div id="x-ag.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.beckers.2015.353">Beckers A, Lodish MB, Trivellin G, Rostomyan L, Lee M, Faucz FR, Yuan B, Choong CS, Caberg JH, Verrua E, Naves LA, Cheetham TD, Young J, Lysy PA, Petrossians P, Cotterill A, Shah NS, Metzger D, Castermans E, Ambrosio MR, Villa C, Strebkova N, Mazerkina N, Gaillard S, Barra GB, Casulari LA, Neggers SJ, Salvatori R, Jaffrain-Rea ML, Zacharin M, Santamaria BL, Zacharieva S, Lim EM, Mantovani G, Zatelli MC, Collins MT, Bonneville JF, Quezado M, Chittiboina P, Oldfield EH, Bours V, Liu P, de Herder W, Pellegata W, Lupski N JR, Daly AF, Stratakis CA. X-linked acrogigantism syndrome: clinical profile and therapeutic responses. <span><span class="ref-journal">Endocr Relat Cancer. </span>2015;<span class="ref-vol">22</span>:353–67.</span> [<a href="/pmc/articles/PMC4433400/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4433400</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25712922" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25712922</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.beckers.2017.l17">Beckers A, Fernandes D, Fina F, Novak M, Abati A, Rostomyan L, Thiry A, Ouafik L, Pasture B, Pinhasi R, Daly AF. Paleogenetic study of ancient DNA suggestive of X-linked acrogigantism. <span><span class="ref-journal">Endocr Relat Cancer. </span>2017;<span class="ref-vol">24</span>:L17–L20.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28049632" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28049632</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.caimari.2016.5030">Caimari F, Korbonits M. Novel genetic causes of pituitary adenomas. <span><span class="ref-journal">Clin Cancer Res. </span>2016;<span class="ref-vol">22</span>:5030–42.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27742789" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27742789</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.cairns.2010.666">Cairns SR, Scholefield JH, Steele RJ, Dunlop MG, Thomas HJ, Evans GD, Eaden JA, Rutter MD, Atkin WP, Saunders BP, Lucassen A, Jenkins P, Fairclough PD, Woodhouse CR., British Society of Gastroenterology, Association of Coloproctology for Great Britain and Ireland. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). <span><span class="ref-journal">Gut. </span>2010;<span class="ref-vol">59</span>:666–89.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20427401" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20427401</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.daly.2016a.161">Daly AF, Lysy P, Defilles C, Rostomyan L, Mohamed A, Caberg JH, Raverot V, Castermans E, Marbaix E, Maiter D, Brunelle C, Trivellin G, Stratakis CA, Bours V, Raftopoulos C, Beauloye V, Barlier A, Beckers A. Growth hormone releasing hormone excess and blockade in X-LAG syndrome. <span><span class="ref-journal">Endocr Relat Cancer. </span>2016a;<span class="ref-vol">23</span>:161–70.</span> [<a href="/pmc/articles/PMC6300999/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6300999</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26671997" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26671997</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.daly.2016b.221">Daly AF, Yuan B, Fina F, Caberg JH, Trivellin G, Rostomyan L, de Herder WW, Naves LA, Metzger D, Cuny T, Rabl W, Shah N, Jaffrain-Rea ML, Zatelli MC, Faucz FR, Castermans E, Nanni-Metellus I, Lodish M, Muhammad A, Palmeira L, Potorac I, Mantovani G, Neggers SJ, Klein M, Barlier A, Liu P, Ouafik L, Bours V, Lupski JR, Stratakis CA, Beckers A. Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects. <span><span class="ref-journal">Endocr Relat Cancer. </span>2016b;<span class="ref-vol">23</span>:221–33.</span> [<a href="/pmc/articles/PMC4877443/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4877443</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26935837" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26935837</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.de_laat.2016.182">de Laat JM, van der Luijt RB, Pieterman CR, Oostveen MP, Hermus AR, Dekkers OM, de Herder WW, van der Horst-Schrivers AN, Drent ML, Bisschop PH, Havekes B, Vriens MR, Valk GD. MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients. <span><span class="ref-journal">BMC Med. </span>2016;<span class="ref-vol">14</span>:182.</span> [<a href="/pmc/articles/PMC5109674/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5109674</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27842554" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27842554</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.forlino.2014.1065">Forlino A, Vetro A, Garavelli L, Ciccone R, London E, Stratakis CA, Zuffardi O. PRKACB and Carney complex. <span><span class="ref-journal">N Engl J Med. </span>2014;<span class="ref-vol">370</span>:1065–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24571725" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24571725</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.gordon.2016.560">Gordon RJ, Bell J, Chung WK, David R, Oberfield SE, Wardlaw SL. Childhood acromegaly due to X-linked acrogigantism: long term follow-up. <span><span class="ref-journal">Pituitary. </span>2016;<span class="ref-vol">19</span>:560–4.</span> [<a href="/pmc/articles/PMC5244823/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5244823</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27631333" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27631333</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.hern_ndezram_rez.2017.918">Hernández-Ramírez LC, Tatsi C, Lodish MB, Faucz FR, Pankratz N, Chittiboina P, Lane J, Kay DM, Valdes N, Dimopulos A, Mills JL, Stratakis CA. Corticotropinoma as a component of Carney complex. <span><span class="ref-journal">J Endocr Soc. </span>2017;<span class="ref-vol">1</span>:918–25.</span> [<a href="/pmc/articles/PMC5686778/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5686778</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29264542" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29264542</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.iacovazzo.2016.56">Iacovazzo D, Caswell R, Bunce B, Jose S, Yuan B, Hernandez-Ramirez LC, Kapur S, Caimari F, Evanson J, Ferrau F, Dang MN, Gabrovska P, Larkin SJ, Ansorge O, Rodd C, Vance ML, Ramirez-Renteria C, Mercado M, Goldstone AP, Buchfelder M, Burren CP, Gurlek A, Dutta P, Choong CS, Cheetham T, Trivellin G, Stratakis CA, Lopes MB, Grossman AB, Trouillas J, Lupski JR, Ellard S, Sampson JR, Roncaroli F, Korbonits M. Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. <span><span class="ref-journal">Acta Neuropathol Commun. </span>2016;<span class="ref-vol">4</span>:56.</span> [<a href="/pmc/articles/PMC4888203/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4888203</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27245663" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27245663</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.jayasena.2011.220">Jayasena CN, Comninos AN, Clarke H, Donaldson M, Meeran K, Dhillo W S. The effects of long-term growth hormone and insulin-like growth factor-1 exposure on the development of cardiovascular, cerebrovascular and metabolic co-morbidities in treated patients with acromegaly. <span><span class="ref-journal">Clin Endocrinol (Oxf). </span>2011;<span class="ref-vol">75</span>:220–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21521288" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21521288</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.kiefer.2017.k7">Kiefer FW, Winhofer Y, Iacovazzo D, Korbonits M, Wolfsberger S, Knosp E, Trautinger F, Hoftberger R, Krebs M, Luger A, Gessl A. PRKAR1A mutation causing pituitary-dependent Cushing disease in a patient with Carney complex. <span><span class="ref-journal">Eur J Endocrinol. </span>2017;<span class="ref-vol">177</span>:K7–K12.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28522647" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28522647</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.killinger.2010.713">Killinger Z, Payer J, Lazurova I, Imrich R, Homerova Z, Kuzma M, Rovensky J. Arthropathy in acromegaly. <span><span class="ref-journal">Rheum Dis Clin North Am. </span>2010;<span class="ref-vol">36</span>:713–20.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21092848" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21092848</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.melmed.2013.294">Melmed S, Casanueva FF, Klibanski A, Bronstein MD, Chanson P, Lamberts SW, Strasburger CJ, Wass JA, Giustina A. A consensus on the diagnosis and treatment of acromegaly complications. <span><span class="ref-journal">Pituitary. </span>2013;<span class="ref-vol">16</span>:294–302.</span> [<a href="/pmc/articles/PMC3730092/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3730092</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22903574" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22903574</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.moran.1990.322">Moran A, Asa SL, Kovacs K, Horvath E, Singer W, Sagman U, Reubi JC, Wilson CB, Larson R, Pescovitz OH. Gigantism due to pituitary mammosomatotroph hyperplasia. <span><span class="ref-journal">N Engl J Med. </span>1990;<span class="ref-vol">323</span>:322–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/2164153" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2164153</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.naves.2016.236">Naves LA, Daly AF, Dias LA, Yuan B, Zakir JC, Barra GB, Palmeira L, Villa C, Trivellin G, Junior AJ, Neto FF, Liu P, Pellegata NS, Stratakis CA, Lupski JR, Beckers A. Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome. <span><span class="ref-journal">Endocrine. </span>2016;<span class="ref-vol">51</span>:236–44.</span> [<a href="/pmc/articles/PMC5497487/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5497487</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26607152" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26607152</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.ritvonen.2016.469">Ritvonen E, Loyttyniemi E, Jaatinen P, Ebeling T, Moilanen L, Nuutila P, Kauppinen-Makelin R, Schalin-Jantti C. Mortality in acromegaly: a 20-year follow-up study. <span><span class="ref-journal">Endocr Relat Cancer. </span>2016;<span class="ref-vol">23</span>:469–80.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27185871" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27185871</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.rodd.2016.1927">Rodd C, Millette M, Iacovazzo D, Stiles CE, Barry S, Evanson J, Albrecht S, Caswell R, Bunce B, Jose S, Trouillas J, Roncaroli F, Sampson J, Ellard S, Korbonits M. Somatic GPR101 duplication causing X-linked acrogigantism (XLAG)-Diagnosis and management. <span><span class="ref-journal">J Clin Endocrinol Metab. </span>2016;<span class="ref-vol">101</span>:1927–30.</span> [<a href="/pmc/articles/PMC4870851/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4870851</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26982009" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26982009</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.rostomyan.2015.745">Rostomyan L, Daly AF, Petrossians P, Nachev E, Lila AR, Lecoq AL, Lecumberri B, Trivellin G, Salvatori R, Moraitis AG, Holdaway I, Kranenburg-van Klaveren DJ, Chiara Zatelli M, Palacios N, Nozieres C, Zacharin M, Ebeling T, Ojaniemi M, Rozhinskaya L, Verrua E, Jaffrain-Rea ML, Filipponi S, Gusakova D, Pronin V, Bertherat J, Belaya Z, Ilovayskaya I, Sahnoun-Fathallah M, Sievers C, Stalla GK, Castermans E, Caberg JH, Sorkina E, Auriemma RS, Mittal S, Kareva M, Lysy PA, Emy P, De Menis E, Choong CS, Mantovani G, Bours V, De Herder W, Brue T, Barlier A, Neggers SJ, Zacharieva S, Chanson P, Shah NS, Stratakis CA, Naves LA, Beckers A. Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. <span><span class="ref-journal">Endocr Relat Cancer. </span>2015;<span class="ref-vol">22</span>:745–57.</span> [<a href="/pmc/articles/PMC6533620/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6533620</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26187128" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26187128</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.tagliafico.2008.369">Tagliafico A, Resmini E, Nizzo R, Derchi LE, Minuto F, Giusti M, Martinoli C, Ferone D. The pathology of the ulnar nerve in acromegaly. <span><span class="ref-journal">Eur J Endocrinol. </span>2008;<span class="ref-vol">159</span>:369–73.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18632873" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18632873</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.trivellin.2014.2363">Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, Schernthaner-Reiter MH, Szarek E, Leal LF, Caberg JH, Castermans E, Villa C, Dimopoulos A, Chittiboina P, Xekouki P, Shah N, Metzger D, Lysy PA, Ferrante E, Strebkova N, Mazerkina N, Zatelli MC, Lodish M, Horvath A, de Alexandre RB, Manning AD, Levy I, Keil MF, Sierra Mde L, Palmeira L, Coppieters W, Georges M, Naves LA, Jamar M, Bours V, Wu TJ, Choong CS, Bertherat J, Chanson P, Kamenicky P, Farrell WE, Barlier A, Quezado M, Bjelobaba I, Stojilkovic SS, Wess J, Costanzi S, Liu P, Lupski JR, Beckers A, Stratakis CA. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. <span><span class="ref-journal">N Engl J Med. </span>2014;<span class="ref-vol">371</span>:2363–74.</span> [<a href="/pmc/articles/PMC4291174/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4291174</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25470569" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25470569</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.trivellin.2016.97">Trivellin G, Bjelobaba I, Daly AF, Larco DO, Palmeira L, Faucz FR, Thiry A, Leal LF, Rostomyan L, Quezado M, Schernthaner-Reiter MH, Janjic MM, Villa C, Wu TJ, Stojilkovic SS, Beckers A, Feldman B, Stratakis CA. Characterization of GPR101 transcript structure and expression patterns. <span><span class="ref-journal">J Mol Endocrinol. </span>2016;<span class="ref-vol">57</span>:97–111.</span> [<a href="/pmc/articles/PMC4959428/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4959428</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27282544" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27282544</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.verg_s.2002.457">Vergès B, Boureille F, Goudet P, Murat A, Beckers A, Sassolas G, Cougard P, Chambe B, Montvernay C, Calender A. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. <span><span class="ref-journal">J Clin Endocrinol Metab. </span>2002;2002;<span class="ref-vol">87</span>:457–65.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11836268" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11836268</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="x-ag.REF.xekouki.2013.l11">Xekouki P, Mastroyiannis SA, Avgeropoulos D, de la Luz Sierra M, Trivellin G, Gourgari EA, Lyssikatos C, Quezado M, Patronas N, Kanaka-Gantenbein C, Chrousos GP, Stratakis CA. Familial pituitary apoplexy as the only presentation of a novel AIP mutation. <span><span class="ref-journal">Endocr Relat Cancer. </span>2013;<span class="ref-vol">20</span>:L11–4.</span> [<a href="/pmc/articles/PMC3818689/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3818689</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24025584" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24025584</span></a>]</div></li></ul></div></div><div id="x-ag.Chapter_Notes"><h2 id="_x-ag_Chapter_Notes_">Chapter Notes</h2><div id="x-ag.Author_Notes"><h3>Author Notes</h3><p><b>Website:</b>
|
||
<a href="https://www.qmul.ac.uk/fipa-patients/about-us/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.fipapatients.org</a></p><p>The FIPA patients website, established by Dr Korbonits in collaboration with the <a href="https://www.qmul.ac.uk/fipa-patients/fipa-consortium/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FIPA Consortium</a>, is an information resource for patients and families with <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> pituitary adenoma (FIPA) and other rare conditions predisposing to pituitary adenomas. It also provides general information for medical professionals on <a href="https://www.qmul.ac.uk/fipa-patients/research/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">research</a> in this field, including <a href="https://www.qmul.ac.uk/fipa-patients/research/references/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">links to relevant publications</a>.</p><p>The authors welcome comments and inquiries to <a href="mailto:dev@null" data-email="gro.stneitapapif@ofni" class="oemail">gro.stneitapapif@ofni</a>.</p><p>Contact information for the laboratories that originally reported the genetic etiology of <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> acrogigantism and continue to actively conduct research on the condition is provided below:</p><p><b>Dr Constantine A Stratakis' laboratory</b><br />NIH/NICHD, DEB, SEGEN<br />10 Center Drive, CRC, Rm 1E-3216<br />Bethesda, MD 20892-1862 USA<br />Email: stratakc@cc1.nichd.nih.gov; giampaolo.trivellin@nih.gov<br />Phone: 301-402-1998; 301-451-8034<br />Website: <a href="https://science.nichd.nih.gov/confluence/display/segen/Pediatric+Gigantism+and+Acromegaly/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Pediatric Gigantism and Acromegaly</a></p><p><b>Prof Albert Beckers' laboratory</b><br />Department of Endocrinology CHU Sart Tilman B35<br />Domaine Universitaire du Sart-Tilman<br />University of Liège, 4000 Liège, Belgium<br />Email: albert.beckers@chu.ulg.ac.be; adrian.daly@ulg.ac.be<br />Phone: 0032 4 3667083</p></div><div id="x-ag.Acknowledgments"><h3>Acknowledgments</h3><p>We are grateful to referring colleagues and patients for providing information on this disease. We gratefully acknowledge Dr Celia Rodd (University of Manitoba, Winnipeg, Canada) and Dr Christine Burren (University Hospitals Bristol NHS Foundation Trust, Bristol, UK) for providing the patients' pictures.</p></div><div id="x-ag.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>1 February 2018 (bp) Review posted live</div></li><li class="half_rhythm"><div>19 October 2016 (mk) Original submission</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
|
||
<div class="post-content"><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 class="small"><span class="label">Bookshelf ID: NBK476671</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/29389097" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">29389097</a></span></div><div style="margin-top:2em" class="bk_noprnt"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/wss/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/x-ald/" title="Next page in this title">Next ></a></div></div></div></div>
|
||
|
||
</div>
|
||
|
||
<!-- Custom content below content -->
|
||
<div class="col4">
|
||
|
||
</div>
|
||
|
||
|
||
<!-- Book content -->
|
||
|
||
<!-- Custom contetnt below bottom nav -->
|
||
<div class="col5">
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div id="rightcolumn" class="four_col col last">
|
||
<!-- Custom content above discovery portlets -->
|
||
<div class="col6">
|
||
<div id="ncbi_share_book"><a href="#" class="ncbi_share" data-ncbi_share_config="popup:false,shorten:true" ref="id=NBK476671&db=books">Share</a></div>
|
||
|
||
</div>
|
||
<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK476671/?report=reader">PubReader</a></li><li><a href="/books/NBK476671/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK476671" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK476671" style="display:none" title="Cite this Page"><div class="bk_tt">Iacovazzo D, Korbonits M. X-Linked Acrogigantism. 2018 Feb 1. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK476671/pdf/Bookshelf_NBK476671.pdf">PDF version of this page</a> (2.1M)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this GeneReview</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#x-ag.Summary" ref="log$=inpage&link_id=inpage">Summary</a></li><li><a href="#x-ag.Diagnosis" ref="log$=inpage&link_id=inpage">Diagnosis</a></li><li><a href="#x-ag.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#x-ag.Genetically_Related_Allelic_Disorde" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#x-ag.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#x-ag.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#x-ag.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#x-ag.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#x-ag.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#x-ag.References" ref="log$=inpage&link_id=inpage">References</a></li><li><a href="#x-ag.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/ca/84/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download GeneReviews data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>GeneReviews Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/gene/advanced/"><i>GeneReviews</i> Advanced Search</a></li><li><a href="/books/n/gene/glossary/"><i>GeneReviews</i> Glossary</a></li><li><a href="/books/n/gene/resource_mats/">Resource Materials</a> <span class="bk_hlight1">NEW FEATURE</span></li><li><a href="/books/n/gene/updates/">New in <i>GeneReviews</i></a></li><li><a href="/books/n/gene/authors/">Author List</a></li><li><a href="/books/n/gene/prospective_authors/">For Current/Prospective Authors</a></li><li><a href="/books/n/gene/GRpersonnel/"><i>GeneReviews</i> Personnel</a></li><li><a href="/books/n/gene/howto_linkin/">Download/Link to <i>GeneReviews</i></a></li><li><a href="/books/n/gene/contact_us/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Tests in GTR by Gene</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
|
||
<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=83550[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">GPR101</a>
|
||
</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=omim&DbFrom=books&Cmd=Link&LinkName=books_omim&IdsFromResult=4497332" ref="log$=recordlinks">OMIM</a><div class="brieflinkpop offscreen_noflow">Related OMIM records</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=4497332" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=4497332" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=gene&DbFrom=books&Cmd=Link&LinkName=books_gene&IdsFromResult=4497332" ref="log$=recordlinks">Gene</a><div class="brieflinkpop offscreen_noflow">Locus Links</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301668" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hemophilia B.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hemophilia B.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Konkle BA, Nakaya Fletcher S. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/32491315" ref="ordinalpos=1&linkpos=2&log$=relatedarticles&logdbfrom=pubmed">Genetics, X-Linked Inheritance.</a><span class="source">[StatPearls. 2025]</span><div class="brieflinkpop offscreen_noflow">Genetics, X-Linked Inheritance.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Basta M, Pandya AM. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">StatPearls. 2025 Jan</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/24006547" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Ornithine Transcarbamylase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Ornithine Transcarbamylase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Lichter-Konecki U, Caldovic L, Morizono H, Simpson K, Ah Mew N, MacLeod E. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301578" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hemophilia A.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hemophilia A.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Konkle BA, Nakaya Fletcher S. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301631" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Citrullinemia Type I.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Citrullinemia Type I.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Quinonez SC, Lee KN. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=29389097" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=29389097" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67d2b17fa68b6b5afca4fb32">X-Linked Acrogigantism - GeneReviews®</a><div class="ralinkpop offscreen_noflow">X-Linked Acrogigantism - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=2" href="/portal/utils/pageresolver.fcgi?recordid=67d2b17ca68b6b5afca4e387">Woodhouse-Sakati Syndrome - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Woodhouse-Sakati Syndrome - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=3" href="/portal/utils/pageresolver.fcgi?recordid=67d2b17af4a390645e5bbdb9">Wilson Disease - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Wilson Disease - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=4" href="/portal/utils/pageresolver.fcgi?recordid=67d2b174f4a390645e5b9b91">Wiedemann-Steiner Syndrome - GeneReviews®</a><div class="ralinkpop offscreen_noflow">Wiedemann-Steiner Syndrome - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=5" href="/portal/utils/pageresolver.fcgi?recordid=67d2b171b15b832ebc3d5e47">White-Sutton Syndrome - GeneReviews®</a><div class="ralinkpop offscreen_noflow">White-Sutton Syndrome - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li></ul><p class="HTOn">Your browsing activity is empty.</p><p class="HTOff">Activity recording is turned off.</p><p id="turnOn" class="HTOff"><a href="javascript:historyDisplayState('HTOn')">Turn recording back on</a></p><a class="seemore" href="/sites/myncbi/recentactivity">See more...</a></div></div></div>
|
||
|
||
<!-- Custom content below discovery portlets -->
|
||
<div class="col7">
|
||
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<!-- Custom content after all -->
|
||
<div class="col8">
|
||
|
||
</div>
|
||
<div class="col9">
|
||
|
||
</div>
|
||
|
||
<script type="text/javascript" src="/corehtml/pmc/js/jquery.scrollTo-1.4.2.js"></script>
|
||
<script type="text/javascript">
|
||
(function($){
|
||
$('.skiplink').each(function(i, item){
|
||
var href = $($(item).attr('href'));
|
||
href.attr('tabindex', '-1').addClass('skiptarget'); // ensure the target can receive focus
|
||
$(item).on('click', function(event){
|
||
event.preventDefault();
|
||
$.scrollTo(href, 0, {
|
||
onAfter: function(){
|
||
href.focus();
|
||
}
|
||
});
|
||
});
|
||
});
|
||
})(jQuery);
|
||
</script>
|
||
</div>
|
||
<div class="bottom">
|
||
|
||
<div id="NCBIFooter_dynamic">
|
||
<!--<component id="Breadcrumbs" label="breadcrumbs"/>
|
||
<component id="Breadcrumbs" label="helpdesk"/>-->
|
||
|
||
</div>
|
||
|
||
<div class="footer" id="footer">
|
||
<section class="icon-section">
|
||
<div id="icon-section-header" class="icon-section_header">Follow NCBI</div>
|
||
<div class="grid-container container">
|
||
<div class="icon-section_container">
|
||
<a class="footer-icon" id="footer_twitter" href="https://twitter.com/ncbi" aria-label="Twitter"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<defs>
|
||
<style>
|
||
.cls-11 {
|
||
fill: #737373;
|
||
}
|
||
</style>
|
||
</defs>
|
||
<title>Twitter</title>
|
||
<path class="cls-11" d="M250.11,105.48c-7,3.14-13,3.25-19.27.14,8.12-4.86,8.49-8.27,11.43-17.46a78.8,78.8,0,0,1-25,9.55,39.35,39.35,0,0,0-67,35.85,111.6,111.6,0,0,1-81-41.08A39.37,39.37,0,0,0,81.47,145a39.08,39.08,0,0,1-17.8-4.92c0,.17,0,.33,0,.5a39.32,39.32,0,0,0,31.53,38.54,39.26,39.26,0,0,1-17.75.68,39.37,39.37,0,0,0,36.72,27.3A79.07,79.07,0,0,1,56,223.34,111.31,111.31,0,0,0,116.22,241c72.3,0,111.83-59.9,111.83-111.84,0-1.71,0-3.4-.1-5.09C235.62,118.54,244.84,113.37,250.11,105.48Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_facebook" href="https://www.facebook.com/ncbi.nlm" aria-label="Facebook"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<title>Facebook</title>
|
||
<path class="cls-11" d="M210.5,115.12H171.74V97.82c0-8.14,5.39-10,9.19-10h27.14V52l-39.32-.12c-35.66,0-42.42,26.68-42.42,43.77v19.48H99.09v36.32h27.24v109h45.41v-109h35Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_linkedin" href="https://www.linkedin.com/company/ncbinlm" aria-label="LinkedIn"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<title>LinkedIn</title>
|
||
<path class="cls-11" d="M101.64,243.37H57.79v-114h43.85Zm-22-131.54h-.26c-13.25,0-21.82-10.36-21.82-21.76,0-11.65,8.84-21.15,22.33-21.15S101.7,78.72,102,90.38C102,101.77,93.4,111.83,79.63,111.83Zm100.93,52.61A17.54,17.54,0,0,0,163,182v61.39H119.18s.51-105.23,0-114H163v13a54.33,54.33,0,0,1,34.54-12.66c26,0,44.39,18.8,44.39,55.29v58.35H198.1V182A17.54,17.54,0,0,0,180.56,164.44Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_github" href="https://github.com/ncbi" aria-label="GitHub"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<defs>
|
||
<style>
|
||
.cls-11,
|
||
.cls-12 {
|
||
fill: #737373;
|
||
}
|
||
|
||
.cls-11 {
|
||
fill-rule: evenodd;
|
||
}
|
||
</style>
|
||
</defs>
|
||
<title>GitHub</title>
|
||
<path class="cls-11" d="M151.36,47.28a105.76,105.76,0,0,0-33.43,206.1c5.28,1,7.22-2.3,7.22-5.09,0-2.52-.09-10.85-.14-19.69-29.42,6.4-35.63-12.48-35.63-12.48-4.81-12.22-11.74-15.47-11.74-15.47-9.59-6.56.73-6.43.73-6.43,10.61.75,16.21,10.9,16.21,10.9,9.43,16.17,24.73,11.49,30.77,8.79,1-6.83,3.69-11.5,6.71-14.14C108.57,197.1,83.88,188,83.88,147.51a40.92,40.92,0,0,1,10.9-28.39c-1.1-2.66-4.72-13.42,1-28,0,0,8.88-2.84,29.09,10.84a100.26,100.26,0,0,1,53,0C198,88.3,206.9,91.14,206.9,91.14c5.76,14.56,2.14,25.32,1,28a40.87,40.87,0,0,1,10.89,28.39c0,40.62-24.74,49.56-48.29,52.18,3.79,3.28,7.17,9.71,7.17,19.58,0,14.15-.12,25.54-.12,29,0,2.82,1.9,6.11,7.26,5.07A105.76,105.76,0,0,0,151.36,47.28Z">
|
||
</path>
|
||
<path class="cls-12" d="M85.66,199.12c-.23.52-1.06.68-1.81.32s-1.2-1.06-.95-1.59,1.06-.69,1.82-.33,1.21,1.07.94,1.6Zm-1.3-1">
|
||
</path>
|
||
<path class="cls-12" d="M90,203.89c-.51.47-1.49.25-2.16-.49a1.61,1.61,0,0,1-.31-2.19c.52-.47,1.47-.25,2.17.49s.82,1.72.3,2.19Zm-1-1.08">
|
||
</path>
|
||
<path class="cls-12" d="M94.12,210c-.65.46-1.71,0-2.37-.91s-.64-2.07,0-2.52,1.7,0,2.36.89.65,2.08,0,2.54Zm0,0"></path>
|
||
<path class="cls-12" d="M99.83,215.87c-.58.64-1.82.47-2.72-.41s-1.18-2.06-.6-2.7,1.83-.46,2.74.41,1.2,2.07.58,2.7Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M107.71,219.29c-.26.82-1.45,1.2-2.64.85s-2-1.34-1.74-2.17,1.44-1.23,2.65-.85,2,1.32,1.73,2.17Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M116.36,219.92c0,.87-1,1.59-2.24,1.61s-2.29-.68-2.3-1.54,1-1.59,2.26-1.61,2.28.67,2.28,1.54Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M124.42,218.55c.15.85-.73,1.72-2,1.95s-2.37-.3-2.52-1.14.73-1.75,2-2,2.37.29,2.53,1.16Zm0,0"></path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_blog" href="https://ncbiinsights.ncbi.nlm.nih.gov/" aria-label="Blog">
|
||
<svg xmlns="http://www.w3.org/2000/svg" id="Layer_1" data-name="Layer 1" viewBox="0 0 40 40">
|
||
<defs><style>.cls-1{fill:#737373;}</style></defs>
|
||
<title>NCBI Insights Blog</title>
|
||
<path class="cls-1" d="M14,30a4,4,0,1,1-4-4,4,4,0,0,1,4,4Zm11,3A19,19,0,0,0,7.05,15a1,1,0,0,0-1,1v3a1,1,0,0,0,.93,1A14,14,0,0,1,20,33.07,1,1,0,0,0,21,34h3a1,1,0,0,0,1-1Zm9,0A28,28,0,0,0,7,6,1,1,0,0,0,6,7v3a1,1,0,0,0,1,1A23,23,0,0,1,29,33a1,1,0,0,0,1,1h3A1,1,0,0,0,34,33Z"></path>
|
||
</svg>
|
||
</a>
|
||
</div>
|
||
</div>
|
||
</section>
|
||
|
||
<section class="container-fluid bg-primary">
|
||
<div class="container pt-5">
|
||
<div class="row mt-3">
|
||
<div class="col-lg-3 col-12">
|
||
<p><a class="text-white" href="https://www.nlm.nih.gov/socialmedia/index.html">Connect with NLM</a></p>
|
||
<ul class="list-inline social_media">
|
||
<li class="list-inline-item"><a href="https://twitter.com/NLM_NIH" aria-label="Twitter" target="_blank" rel="noopener noreferrer"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<style type="text/css">
|
||
.st20 {
|
||
fill: #FFFFFF;
|
||
}
|
||
|
||
.st30 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
</style>
|
||
<title>Twitter</title>
|
||
<g>
|
||
<g>
|
||
<g>
|
||
<path class="st20" d="M192.9,88.1c-5,2.2-9.2,2.3-13.6,0.1c5.7-3.4,6-5.8,8.1-12.3c-5.4,3.2-11.4,5.5-17.6,6.7 c-10.5-11.2-28.1-11.7-39.2-1.2c-7.2,6.8-10.2,16.9-8,26.5c-22.3-1.1-43.1-11.7-57.2-29C58,91.6,61.8,107.9,74,116 c-4.4-0.1-8.7-1.3-12.6-3.4c0,0.1,0,0.2,0,0.4c0,13.2,9.3,24.6,22.3,27.2c-4.1,1.1-8.4,1.3-12.5,0.5c3.6,11.3,14,19,25.9,19.3 c-11.6,9.1-26.4,13.2-41.1,11.5c12.7,8.1,27.4,12.5,42.5,12.5c51,0,78.9-42.2,78.9-78.9c0-1.2,0-2.4-0.1-3.6 C182.7,97.4,189.2,93.7,192.9,88.1z"></path>
|
||
</g>
|
||
</g>
|
||
<circle class="st30" cx="124.4" cy="128.8" r="108.2"></circle>
|
||
</g>
|
||
</svg></a></li>
|
||
<li class="list-inline-item"><a href="https://www.facebook.com/nationallibraryofmedicine" aria-label="Facebook" rel="noopener noreferrer" target="_blank">
|
||
<svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<style type="text/css">
|
||
.st10 {
|
||
fill: #FFFFFF;
|
||
}
|
||
|
||
.st110 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
</style>
|
||
<title>Facebook</title>
|
||
<g>
|
||
<g>
|
||
<path class="st10" d="M159,99.1h-24V88.4c0-5,3.3-6.2,5.7-6.2h16.8V60l-24.4-0.1c-22.1,0-26.2,16.5-26.2,27.1v12.1H90v22.5h16.9 v67.5H135v-67.5h21.7L159,99.1z"></path>
|
||
</g>
|
||
</g>
|
||
<circle class="st110" cx="123.6" cy="123.2" r="108.2"></circle>
|
||
</svg>
|
||
</a></li>
|
||
<li class="list-inline-item"><a href="https://www.youtube.com/user/NLMNIH" aria-label="Youtube" target="_blank" rel="noopener noreferrer"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<title>Youtube</title>
|
||
<style type="text/css">
|
||
.st4 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
|
||
.st5 {
|
||
fill: #FFFFFF;
|
||
}
|
||
</style>
|
||
<circle class="st4" cx="124.2" cy="123.4" r="108.2"></circle>
|
||
<g transform="translate(0,-952.36218)">
|
||
<path class="st5" d="M88.4,1037.4c-10.4,0-18.7,8.3-18.7,18.7v40.1c0,10.4,8.3,18.7,18.7,18.7h72.1c10.4,0,18.7-8.3,18.7-18.7 v-40.1c0-10.4-8.3-18.7-18.7-18.7H88.4z M115.2,1058.8l29.4,17.4l-29.4,17.4V1058.8z"></path>
|
||
</g>
|
||
</svg></a></li>
|
||
</ul>
|
||
</div>
|
||
<div class="col-lg-3 col-12">
|
||
<p class="address_footer text-white">National Library of Medicine<br />
|
||
<a href="https://www.google.com/maps/place/8600+Rockville+Pike,+Bethesda,+MD+20894/@38.9959508,-77.101021,17z/data=!3m1!4b1!4m5!3m4!1s0x89b7c95e25765ddb:0x19156f88b27635b8!8m2!3d38.9959508!4d-77.0988323" class="text-white" target="_blank" rel="noopener noreferrer">8600 Rockville Pike<br />
|
||
Bethesda, MD 20894</a></p>
|
||
</div>
|
||
<div class="col-lg-3 col-12 centered-lg">
|
||
<p><a href="https://www.nlm.nih.gov/web_policies.html" class="text-white">Web Policies</a><br />
|
||
<a href="https://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/freedom-information-act-office" class="text-white">FOIA</a><br />
|
||
<a href="https://www.hhs.gov/vulnerability-disclosure-policy/index.html" class="text-white" id="vdp">HHS Vulnerability Disclosure</a></p>
|
||
</div>
|
||
<div class="col-lg-3 col-12 centered-lg">
|
||
<p><a class="supportLink text-white" href="https://support.nlm.nih.gov/">Help</a><br />
|
||
<a href="https://www.nlm.nih.gov/accessibility.html" class="text-white">Accessibility</a><br />
|
||
<a href="https://www.nlm.nih.gov/careers/careers.html" class="text-white">Careers</a></p>
|
||
</div>
|
||
</div>
|
||
<div class="row">
|
||
<div class="col-lg-12 centered-lg">
|
||
<nav class="bottom-links">
|
||
<ul class="mt-3">
|
||
<li>
|
||
<a class="text-white" href="//www.nlm.nih.gov/">NLM</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.nih.gov/">NIH</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.hhs.gov/">HHS</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.usa.gov/">USA.gov</a>
|
||
</li>
|
||
</ul>
|
||
</nav>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
</section>
|
||
<script type="text/javascript" src="/portal/portal3rc.fcgi/rlib/js/InstrumentOmnitureBaseJS/InstrumentNCBIConfigJS/InstrumentNCBIBaseJS/InstrumentPageStarterJS.js?v=1"> </script>
|
||
<script type="text/javascript" src="/portal/portal3rc.fcgi/static/js/hfjs2.js"> </script>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
<!--/.page-->
|
||
</div>
|
||
<!--/.wrap-->
|
||
</div><!-- /.twelve_col -->
|
||
</div>
|
||
<!-- /.grid -->
|
||
|
||
<span class="PAFAppResources"></span>
|
||
|
||
<!-- BESelector tab -->
|
||
|
||
|
||
|
||
<noscript><img alt="statistics" src="/stat?jsdisabled=true&ncbi_db=books&ncbi_pdid=book-part&ncbi_acc=NBK476671&ncbi_domain=gene&ncbi_report=record&ncbi_type=fulltext&ncbi_objectid=&ncbi_pcid=/NBK476671/&ncbi_pagename=X-Linked Acrogigantism - GeneReviews® - NCBI Bookshelf&ncbi_bookparttype=chapter&ncbi_app=bookshelf" /></noscript>
|
||
|
||
|
||
<!-- usually for JS scripts at page bottom -->
|
||
<!--<component id="PageFixtures" label="styles"></component>-->
|
||
|
||
|
||
<!-- CE8B5AF87C7FFCB1_0191SID /projects/books/PBooks@9.11 portal105 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/3879255/4121861/3501987/4008961/3893018/3821238/4062932/4209313/4212053/4076480/3921943/3400083/3426610.js" snapshot="books"></script></body>
|
||
</html> |