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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Disorders of GNAS Inactivation" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2017/10/26" /><meta name="citation_author" content="Chad R Haldeman-Englert" /><meta name="citation_author" content="Anna CE Hurst" /><meta name="citation_author" content="Michael A Levine" /><meta name="citation_pmid" content="29072892" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK459117/" /><meta name="citation_keywords" content="Gsα Deficiency" /><meta name="citation_keywords" content="Gsa Deficiency" /><meta name="citation_keywords" content="Pseudohypoparathyroidism Ia (PHP-Ia)" /><meta name="citation_keywords" content="Progressive Osseus Heteroplasia (POH)" /><meta name="citation_keywords" content="Pseudohypoparathyroidism Ib (PHP-Ib)" /><meta name="citation_keywords" content="Guanine nucleotide-binding protein G(s) subunit alpha isoforms short" /><meta name="citation_keywords" content="Syntaxin-16" /><meta name="citation_keywords" content="GNAS" /><meta name="citation_keywords" content="STX16" /><meta name="citation_keywords" content="Disorders of GNAS Inactivation" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Disorders of GNAS Inactivation" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Chad R Haldeman-Englert" /><meta name="DC.Contributor" content="Anna CE Hurst" /><meta name="DC.Contributor" content="Michael A Levine" /><meta name="DC.Date" content="2017/10/26" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK459117/" /><meta name="description" content="Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC)." /><meta name="og:title" content="Disorders of GNAS Inactivation" /><meta name="og:type" content="book" /><meta name="og:description" content="Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC)." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK459117/" /><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/gnas-dis/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK459117/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script><meta name="book-collection" content="NONE" />
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK459117_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK459117_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/dcm-ov/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/cbl/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK459117_"><span class="title" itemprop="name">Disorders of <i>GNAS</i> Inactivation</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: Gsα Deficiency</div><p class="contrib-group"><span itemprop="author">Chad R Haldeman-Englert</span>, MD, FACMG, <span itemprop="author">Anna CE Hurst</span>, MD, MS, and <span itemprop="author">Michael A Levine</span>, MD, FAAP, FACP, MACE.</p><a data-jig="ncbitoggler" href="#__NBK459117_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK459117_ai__"><div class="contrib half_rhythm"><span itemprop="author">Chad R Haldeman-Englert</span>, MD, FACMG<div class="affiliation small">Fullerton Genetics Center<br />Asheville, North Carolina<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.jsm@trelgne-namedlah.dahc" class="oemail">gro.jsm@trelgne-namedlah.dahc</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Anna CE Hurst</span>, MD, MS<div class="affiliation small">Department of Genetics<br />University of Alabama at Birmingham<br />Birmingham, Alabama<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.bau@tsruheca" class="oemail">ude.bau@tsruheca</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Michael A Levine</span>, MD, FAAP, FACP, MACE<div class="affiliation small">Department of Pediatrics, Division of Endocrinology and Diabetes<br />Children's Hospital of Philadelphia;<br />University of Pennsylvania Perelman School of Medicine<br />Philadelphia, Pennsylvania<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.pohc@menivel" class="oemail">ude.pohc@menivel</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">October 26, 2017</span>.</p><p><em>Estimated reading time: 37 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="gnas-dis.Summary" itemprop="description"><h2 id="_gnas-dis_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Disorders of <i>GNAS</i> inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC).</p><p>PHP-Ia and PHP-Ic are characterized by:</p><ul><li class="half_rhythm"><div>End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and</div></li><li class="half_rhythm"><div>The Albright hereditary osteodystrophy (AHO) <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb).</div></li></ul><p>Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly).</p><p>PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> without the hormone resistance or obesity.</p><p>POH and OC are even more restricted variants of PPHP:</p><ul><li class="half_rhythm"><div>POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia.</div></li><li class="half_rhythm"><div>OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues.</div></li></ul></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of a disorder of <i>GNAS</i> inactivation is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with all or some of the characteristic clinical and endocrine findings and evidence on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> of a genetic or <a class="def" href="/books/n/gene/glossary/def-item/epigenetic/">epigenetic</a> alteration resulting in lack of expression/function of the <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a>.</p><p>PHP-Ia,.-Ib, and -Ic are associated with reduced or absent expression/function of the protein Gsα (encoded by the maternal <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a>) due to one of the following:</p><ul><li class="half_rhythm"><div>An <a class="def" href="/books/n/gene/glossary/def-item/inactivating/">inactivating</a> <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a></div></li><li class="half_rhythm"><div>A genetic alteration in the <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> regulatory elements in the <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> or the nearby <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>, <i>STX16</i>, that prevents proper maternal imprint of the <i>GNAS</i> complex locus</div></li><li class="half_rhythm"><div>Isolated epimutations</div></li><li class="half_rhythm"><div>Paternal 20q disomy</div></li></ul><p>PPHP and POH/OC phenotypes are associated with lack of expression/function of Gsα encoded by the paternal <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> due to an <a class="def" href="/books/n/gene/glossary/def-item/inactivating/">inactivating</a> <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>; the POH/OC phenotypes are also associated with lack of expression/function of Gsα (encoded by the maternal <i>GNAS</i> allele) as a result of an inactivating <i>GNAS</i> pathogenic variant.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Deficiencies of parathyroid hormone, thyroid hormone, and gonadotropins due to hormone resistance are treated in a standard manner. Growth hormone replacement therapy should be considered if screening for growth hormone deficiency with appropriate provocative testing is abnormal. Subcutaneous ossifications that are superficial and well circumscribed may be surgically removed when they are large or cause local irritation, although they may recur. Obesity tends to be the most difficult manifestation to treat as individuals with PHP-Ia and PHP-Ic have decreased resting energy expenditure and hyperphagia; thus, the usual recommendation of reduced caloric intake and increased physical activity may be less successful than in persons with obesity from other causes.</p><p><i>Surveillance:</i> Routine monitoring of:</p><ul><li class="half_rhythm"><div>Endocrine function: measurement of serum concentration of PTH, calcium and phosphate, TSH and free T4, and urinary calcium excretion;</div></li><li class="half_rhythm"><div>Growth velocity and growth hormone status (serum IGF1 and/or stimulated growth hormone testing);</div></li><li class="half_rhythm"><div>New and/or enlarging ectopic ossifications;</div></li><li class="half_rhythm"><div>Development of and/or progression of cataracts; and</div></li><li class="half_rhythm"><div>Psychoeducational needs regarding school assistance / educational support and developmental therapies (e.g., physical, occupational, and speech therapy).</div></li></ul><p><i>Agents/circumstances to avoid:</i> Limit dietary intake of phosphorus (dairy products and meats) in persons with persistently elevated serum levels of phosphate.</p><p><i>Evaluation of relatives at risk:</i> It is appropriate to evaluate apparently asymptomatic first-degree relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment.</p><p><i>Pregnancy management:</i> For women with a disorder of <i>GNAS</i> inactivation that affects the maternal <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>: Monitoring of serum concentration of calcium and thyroid studies (TSH, free T4) throughout pregnancy, labor, and the postpartum period and supplementation of calcium, vitamin D, and thyroid hormone as needed.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Disorders of <i>GNAS</i> inactivation are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner with the specific <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> determined by the parental origin of the defective <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>. Of individuals with a disorder of <i>GNAS</i> inactivation, approximately 38% have an affected parent and 38% have a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
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<i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>; in the remaining approximately 25% the cause is unknown.</p><p>Each child of an individual with a disorder of <i>GNAS</i> inactivation has a 50% chance of inheriting the parent's genetic alteration (except for <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases with PHP-1b for whom the <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a> is not well established). If the maternal <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> is affected, her offspring are at risk for PHP-Ia, PHP-Ib (when associated with deletions at the <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> regulatory elements), or PHP-Ic; if the paternal <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> has an <a class="def" href="/books/n/gene/glossary/def-item/inactivating/">inactivating</a> <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, his offspring are at risk for PPHP or POH/OC. If the genetic alteration in the <i>GNAS</i> complex locus or the <i>GNAS</i> pathogenic variant has been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are technically possible.</p></div></div><div id="gnas-dis.GeneReview_Scope"><h2 id="_gnas-dis_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><div id="gnas-dis.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK459117/table/gnas-dis.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gnas-dis.Tc_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gnas-dis.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Disorders of <i>GNAS</i> Inactivation: Included Phenotypes <sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_gnas-dis.Tc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><ul><li class="half_rhythm"><div>Pseudohypoparathyroidism Ia (PHP-Ia)</div></li><li class="half_rhythm"><div>Pseudohypoparathyroidism Ib (PHP-Ib)</div></li><li class="half_rhythm"><div>Pseudohypoparathyroidism Ic (PHP-Ic)</div></li><li class="half_rhythm"><div>Pseudopseudohypoparathyroidism (PPHP)</div></li><li class="half_rhythm"><div>Progressive osseous heteroplasia (POH)</div></li><li class="half_rhythm"><div>Osteoma cutis (OC)</div></li></ul>
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</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="gnas-dis.TF.c.1"><p class="no_margin">For other genetic causes of these phenotypes see <a href="#gnas-dis.Differential_Diagnosis">Differential Diagnosis</a>.</p></div></dd></dl></div></div></div></div><div id="gnas-dis.Diagnosis"><h2 id="_gnas-dis_Diagnosis_">Diagnosis</h2><p>No specific clinical criteria establish the diagnosis of a disorder of <i>GNAS</i> inactivation.</p><div id="gnas-dis.Suggestive_Findings"><h3>Suggestive Findings</h3><p>A disorder of <i>GNAS</i> inactivation <b>should be suspected</b> in individuals with the following phenotypes.</p><p><b>Pseudohypoparathyroidism Ia (PHP-Ia)</b> and <b>pseudohypoparathyroidism Ic (PHP-Ic)</b>. The most readily recognized form of PHP is PHP-Ia, which has clinical and endocrine features similar to PHP-Ic. Note: PHP-Ic differs from PHP-Ia on the basis of normal functional activity of Gsα (the protein encoded by <i>GNAS</i>) determined in some biochemical assays based on receptor-independent activation of Gsα [<a class="bk_pop" href="#gnas-dis.REF.levine.2012.443">Levine 2012</a>].</p><p><b>PHP-Ia and PHP-Ic</b> should be suspected in individuals with some of the following clinical and endocrine findings (which may emerge over time):</p><ul><li class="half_rhythm"><div>End-organ resistance to several endocrine hormones:</div><ul><li class="half_rhythm"><div class="half_rhythm">Parathyroid hormone (PTH), usually manifest as elevated PTH levels, hyperphosphatemia, and hypocalcemia, in the absence of vitamin D deficiency or magnesium deficiency</div></li><li class="half_rhythm"><div class="half_rhythm">Thyroid-stimulating hormone (TSH), manifest as hypothyroidism and elevated TSH levels in the absence of goiter or evidence of autoimmune thyroid disease</div></li><li class="half_rhythm"><div class="half_rhythm">Gonadotropins (LH and FSH), which may manifest in some females as reduced fertility and menstrual disorders/irregularities and in some males as cryptorchidism (often bilateral) and elevated LH and FSH levels.</div><div class="half_rhythm">In some females, metabolic or endocrine disturbances may alter LH and FSH secretion to produce the biochemical appearance of hypothalamic amenorrhea.</div></li><li class="half_rhythm"><div class="half_rhythm">Growth hormone-releasing hormone (GHRH), manifest as growth hormone (hGH) deficiency with consequent poor growth and/or short stature, in 50% to 80% of the individuals tested. Note that IGF1 levels are often normal at diagnosis.</div></li><li class="half_rhythm"><div class="half_rhythm">Calcitonin, with asymptomatic hypercalcitonemia</div></li><li class="half_rhythm"><div class="half_rhythm">CNS neurotransmitters, leading to obesity and variable degrees of intellectual disability and developmental delay</div><div class="half_rhythm">Note: Many affected individuals have normal neurocognitive function.</div></li></ul></li><li class="half_rhythm"><div>Albright hereditary osteodystrophy (AHO) <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>:</div><ul><li class="half_rhythm"><div class="half_rhythm">Short stature</div></li><li class="half_rhythm"><div class="half_rhythm">Round facies</div></li><li class="half_rhythm"><div class="half_rhythm">Subcutaneous ossifications</div></li><li class="half_rhythm"><div class="half_rhythm">Brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb)</div><div class="half_rhythm">Note: Shortened metacarpals may be recognized by the replacement of knuckles by dimples when making a fist.</div></li><li class="half_rhythm"><div class="half_rhythm">Intrauterine growth restriction</div></li></ul></li></ul><p><b>Pseudohypoparathyroidism Ib (PHP-Ib).</b> Suggestive findings include:</p><ul><li class="half_rhythm"><div>PTH resistance, the principal endocrine abnormality</div></li><li class="half_rhythm"><div>In some affected individuals:</div><ul><li class="half_rhythm"><div>Partial TSH resistance with slightly elevated TSH levels and generally normal (or low) serum concentrations of thyroid hormones [<a class="bk_pop" href="#gnas-dis.REF.levine.2012.443">Levine 2012</a>]</div></li><li class="half_rhythm"><div>Mild brachydactyly (despite absence of the classic AHO <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>)</div></li><li class="half_rhythm"><div>Enhanced intrauterine growth [<a class="bk_pop" href="#gnas-dis.REF.br_hin.2015.e623">Bréhin et al 2015</a>] (See <a href="/books/NBK459117/table/gnas-dis.T.phenotypes_and_genetic_mechan/?report=objectonly" target="object" rid-ob="figobgnasdisTphenotypesandgeneticmechan">Table 2</a>.)</div></li><li class="half_rhythm"><div>Madelung deformity [<a class="bk_pop" href="#gnas-dis.REF.sanchez.2011.e1507">Sanchez et al 2011</a>]</div></li></ul></li></ul><p><b>Pseudopseudohypoparathyroidism (PPHP),</b> a more limited form of PHP-Ia, involves various manifestations of the AHO <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> without hormone resistance or obesity.</p><p><b>Progressive osseous heteroplasia (POH),</b> a more restricted variant of PPHP, consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia [<a class="bk_pop" href="#gnas-dis.REF.kaplan.1994.425">Kaplan et al 1994</a>].</p><p><b>Osteoma cutis (OC),</b> another more restricted variant of PPHP, consists of extraskeletal ossification limited to the dermis and subcutaneous tissues.</p></div><div id="gnas-dis.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of a disorder of <i>GNAS</i> inactivation <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with all or some of the <a href="#gnas-dis.Suggestive_Findings">above clinical findings</a> and evidence on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> of a genetic or <a class="def" href="/books/n/gene/glossary/def-item/epigenetic/">epigenetic</a> alteration resulting in lack of expression/function of the <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a>. See <a href="/books/NBK459117/table/gnas-dis.T.molecular_genetic_testing_use/?report=objectonly" target="object" rid-ob="figobgnasdisTmoleculargenetictestinguse">Table 1</a> for a summary of molecular genetic testing, <a href="/books/NBK459117/table/gnas-dis.T.phenotypes_and_genetic_mechan/?report=objectonly" target="object" rid-ob="figobgnasdisTphenotypesandgeneticmechan">Table 2</a> for a summary of the phenotypes and genetic mechanisms of disorders of <i>GNAS</i> inactivation, and <a href="#gnas-dis.Molecular_Genetics">Molecular Genetics</a> for details of the <i>GNAS</i> molecular defects.</p><p>The <b>PHP-Ia</b>, <b>-Ib</b>, and <b>-Ic</b>
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<b>phenotypes</b> are associated with lack of expression/function of the protein Gsα (encoded by the maternal <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a>) as a result of one of the following:</p><ul><li class="half_rhythm"><div>An <a class="def" href="/books/n/gene/glossary/def-item/inactivating/">inactivating</a> <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a></div></li><li class="half_rhythm"><div>A genetic alteration in the <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> regulatory elements in the <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> or the nearby <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>, <i>STX16</i>, that prevents proper maternal imprint of the <i>GNAS</i> complex locus</div></li><li class="half_rhythm"><div>Isolated epimutations [<a class="bk_pop" href="#gnas-dis.REF.takatani.2015.15">Takatani et al 2015</a>]</div></li><li class="half_rhythm"><div>Uniparental paternal 20q disomy [<a class="bk_pop" href="#gnas-dis.REF.takatani.2015.15">Takatani et al 2015</a>]</div></li></ul><p>The <b>PPHP</b> and <b>POH/OC phenotypes</b> are associated with lack of expression/function of Gsα (encoded by the paternal <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>) due to an <a class="def" href="/books/n/gene/glossary/def-item/inactivating/">inactivating</a> <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>; the POH/OC phenotypes are also associated with lack of expression/function of Gsα (encoded by the maternal <i>GNAS</i> allele) caused by an inactivating <i>GNAS</i> pathogenic variant.</p><p>Molecular genetic testing approaches can include a combination of <b><a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>, single-gene testing) and <b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (comprehensive genomic sequencing) depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p><p>Gene-targeted testing requires the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing may not. Because of the varied manifestations of the disorders of <i>GNAS</i> inactivation, individuals with the findings of one of the distinctive phenotypes described in <a href="#gnas-dis.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#gnas-dis.Option_1">Option 1</a>), whereas those with clinical findings indistinguishable from other inherited disorders with similar endocrine abnormalities are more likely to be diagnosed using genomic testing (see <a href="#gnas-dis.Option_2">Option 2</a>).</p><div id="gnas-dis.Option_1"><h4>Option 1</h4><p>When the clinical and endocrine findings suggest one of the distinctive phenotypes, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> approaches can include <b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b>
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<b>and</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/methylation-analysis/">methylation analysis</a></b> or use of a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b>.</p><p>
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<b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing and <a class="def" href="/books/n/gene/glossary/def-item/methylation-analysis/">methylation analysis</a></b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of exons 1 through 13 of <i>GNAS</i> is performed first, followed by gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> if no <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is found.</div><div class="half_rhythm">Note: In persons with the PHP-Ib <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>, <i>STX16</i> <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> should be performed if no <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is identified and if <a class="def" href="/books/n/gene/glossary/def-item/methylation/">methylation</a> defects are limited to <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> A/B differentially methylated region (DMR) (also referred to as exon 1A or <i>GNAS A/B</i>:TSS-DMR).</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Methylation analysis</b> examines differentially methylated regions (DMRs) of the <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> for loss of the normal <a class="def" href="/books/n/gene/glossary/def-item/methylation/">methylation</a> pattern on the maternal <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> (i.e., an <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> defect). When a <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is not identified on <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, it is appropriate to perform <a class="def" href="/books/n/gene/glossary/def-item/methylation-analysis/">methylation analysis</a>. Note: Although loss of methylation can identify the presence of an imprinting defect, it cannot identify the cause of the imprinting defect.</div><div class="half_rhythm"><b>PHP-Ia.</b> In some instances, individuals with PHP-Ia may have partial <a class="def" href="/books/n/gene/glossary/def-item/methylation/">methylation</a> defects of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>.</div><div class="half_rhythm"><b>PHP-Ib.</b> Because alterations of various <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> control regions are associated with PHP-Ib, loss of <a class="def" href="/books/n/gene/glossary/def-item/methylation/">methylation</a> at the <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> A/B DMR of the maternal <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> is observed in all affected individuals; thus, <a class="def" href="/books/n/gene/glossary/def-item/methylation-analysis/">methylation analysis</a> should be the initial test in individuals with findings suggestive of PHP-1b.</div><ul><li class="half_rhythm"><div class="half_rhythm"><b>Familial PHP-Ib</b> is in most instances caused either by multiexon deletions disrupting the upstream <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> <i>STX16</i> or (less frequently) by deletions involving <i>NESP</i> (<a class="figpopup" href="/books/NBK459117/figure/gnas-dis.F1/?report=objectonly" target="object" rid-figpopup="figgnasdisF1" rid-ob="figobgnasdisF1">Figure 1</a>) [<a class="bk_pop" href="#gnas-dis.REF.elli.2014a.e508">Elli et al 2014a</a>].</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Sporadic PHP-Ib.</b> The genetic basis for the <a class="def" href="/books/n/gene/glossary/def-item/methylation/">methylation</a> defect in <a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a> PHP-Ib is usually unknown; however, broad <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> abnormalities involving multiple DMRs have been observed in most affected individuals, some of whom had molecular genetic findings consistent with paternal uniparental 20q isodisomy [<a class="bk_pop" href="#gnas-dis.REF.takatani.2015.15">Takatani et al 2015</a>] (<a href="/books/NBK459117/table/gnas-dis.T.phenotypes_and_genetic_mechan/?report=objectonly" target="object" rid-ob="figobgnasdisTphenotypesandgeneticmechan">Table 2</a>).</div><div class="half_rhythm">Note: in some cases, deletions encompassing the whole <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> can mimic <a class="def" href="/books/n/gene/glossary/def-item/methylation/">methylation</a> defects associated with <a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a> PHP-Ib. In case of an overall methylation defect, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> should be performed.</div></li></ul></li></ul><div class="iconblock whole_rhythm clearfix ten_col fig" id="figgnasdisF1" co-legend-rid="figlgndgnasdisF1"><a href="/books/NBK459117/figure/gnas-dis.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figgnasdisF1" rid-ob="figobgnasdisF1"><img class="small-thumb" src="/books/NBK459117/bin/gnas-dis-Image001.gif" src-large="/books/NBK459117/bin/gnas-dis-Image001.jpg" alt="Figure 1. . Schematic of the GNAS complex locus and nearby gene, STX16." /></a><div class="icnblk_cntnt" id="figlgndgnasdisF1"><h4 id="gnas-dis.F1"><a href="/books/NBK459117/figure/gnas-dis.F1/?report=objectonly" target="object" rid-ob="figobgnasdisF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">Schematic of the <i>GNAS</i> complex locus and nearby gene, <i>STX16</i>. <i>GNAS</i> exons 1-13 encode Gsα. See Additional transcripts of the <i>GNAS</i> complex locus (pdf) for more details about <i>GNAS</i> alternative first exons. <i>STX16</i> is centromeric to the <i>GNAS</i> complex locus <a href="/books/NBK459117/figure/gnas-dis.F1/?report=objectonly" target="object" rid-ob="figobgnasdisF1">(more...)</a></p></div></div><p>
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<b>Multigene panel</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm">A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a> that includes <i>GNAS</i> and other genes of interest (see <a href="#gnas-dis.Differential_Diagnosis">Differential Diagnosis</a>) may also be considered. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests. These approaches do not allow the characterization of <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> defects.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul></div><div id="gnas-dis.Option_2"><h4>Option 2</h4><p>When the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> is indistinguishable from other inherited disorders with similar endocrine abnormalities, <b>comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a> or <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>) can be considered.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><p>Note: Genomic testing does not allow characterization of <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> defects.</p><div id="gnas-dis.T.molecular_genetic_testing_use" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Disorders of <i>GNAS</i> Inactivation</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK459117/table/gnas-dis.T.molecular_genetic_testing_use/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gnas-dis.T.molecular_genetic_testing_use_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gnas-dis.T.molecular_genetic_testing_use_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_gnas-dis.T.molecular_genetic_testing_use_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_gnas-dis.T.molecular_genetic_testing_use_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Diagnostic Change <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_gnas-dis.T.molecular_genetic_testing_use_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GNAS</i>
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</td><td headers="hd_h_gnas-dis.T.molecular_genetic_testing_use_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_gnas-dis.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">62%-82% <sup>4</sup></td></tr><tr><td headers="hd_h_gnas-dis.T.molecular_genetic_testing_use_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>5</sup></td><td headers="hd_h_gnas-dis.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10 deletions reported to date <sup>6</sup></td></tr><tr><td headers="hd_h_gnas-dis.T.molecular_genetic_testing_use_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Methylation analysis <sup>7</sup></td><td headers="hd_h_gnas-dis.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10%-60% (virtually 100% for PHP-Ib) <sup>4</sup></td></tr><tr><td headers="hd_h_gnas-dis.T.molecular_genetic_testing_use_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Chromosomal microarray analysis <sup>8</sup></td><td headers="hd_h_gnas-dis.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10% <sup>9</sup></td></tr><tr><td headers="hd_h_gnas-dis.T.molecular_genetic_testing_use_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>STX16</i>
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</td><td headers="hd_h_gnas-dis.T.molecular_genetic_testing_use_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/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>5</sup></td><td headers="hd_h_gnas-dis.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 10.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="gnas-dis.TF.1.1"><p class="no_margin">See <a href="/books/NBK459117/#gnas-dis.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="gnas-dis.TF.1.2"><p class="no_margin">See <a href="#gnas-dis.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="gnas-dis.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="gnas-dis.TF.1.4"><p class="no_margin"><a class="bk_pop" href="#gnas-dis.REF.ahrens.2001.4630">Ahrens et al [2001]</a>, <a class="bk_pop" href="#gnas-dis.REF.linglart.2002.189">Linglart et al [2002]</a>, <a class="bk_pop" href="#gnas-dis.REF.shore.2002.99">Shore et al [2002]</a>, <a class="bk_pop" href="#gnas-dis.REF.mantovani.2010.5011">Mantovani et al [2010]</a>, <a class="bk_pop" href="#gnas-dis.REF.elli.2013a.276">Elli et al [2013a]</a>, <a class="bk_pop" href="#gnas-dis.REF.takatani.2015.15">Takatani et al [2015]</a></p></div></dd><dt>5. </dt><dd><div id="gnas-dis.TF.1.5"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd><dt>6. </dt><dd><div id="gnas-dis.TF.1.6"><p class="no_margin">Includes: two girls with a very small interstitial <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> of the long arm of <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> 20 presenting with severe pre- and postnatal growth restriction and clinical manifestations suggestive of PPHP [<a class="bk_pop" href="#gnas-dis.REF.genevi_ve.2005.1033">Geneviève et al 2005</a>]; a female with PHP-Ia and a 30-kb deletion (including <i>GNAS</i> exons 1-5) inherited from her mother, who was mosaic for this <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> deletion [<a class="bk_pop" href="#gnas-dis.REF.fernandezrebollo.2010.765">Fernandez-Rebollo et al 2010</a>]; brothers with PHP-Ia and an 850-kb deletion (involving all of <i>GNAS</i> as well as other genes) that was inherited from their mother, who had PPHP [<a class="bk_pop" href="#gnas-dis.REF.mitsui.2012.261">Mitsui et al 2012</a>]; and seven novel <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> deletions ranging from 106 bp to 2.6 Mb in families with PHP-Ia [<a class="bk_pop" href="#gnas-dis.REF.garin.2015.e681">Garin et al 2015</a>]</p></div></dd><dt>7. </dt><dd><div id="gnas-dis.TF.1.7"><p class="no_margin">Methylation analysis examines differentially methylated regions (DMRs) of the <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> for loss of the normal <a class="def" href="/books/n/gene/glossary/def-item/methylation/">methylation</a> pattern on the maternal <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>.</p></div></dd><dt>8. </dt><dd><div id="gnas-dis.TF.1.8"><p class="no_margin">Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a>/<i>STX16</i> region. Note: The <i>GNAS</i> complex locus/<i>STX16</i> <a class="def" href="/books/n/gene/glossary/def-item/recurrent-deletion/">recurrent deletion</a> may not have been detectable by older oligonucleotide or BAC platforms.</p></div></dd><dt>9. </dt><dd><div id="gnas-dis.TF.1.9"><p class="no_margin">Includes UPD(20q)pat [<a class="bk_pop" href="#gnas-dis.REF.fernandezrebollo.2010.765">Fernandez-Rebollo et al 2010</a>, <a class="bk_pop" href="#gnas-dis.REF.linglart.2013.119">Linglart et al 2013</a>]</p></div></dd><dt>10. </dt><dd><div id="gnas-dis.TF.1.10"><p class="no_margin">Relevant for testing those with the PHP-Ib <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> who: do not have an identified maternal <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>; and do have a <a class="def" href="/books/n/gene/glossary/def-item/methylation/">methylation</a> defect at <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> A/B DMR (also referred to as exon 1A or <i>GNAS A/B</i>:TSS-DMR)</p></div></dd></dl></div></div></div></div></div></div><div id="gnas-dis.Clinical_Characteristics"><h2 id="_gnas-dis_Clinical_Characteristics_">Clinical Characteristics</h2><div id="gnas-dis.Clinical_Description"><h3>Clinical Description</h3><p>Disorders of <i>GNAS</i> inactivation include pseudohypoparathyroidism Ia (PHP-Ia), Ib (PHP-Ib), and Ic (PHP-Ic), as well as pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC) (see <a href="/books/NBK459117/table/gnas-dis.T.phenotypes_and_genetic_mechan/?report=objectonly" target="object" rid-ob="figobgnasdisTphenotypesandgeneticmechan">Table 2</a>).</p><p>The term pseudohypoparathyroidism (PHP) refers to disorders with hypocalcemia and hyperphosphatemia (which are typical of hypoparathyroidism) that result from end-organ resistance to ‒ rather than deficiency of ‒ parathyroid hormone (PTH).</p><div id="gnas-dis.Pseudohypoparathyroidism_Ia_PHP"><h4>Pseudohypoparathyroidism Ia (PHP-Ia) and PHP-Ic</h4><p>PHP-Ia and PHP-Ic have a similar <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> and are distinguished only by <i>ex vivo</i> assays of Gsα protein function that are based on hormone receptor activation of Gsα; in these assays Gsα activity is reduced by approximately 50% in PHP-Ia and normal in PHP-Ic (<a href="/books/NBK459117/table/gnas-dis.T.phenotypes_and_genetic_mechan/?report=objectonly" target="object" rid-ob="figobgnasdisTphenotypesandgeneticmechan">Table 2</a>).</p><p><b>Endocrine.</b> The clinical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> consists of metabolic resistance to multiple endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), growth hormone-releasing hormone (GHRH), calcitonin, and often gonadotropins [<a class="bk_pop" href="#gnas-dis.REF.levine.2012.443">Levine 2012</a>]. The most common endocrinopathies are biochemical hypoparathyroidism, primary hypothyroidism (without goiter), and growth hormone deficiency (demonstrated in 50%-70% of affected individuals) [<a class="bk_pop" href="#gnas-dis.REF.de_sanctis.2007.97">de Sanctis et al 2007</a>]. Obesity, due to decreased resting energy expenditure [<a class="bk_pop" href="#gnas-dis.REF.roizen.2016.880">Roizen et al 2016</a>], appears to result from impaired Gsα-coupled signaling in <a class="def" href="/books/n/gene/glossary/def-item/imprinted/">imprinted</a> regions of the hypothalamus (which, based on mouse studies, is likely to be in the dorsomedial hypothalamus) [<a class="bk_pop" href="#gnas-dis.REF.chen.2017.500">Chen et al 2017</a>].</p><p>The development of the endocrine features occurs over time. The earliest manifestation of hormone resistance is usually mild hypothyroidism, which is often discovered during newborn screening as an elevated TSH with normal serum levels of thyroid hormones. The average age at diagnosis of PHP-Ia is around age seven years, when PTH resistance and hypocalcemia are recognized; however, individuals with milder manifestations may not be diagnosed until the third decade of life [<a class="bk_pop" href="#gnas-dis.REF.linglart.2013.119">Linglart et al 2013</a>, <a class="bk_pop" href="#gnas-dis.REF.turan.2015.146">Turan & Bastepe 2015</a>].</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>TSH resistance</b> is variable and may manifest as <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> hypothyroidism; however, TSH may be elevated in individuals who are euthyroid, or only after formal TRH stimulation testing. Serum levels of thyroid hormone are usually normal or only mildly depressed.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>PTH resistance.</b> Although random PTH levels are often elevated in PHP-Ia, hypocalcemia may fluctuate and may not become clinically significant until later childhood. Hyperphosphatemia usually precedes hypocalcemia. Some individuals remain eucalcemic.</div><div class="half_rhythm">Occasionally, early PTH resistance is associated with hypercalcemia rather than hypocalcemia. Presumably, in these individuals the kidney retains the ability to increase production of 1,25(OH)<sub>2</sub>D, the active form of vitamin D, in response to the elevated levels of circulating PTH that result from decreased ability to excrete urinary phosphate [MA Levine, personal observation].</div><div class="half_rhythm">As in PTH-deficient hypoparathyroidism, protracted hypocalcemia and hyperphosphatemia lead to ectopic calcification, particularly in the brain at the grey-white cerebral intersection and the basal ganglia and ocular lenses, manifesting as posterior subcapsular cataracts.</div><div class="half_rhythm">Bone density is often increased [<a class="bk_pop" href="#gnas-dis.REF.long.2010.4465">Long et al 2010</a>].</div><div class="half_rhythm">Unrecognized hypocalcemia may present with tetany, seizures, or laryngeal spasm; seizures appear to be more common, independent of hypocalcemia [<a class="bk_pop" href="#gnas-dis.REF.fitch.1982.11">Fitch 1982</a>]. Cataracts can also be seen in the setting of prolonged hypocalcemia.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Gonadotropin</b>
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<b>resistance</b> may result in delayed puberty and incomplete development of secondary sex characteristics, menstrual irregularities, or reduced fertility.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Early-onset morbid obesity</b> can begin in infancy [<a class="bk_pop" href="#gnas-dis.REF.dekelbab.2009.249">Dekelbab et al 2009</a>]. At least 65% of those younger than age 18 years are obese [<a class="bk_pop" href="#gnas-dis.REF.fitch.1982.11">Fitch 1982</a>].</div></li></ul><p>Sleep apnea is also common (45% of individuals), but is only partly explained by obesity, as individuals with PHP-Ia have a fourfold increased risk for sleep apnea compared to similarly obese individuals. This increase may be due to hypotonia as well as the effects of Gsα inactivation on the normal sleep cycle [<a class="bk_pop" href="#gnas-dis.REF.landreth.2015.1">Landreth et al 2015</a>].</p><p><b>Musculoskeletal.</b> At birth growth parameters are usually normal, but can be below normal [<a class="bk_pop" href="#gnas-dis.REF.wilson.2006.671">Wilson 2006</a>]; however, neonates may then present with <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> hypothyroidism or ectopic ossifications.</p><p>Linear growth may initially be normal or advanced due to obesity; bone age is frequently advanced beyond chronologic age [<a class="bk_pop" href="#gnas-dis.REF.fitch.1982.11">Fitch 1982</a>]. Linear growth slows soon after early childhood and prematurely ceases in early puberty, leading to height below the third percentile in the majority of adults [<a class="bk_pop" href="#gnas-dis.REF.fitch.1982.11">Fitch 1982</a>, <a class="bk_pop" href="#gnas-dis.REF.wilson.2006.671">Wilson 2006</a>] primarily due to premature closure of epiphyseal growth plates; however, GH deficiency may also be a contributing factor.</p><p>Affected individuals display clinical features of Albright hereditary osteodystrophy (AHO) comprising a round face, short stature, brachydactyly/brachymetacarpia, and heterotopic ossification of the dermis and subcutaneous tissues. Macrocephaly relative to height is typical: 40% have a head circumference above the 90th percentile [<a class="bk_pop" href="#gnas-dis.REF.fitch.1982.11">Fitch 1982</a>, <a class="bk_pop" href="#gnas-dis.REF.wilson.2006.671">Wilson 2006</a>].</p><p>The most common musculoskeletal feature is brachydactyly; brachydactyly type E is manifest as shortened metacarpals (particularly 4th and 5th) and metatarsals (particularly 3rd and 4th) plus brachydactyly type D, manifest as shortening of the distal phalanx of the thumb.</p><p>Even in the absence of brachymetacarpia, individuals with AHO usually have brachydactyly type D, a shortened distal thumb phalanx and short, broad thumbnails, associated radiographically with cone-shaped epiphyses [<a class="bk_pop" href="#gnas-dis.REF.fitch.1982.11">Fitch 1982</a>].</p><p>Brachydactyly may lead to carpal tunnel syndrome with symptomatic paresthesia, which may be confused with the symptoms of hypocalcemia [<a class="bk_pop" href="#gnas-dis.REF.joseph.2011.2065">Joseph et al 2011</a>].</p><p>Other reported musculoskeletal features include craniosynostosis, hyperostosis of the cranial vault, absence of normal caudal widening of the lumbar interpedicular distances (associated with spinal stenosis), ossification of paravertebral ligaments, shortened distal ulnas, bowing of the tibia and radius, small capital femoral epiphyses, coxa vara, coxa valga, increased prevalence of bony exostoses, and carpal tunnel syndrome [<a class="bk_pop" href="#gnas-dis.REF.wilson.2002.273">Wilson & Hall 2002</a>, <a class="bk_pop" href="#gnas-dis.REF.van_lindert.2008.337">van Lindert et al 2008</a>, <a class="bk_pop" href="#gnas-dis.REF.joseph.2011.2065">Joseph et al 2011</a>].</p><p><b>Skin.</b> Ectopic ossifications (also known as osteoma cutis) are true heterotopic intramembraneous bone which occur in 60%-70% of affected individuals, independent of calcium, phosphate, or PTH levels [<a class="bk_pop" href="#gnas-dis.REF.prendiville.1992.11">Prendiville et al 1992</a>].</p><p>Ectopic ossifications are most commonly cutaneous, either within subdermal fat or in the dermis. They are located most commonly in the scalp and extremities (particularly the periarticular areas of the hands and feet). These lesions may be very small and asymptomatic, or painful; occasionally lesions can extrude a chalky material. Removal of ectopic ossifications does not result in progression or exacerbation although they may recur if removal is incomplete [<a class="bk_pop" href="#gnas-dis.REF.fitch.1982.11">Fitch 1982</a>, <a class="bk_pop" href="#gnas-dis.REF.prendiville.1992.11">Prendiville et al 1992</a>, <a class="bk_pop" href="#gnas-dis.REF.wilson.2006.671">Wilson 2006</a>].</p><p>Other areas of ectopic ossification include the sclera and choroid of the eye and cardiac ventricular septum. Visceral involvement is rare [<a class="bk_pop" href="#gnas-dis.REF.fitch.1982.11">Fitch 1982</a>].</p><p>Dental changes such as enamel hypoplasia, widened root canals, shortened roots with open apices, thickened laminar dura, and delayed dental eruption have been noted in more than 30% of affected individuals, often with impacted second molars [<a class="bk_pop" href="#gnas-dis.REF.ritchie.1965.565">Ritchie 1965</a>].</p><p><b>Mild-to-moderate intellectual disability</b> is seen in up to 79% of affected individuals [<a class="bk_pop" href="#gnas-dis.REF.mouallem.2008.233">Mouallem et al 2008</a>].</p></div><div id="gnas-dis.Pseudohypoparathyroidism_Ib_PHP"><h4>Pseudohypoparathyroidism Ib (PHP-Ib)</h4><p>PHP-Ib consists of PTH resistance with partial resistance to TSH in some affected individuals. Partial TSH resistance manifests as slightly elevated serum TSH levels with generally normal (or low) serum concentrations of thyroid hormones [<a class="bk_pop" href="#gnas-dis.REF.levine.2012.443">Levine 2012</a>].</p><p>Poorly treated PTH resistance can lead to hyperparathyroid bone disease or tertiary hyperparathyroidism. Very rarely bone density can be elevated [<a class="bk_pop" href="#gnas-dis.REF.sbrocchi.2011.295">Sbrocchi et al 2011</a>].</p><p>Patterns of excessive growth or weight gain have been described in newborns or during early infancy and childhood.</p><p>Individuals with PHP-Ib may have growth-plate defects such as mild brachydactyly or a Madelung deformity-like defect [<a class="bk_pop" href="#gnas-dis.REF.sanchez.2011.e1507">Sanchez et al 2011</a>], but lack the complete constellation of features seen in AHO. Intellect is typically normal.</p><p>The average age of diagnosis for symptomatic individuals is age ten to 12 years [<a class="bk_pop" href="#gnas-dis.REF.linglart.2007.822">Linglart et al 2007</a>], which is later than for PHP-Ia.</p></div><div id="gnas-dis.Pseudopseudohypoparathyroidism"><h4>Pseudopseudohypoparathyroidism (PPHP)</h4><p>The <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> is heterogeneous with a wide differential diagnosis (see <a href="#gnas-dis.Differential_Diagnosis">Differential Diagnosis</a>).</p><p>Intrauterine growth restriction is common.</p><p>Ectopic ossifications are frequent and almost pathognomonic of Gsα deficiency.</p><p>Individuals with PPHP have normocalcemia and no endocrine defects, but have the physical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of Albright hereditary osteodystrophy.</p><p>Obesity and intellectual disabilities (10%) are less prevalent than in PHP-Ia [<a class="bk_pop" href="#gnas-dis.REF.long.2007.1073">Long et al 2007</a>, <a class="bk_pop" href="#gnas-dis.REF.mouallem.2008.233">Mouallem et al 2008</a>].</p></div><div id="gnas-dis.Progressive_Osseous_Heteroplasi"><h4>Progressive Osseous Heteroplasia (POH)</h4><p>Individuals with POH have no endocrine defects or features of AHO, but have progressive ectopic ossification that extends to deep connective tissues, often with debilitating effects [<a class="bk_pop" href="#gnas-dis.REF.levine.2012.443">Levine 2012</a>, <a class="bk_pop" href="#gnas-dis.REF.pignolo.2015.37">Pignolo et al 2015</a>].</p><p>Of note, POH-like ossifications have been observed rarely in individuals with AHO or PHP-1a.</p></div><div id="gnas-dis.Osteoma_Cutis_OC"><h4>Osteoma Cutis (OC)</h4><p>Individuals with OC develop ossification limited to the dermis and subcutaneous tissues.</p></div></div><div id="gnas-dis.Phenotypes_and_Genetic_Mechanis"><h3>Phenotypes and Genetic Mechanisms of Disorders of <i>GNAS</i> Inactivation</h3><p><a href="/books/NBK459117/table/gnas-dis.T.phenotypes_and_genetic_mechan/?report=objectonly" target="object" rid-ob="figobgnasdisTphenotypesandgeneticmechan">Table 2</a> summarizes the different phenotypes that result from disorders of <i>GNAS</i> inactivation. Note the various molecular defects and associated parental origin. See <a href="#gnas-dis.Molecular_Genetics">Molecular Genetics</a> and <a class="figpopup" href="/books/NBK459117/figure/gnas-dis.F1/?report=objectonly" target="object" rid-figpopup="figgnasdisF1" rid-ob="figobgnasdisF1">Figure 1</a> for a description and map of the <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and the upstream <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>, <i>STX16</i>.</p><div id="gnas-dis.T.phenotypes_and_genetic_mechan" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Phenotypes and Genetic Mechanisms of Disorders of <i>GNAS</i> Inactivation</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK459117/table/gnas-dis.T.phenotypes_and_genetic_mechan/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gnas-dis.T.phenotypes_and_genetic_mechan_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Phenotype</th><th id="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Endocrine Defects</th><th id="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Features</th><th id="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Other Features</th><th id="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parental Origin of the Inactivated <i>GNAS</i> Allele</th><th id="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_6" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Molecular Defect <sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PHP-Ia</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multihormone resistance <sup>2</sup></td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AHO <sup>3</sup>; early-onset obesity</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cognitive disability</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Maternal</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Heterozygous <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in exons 1-12 <sup>4, 5</sup></td></tr><tr><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PHP-Ic</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multihormone resistance <sup>2</sup></td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AHO</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cognitive disability</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Maternal</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Heterozygous <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 13 <sup>6</sup></td></tr><tr><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">PHP-Ib</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PTH resistance; partial TSH resistance in some</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Enhanced intrauterine growth <sup>7</sup>; mild brachydactyly in some</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Loss of <a class="def" href="/books/n/gene/glossary/def-item/methylation/">methylation</a> in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> A/B <sup>1, 7</sup> (<a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a>)</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Maternal</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Imprinting defect: <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> of <i>STX16</i> or regulatory elements in GNAS complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> <sup>1, 8</sup> (<a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a>)</td></tr><tr><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variable degrees of a more global defect in <a class="def" href="/books/n/gene/glossary/def-item/methylation/">methylation</a> at multiple DMRs <sup>3, 4</sup> (<a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a>)</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Paternal 20q disomy or unknown <a class="def" href="/books/n/gene/glossary/def-item/epigenetic/">epigenetic</a> defect (<a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a>) <sup>4</sup></td></tr><tr><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PPHP</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AHO; IUGR <sup>9</sup></td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Paternal</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Heterozygous <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <sup>4, 5</sup></td></tr><tr><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Progressive osseous heteroplasia</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Progressive heterotopic ossification extending to deep connective tissues</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Paternal</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Heterozygous <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <sup>4</sup></td></tr><tr><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Osteoma cutis</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Heterotopic ossification limited to dermis & subcutaneous tissues</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Paternal</td><td headers="hd_h_gnas-dis.T.phenotypes_and_genetic_mechan_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Heterozygous <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <sup>4</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">From <a class="bk_pop" href="#gnas-dis.REF.levine.2012.443">Levine [2012]</a></p></div></dd><dt></dt><dd><div><p class="no_margin">AHO = Albright hereditary osteodystrophy; DMR = differentially methylated region; IUGR = intrauterine growth restriction; PHP = pseudohypoparathyroidism; PTH = parathyroid hormone; TSH = thyroid-stimulating hormone</p></div></dd><dt>1. </dt><dd><div id="gnas-dis.TF.2.1"><p class="no_margin">See <a href="#gnas-dis.Molecular_Genetics">Molecular Genetics</a> and <a class="figpopup" href="/books/NBK459117/figure/gnas-dis.F1/?report=objectonly" target="object" rid-figpopup="figgnasdisF1" rid-ob="figobgnasdisF1">Figure 1</a> for details of the structure and expression of the GNAS complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a>.</p></div></dd><dt>2. </dt><dd><div id="gnas-dis.TF.2.2"><p class="no_margin">Multiple hormone resistance, resistance to PTH, TSH, and GHRH; often gonadotropins (LH and FSH) as well</p></div></dd><dt>3. </dt><dd><div id="gnas-dis.TF.2.3"><p class="no_margin">AHO comprising round face, short stature, brachydactyly/brachymetacarpia, and heterotopic ossification</p></div></dd><dt>4. </dt><dd><div id="gnas-dis.TF.2.4"><p class="no_margin">
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<a class="bk_pop" href="#gnas-dis.REF.takatani.2015.15">Takatani et al [2015]</a>
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</p></div></dd><dt>5. </dt><dd><div id="gnas-dis.TF.2.5"><p class="no_margin">Chromosome abnormalities of <i>GNAS</i>-related disorders are uncommon; however, <a class="bk_pop" href="#gnas-dis.REF.aldred.2002.167">Aldred et al [2002]</a> described two individuals with full deletions of <i>GNAS</i> due to interstitial <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> deletions: one with a maternally derived <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> of chromosome 20q13.31-q13.33 and a diagnosis of PHP-Ia and the other with a paternally inherited deletion of chromosome 20q13.13-q13.32 and a diagnosis of PPHP.</p></div></dd><dt>6. </dt><dd><div id="gnas-dis.TF.2.6"><p class="no_margin">Impairs coupling of Gsα to heptahelical receptors. See <a href="#gnas-dis.Molecular_Genetics">Molecular Genetics</a>.</p></div></dd><dt>7. </dt><dd><div id="gnas-dis.TF.2.7"><p class="no_margin">
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<a class="bk_pop" href="#gnas-dis.REF.br_hin.2015.e623">Bréhin et al [2015]</a>
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</p></div></dd><dt>8. </dt><dd><div id="gnas-dis.TF.2.8"><p class="no_margin"><i>STX16</i> and DMRs associated with <i>GNAS</i> exons designated NESP and GNAS-AS1. See <a class="figpopup" href="/books/NBK459117/figure/gnas-dis.F1/?report=objectonly" target="object" rid-figpopup="figgnasdisF1" rid-ob="figobgnasdisF1">Figure 1</a>; <a class="bk_pop" href="#gnas-dis.REF.elli.2013a.276">Elli et al [2013a]</a> and references therein.</p></div></dd><dt>9. </dt><dd><div id="gnas-dis.TF.2.9"><p class="no_margin">Associated mainly with pathogenic variants in <i>GNAS</i> exons 2-13 [<a class="bk_pop" href="#gnas-dis.REF.richard.2013.e1549">Richard et al 2013</a>]</p></div></dd></dl></div></div></div></div><div id="gnas-dis.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No clear correlation appears to exist between the type and location of <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> / <i>STX16</i> pathogenic variants and disease onset, severity of endocrine resistance, or number of AHO features.</p><p>However, two unique variants affecting both the stability and the activity of Gsα have been described in three unrelated individuals with PHP1a who presented with additional clinical features reflecting enhanced Gsα activity:</p><ul><li class="half_rhythm"><div>A <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variant associated with typical PHP1a features as well as testotoxicosis [<a class="bk_pop" href="#gnas-dis.REF.nakamoto.1996.18">Nakamoto et al 1996</a>]</div></li><li class="half_rhythm"><div>A four amino-acid <a class="def" href="/books/n/gene/glossary/def-item/insertion/">insertion</a> within the Gsα GDP/GTP-binding site identified in a brother and sister with PHP1a with transient neonatal diarrhea and pancreatic insufficiency who inherited the insertion from their unaffected mother, who had <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> [<a class="bk_pop" href="#gnas-dis.REF.aldred.2000.e35">Aldred et al 2000</a>]. Biochemical and intact cell studies suggested that the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> results from Gsα deficiency due to instability of the mutated protein and that the accompanying neonatal diarrhea may result from its enhanced constitutive activity in the intestine [<a class="bk_pop" href="#gnas-dis.REF.makita.2007.17424">Makita et al 2007</a>].</div></li></ul></div><div id="gnas-dis.Penetrance"><h3>Penetrance</h3><p>Disorders of <i>GNAS</i> inactivation show complete <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a>, with manifestations typically appearing during childhood. However, the exact manifestations and severity vary significantly among individuals.</p></div><div id="gnas-dis.Prevalence"><h3>Prevalence</h3><p>The estimated prevalence for pseudohypoparathyroidism (PHP) and Albright hereditary osteodystrophy (AHO) is approximately 0.79 per 100,000 (according to the Orphanet Report Series, November 2008).</p><p>A Japanese study estimated the prevalence of PHP at 3.4 per 1 million individuals [<a class="bk_pop" href="#gnas-dis.REF.nakamura.2000.29">Nakamura et al 2000</a>].</p><p>The prevalence of POH has never been estimated. It is likely extremely rare: fewer than 60 clinically confirmed individuals worldwide have been reported [<a class="bk_pop" href="#gnas-dis.REF.shore.2010.518">Shore & Kaplan 2010</a>].</p></div></div><div id="gnas-dis.Genetically_Related_Allelic_Dis"><h2 id="_gnas-dis_Genetically_Related_Allelic_Dis_">Genetically Related (Allelic) Disorders</h2><p>Postzygotic <i>GNAS</i> somatic pathogenic variants that result in a gain of function in Gsα can be seen in:</p><ul><li class="half_rhythm"><div><a href="/books/n/gene/mccune-albright/">McCune-Albright syndrome</a>, which is characterized by the clinical triad of fibrous dysplasia (monostotic or polyostotic), café au lait macules with irregular borders (so-called "coast of Maine"), and autonomous endocrine function, commonly precocious puberty but also often including other endocrine abnormalities such as thyrotoxicosis, pituitary gigantism, and Cushing syndrome [<a class="bk_pop" href="#gnas-dis.REF.lumbroso.2004.2107">Lumbroso et al 2004</a>]. McCune-Albright syndrome is clinically heterogeneous due to the extent of the various tissues affected in the mosaic state;</div></li><li class="half_rhythm"><div>Isolated features of McCune-Albright syndrome (e.g., monostotic or polyostotic fibrous dysplasia), ovarian cysts and testicular sex cord tumors, acromegaly due to <a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a> growth hormone-secreting adenomas in the pituitary, and ACTH-independent macronodular adrenal hyperplasia (none of which show other features of McCune-Albright syndrome); as well as intraductal papillary mucinous neoplasms of the pancreas [<a class="bk_pop" href="#gnas-dis.REF.furukawa.2011.161">Furukawa et al 2011</a>].</div></li></ul><p>Note that <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> activating <i>GNAS</i> pathogenic variants are presumed to be lethal to the embryo.</p></div><div id="gnas-dis.Differential_Diagnosis"><h2 id="_gnas-dis_Differential_Diagnosis_">Differential Diagnosis</h2><p>Conditions to be considered in the differential diagnosis include the following:</p><ul><li class="half_rhythm"><div><b>2q37 <a class="def" href="/books/n/gene/glossary/def-item/deletion-syndrome/">deletion syndrome</a>,</b> which is characterized by mild-moderate developmental delay/intellectual disability, brachydactyly of digits 3-5 (often digit 4 alone), short stature, obesity, hypotonia, round facies, behavioral abnormalities, joint hypermobility/dislocation, and scoliosis. Affected individuals have normal endocrine function, however. In most individuals with the 2q37 deletion syndrome, the deletion is <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>. This condition can also be associated with <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic variants in <i>HDAC4</i>.</div></li><li class="half_rhythm"><div><b>Idiopathic or primary hypoparathyroidism,</b> resulting from decreased parathyroid function, can have many causes including hypo- or aplasia of the parathyroid gland or autoimmune-related damage. Symptoms include cramping and twitching of the muscles (tetany), paresthesias, fatigue, and abdominal pain. PTH and calcium levels are low and phosphorous levels are elevated.</div></li><li class="half_rhythm"><div><b>Kenny-Caffey syndrome</b> (OMIM <a href="https://omim.org/entry/244460" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">244460</a>) is characterized by proportionate short stature, cortical thickening and medullary stenosis of the tubular bones, delayed closure of the anterior fontanelle, transient hypocalcemia (due to primary hypoparathyroidism), and normal intelligence. An <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> form is caused by mutation of <i>FAM111A</i> (see <a href="/books/n/gene/fam111a-dysp/"><i>FAM111A</i>-Related Skeletal Dysplasias</a>) and an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> form by mutation of <i>TBCE</i> (formerly <i>KCS1</i>).</div></li><li class="half_rhythm"><div><b>Type E brachydactyly</b> (OMIM <a href="https://omim.org/entry/113300" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">113300</a>, <a href="https://omim.org/entry/613382" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613382</a>) shows wide variability with shortening mainly of the metacarpals and metatarsals, but in some cases the phalanges as well. Some individuals have moderate short stature and round facies but do not have ectopic ossification or intellectual disability. Heterozygous pathogenic variants in <i>HOXD13</i> and <i>PTHLH</i> have been found in several affected individuals.</div></li><li class="half_rhythm"><div><b>Acrodysostosis</b> (OMIM <a href="https://omim.org/entry/101800" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">101800</a>, <a href="https://omim.org/entry/614613" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">614613</a>) is characterized by short stature, early-onset diffuse brachydactyly, round face, nasal hypoplasia, advanced bone age, and obesity. Laboratory studies may show resistance to multiple hormones, including PTH (parathyroid hormone), TSH (thyroid-stimulating hormone), calcitonin, growth hormone-releasing hormone (GHRH), and gonadotropins (LH and FSH). Heterozygous pathogenic variants in <i>PRKAR1A</i> or <i>PDE4D</i> have been identified in some affected individuals.</div></li></ul></div><div id="gnas-dis.Management"><h2 id="_gnas-dis_Management_">Management</h2><div id="gnas-dis.Evaluations_Following_Initial_D"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with a disorder of <i>GNAS</i> inactivation, the following evaluations are recommended:</p><ul><li class="half_rhythm"><div>Assessment of height, weight, body mass index, growth velocity, and pubertal development</div></li><li class="half_rhythm"><div>X-ray of hands and feet to classify the type and extent of brachydactyly; bone age study to determine whether skeletal maturation is advanced</div></li><li class="half_rhythm"><div>Endocrinology evaluation, with studies that may include the following:</div><ul><li class="half_rhythm"><div class="half_rhythm">Serum concentration of calcium and phosphorous</div></li><li class="half_rhythm"><div class="half_rhythm">Serum concentration of 25-hydroxyvitamin D and magnesium to evaluate respectively for severe vitamin D deficiency and hypomagnesemia, either of which can cause decreased responsiveness to PTH or secondary hyperparathyroidism</div></li><li class="half_rhythm"><div class="half_rhythm">Parathyroid hormone (PTH)</div></li><li class="half_rhythm"><div class="half_rhythm">Thyroid-stimulating hormone (TSH) and free T4</div></li><li class="half_rhythm"><div class="half_rhythm">Growth hormone evaluation (IGF1, IGFBP3, stimulated GH testing)</div></li><li class="half_rhythm"><div class="half_rhythm">Urinary calcium excretion and tubular reabsorption of phosphorus</div><div class="half_rhythm">Note: Renal responsiveness to PTH (via measurement of the serum or urinary nephrogenous cyclic AMP response to administered PTH) is rarely indicated.</div></li></ul></li><li class="half_rhythm"><div>Psychoeducational profile/developmental assessment</div></li><li class="half_rhythm"><div>Ophthalmologic examination for cataracts</div></li><li class="half_rhythm"><div>Consultation with nutritionist when obesity is present</div></li><li class="half_rhythm"><div>Consultation with a clinical geneticist and/or genetic counselor</div></li></ul></div><div id="gnas-dis.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p><b>Hypocalcemia.</b> Therapy of hypocalcemia is similar to the treatment of other forms of hypoparathyroidism: restoring serum calcium to the normal level using supplemental calcium (1-2 grams or 25-50 mg/kg of elemental calcium per day) and activated forms of vitamin D (calcitriol or 1-alpha calcidiol).</p><p>For all forms of PHP-I, calcium and activated vitamin D doses should be adjusted to try to maintain PTH levels at the upper limit of normal or even slightly higher (e.g., 50-150 pg/mL) to avoid secondary complications of chronic hyperparathyroidism. Urinary calcium excretion should be monitored to detect hypercalciuria; however, because calcium reabsorption in the thick ascending limb of the kidney remains responsive to PTH, hypercalciuria in these individuals is very rare as long as PTH is not suppressed.</p><p>Rarely thiazide diuretics can be considered in individuals who develop hypercalciuria.</p><p>Maintenance of a normal serum calcium-phosphorus product is recommended to minimize the risk of cataract formation and intracerebral calcification. Oral calcium supplements should be taken with meals to reduce serum phosphorus levels. Occasionally, phosphate-binding resins may be required.</p><p>Note: Because individuals with PHP-I do not respond to PTH, there is no role for PTH therapy in these individuals.</p><p><b>Hypothyroidism</b> and gonadotropin resistance are treated in the conventional manner.</p><p><b>Growth hormone deficiency.</b> If screening for growth hormone deficiency with appropriate provocative testing is abnormal, growth hormone replacement therapy should be considered. Note that in small case series treatment with growth hormone replacement increased growth velocity, but did not improve final adult height [<a class="bk_pop" href="#gnas-dis.REF.mantovani.2010.5011">Mantovani et al 2010</a>]. Nevertheless, there are suggestions that growth hormone replacement may also have a salutary effect on weight. Failure to improve final adult height may be due to partial resistance to the paracrine effects of PTH-related peptides in growth plate cartilage, accounting for advanced skeletal maturation, premature closure of the epiphyses, and short stature [<a class="bk_pop" href="#gnas-dis.REF.bastepe.2004.14794">Bastepe et al 2004</a>].</p><p><b>Subcutaneous ossifications</b> may be surgically removed if they are large or cause local irritation. Ossifications may recur if residua are left in situ. Ossifications may enlarge in individuals treated with growth hormone.</p><p><b>Obesity</b> is the greatest treatment challenge. Current strategies involve the usual recommendations of reduced caloric intake and increased physical activity. Given that individuals with PHP-Ia and PHP-Ic have decreased resting energy expenditure and hyperphagia, these efforts may be less successful than in persons with obesity from other causes.</p></div><div id="gnas-dis.Surveillance"><h3>Surveillance</h3><p>Surveillance includes the following:</p><ul><li class="half_rhythm"><div>Once the diagnosis is established, annual monitoring for endocrine abnormalities with measurement of serum concentration of PTH, calcium, and phosphate; TSH and free T4, and urinary calcium excretion (either 24-hour urine collection or random urine collections for determination of the calcium/creatinine ratio). These studies should be begun as soon an individual begins treatment, and may be performed more frequently in growing children who may experience increasing requirements for thyroid hormone and/or activated forms of vitamin D.</div></li><li class="half_rhythm"><div>Growth velocity and growth hormone status (serum IGF1 and/or stimulated growth hormone testing) should be evaluated annually. Individuals who receive growth hormone replacement should be monitored every three to four months per customary protocols.</div></li><li class="half_rhythm"><div>Routine physical examination including assessment of: (1) height to identify changes in growth velocity; (2) the hands and feet for evidence of brachydactyly; and (3) new and/or enlarging ectopic ossifications</div></li><li class="half_rhythm"><div>Annual examination by an ophthalmologist to monitor development of and/or progression of cataracts</div></li><li class="half_rhythm"><div>Periodic assessment of psychoeducational needs regarding school assistance/educational support and developmental therapies (e.g., physical, occupational, and speech therapy)</div></li><li class="half_rhythm"><div>Monitoring of post-pubertal females for disturbances in hypothalamic-pituitary-ovarian function</div></li></ul></div><div id="gnas-dis.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Limit dietary intake of phosphorus (dairy products and meats) in persons with persistently elevated serum levels of phosphate.</p></div><div id="gnas-dis.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to evaluate apparently asymptomatic first-degree relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment. Evaluations can include:</p><ul><li class="half_rhythm"><div>Molecular genetic testing if the genetic mechanism of <i>GNAS</i> inactivation has been identified in the family (<a href="/books/NBK459117/table/gnas-dis.T.phenotypes_and_genetic_mechan/?report=objectonly" target="object" rid-ob="figobgnasdisTphenotypesandgeneticmechan">Table 2</a>).</div></li><li class="half_rhythm"><div>If the genetic mechanism of <i>GNAS</i> inactivation is not known, at-risk relatives can be assessed by physical examination and regular measurement of serum concentrations of parathyroid hormone (PTH), calcium, and phosphorus.</div></li></ul><p>See <a href="#gnas-dis.Related_Genetic_Counseling_Issu">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="gnas-dis.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Serum concentration of calcium and thyroid studies (TSH and free T4) should be monitored throughout pregnancy, labor, and the postpartum period.</p><p>Calcium, vitamin D, and thyroid hormone should be supplemented as needed [<a class="bk_pop" href="#gnas-dis.REF.singh.2012.629583">Singh et al 2012</a>]. Note that requirements for thyroid hormone will increase in early pregnancy, while requirements for activated forms of vitamin D may decline during the third trimester.</p><p>Because breastfeeding can significantly reduce requirements for activated vitamin D, mothers should be monitored for this during lactation and after weaning.</p></div><div id="gnas-dis.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Dr Emily Germain-Lee at the University of Connecticut is recruiting individuals with PHP-Ia and AHO to determine whether growth hormone therapy can improve short stature and obesity.</p><p>Researchers at Vanderbilt University Medical Center are investigating whether theophylline treatment promotes weight loss, improves glucose tolerance, and slows growth plate closure in children and young adults.</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="gnas-dis.Genetic_Counseling"><h2 id="_gnas-dis_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="gnas-dis.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Disorders of <i>GNAS</i> inactivation are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner with the specific <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> determined by the parental origin of the defective <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> [<a class="bk_pop" href="#gnas-dis.REF.lemos.2015.11">Lemos &Thakker 2015</a>].</p><p><b>Pseudohypoparathyroidism (PHP) Ia</b>, <b>Ib</b>, and <b>Ic</b> result from reduced or absent expression/function of the protein Gsα (encoded by the maternal <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a>) due to one of the following:</p><ul><li class="half_rhythm"><div>An <a class="def" href="/books/n/gene/glossary/def-item/inactivating/">inactivating</a> <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a></div></li><li class="half_rhythm"><div>A genetic alteration in the <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> regulatory elements in the <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> or the nearby <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>, <i>STX16</i>, that prevents proper maternal imprint of the <i>GNAS</i> complex locus</div></li><li class="half_rhythm"><div>Isolated epimutations</div></li><li class="half_rhythm"><div>Paternal 20q disomy</div></li></ul><p><b>The PPHP</b> and <b>POH/OC phenotypes</b> are associated with lack of expression/function of Gsα encoded by the paternal <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> due to an <a class="def" href="/books/n/gene/glossary/def-item/inactivating/">inactivating</a> <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>; the POH/OC phenotypes are associated with lack of expression/function of Gsα encoded by the maternal <i>GNAS</i> allele due to an inactivating <i>GNAS</i> pathogenic variant.</p></div><div id="gnas-dis.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>Of individuals with a disorder of <i>GNAS</i> inactivation, approximately 38% have an affected parent and 38% have a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
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<i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>; in the remaining approximately 25% the cause is unknown [<a class="bk_pop" href="#gnas-dis.REF.elli.2016.3657">Elli et al 2016</a>].</p><div id="gnas-dis.T.disorders_of_gnas_inactivatio" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Disorders of <i>GNAS</i> Inactivation: Risk to Sibs of a Proband Based on the Parents' Genetic Status</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK459117/table/gnas-dis.T.disorders_of_gnas_inactivatio/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gnas-dis.T.disorders_of_gnas_inactivatio_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Parent</th><th id="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder in Proband</th><th id="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Status of Parent</th><th id="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation of Parent</th><th id="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Genetic Status of Parent</th><th id="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_6" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Risk to Sibs of Proband</th></tr></thead><tbody><tr><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_1" rowspan="6" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Father</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PHP-Ia</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Not affected</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_4" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Usually no further eval/testing</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_5" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Father will not be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for mechanism of <i>GNAS</i> inactivation identified in <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_6" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Depends on genetic status of mother</td></tr><tr><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">PHP-Ib</td></tr><tr><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">PHP-Ic</td></tr><tr><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">PPHP</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">May be unaffected or have PHP-Ia, PHP-Ic, PPHP, OC, or POH <sup>1,</sup> <sup>2, 3</sup></td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_4" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Test for <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>’s <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a><br />AND/OR<br />Detailed physical examination & measurement of serum concentration of PTH, calcium, phosphorous</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_5" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">If <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>’s <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> not detected in paternal leukocyte DNA, explanations include:
|
||
<ul><li class="half_rhythm"><div><i>De novo</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></div></li><li class="half_rhythm"><div>Paternal <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a></div></li></ul>
|
||
</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_6" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">If father affected: 50% for PPHP or POH/OC<br />If father clinically unaffected: presumed low<br />If <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> not found in paternal leukocyte DNA: slightly > general population (i.e., theoretic possibility of <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>)</td></tr><tr><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">POH</td></tr><tr><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">OC</td></tr><tr><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_1" rowspan="6" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Mother</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PHP-Ia</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">May be unaffected or have PHP-Ic, PPHP, POH, or OC <sup>1, 2, 4</sup></td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_4" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Test for genetic mechanism of <i>GNAS</i> inactivation identified in <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a><br />AND/OR<br />Detailed physical exam & measurement of serum concentration of PTH, calcium, phosphorous</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_5" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">If mechanism of <i>GNAS</i> inactivation in <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> not detected in maternal leukocyte DNA, possible explanations:
|
||
<ul><li class="half_rhythm"><div><i>De novo</i> genetic alteration in <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></div></li><li class="half_rhythm"><div>Isolated <a class="def" href="/books/n/gene/glossary/def-item/epimutation/">epimutation</a> in <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></div></li><li class="half_rhythm"><div>Maternal <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> <sup>5</sup></div></li></ul>
|
||
</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_6" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">If mother affected: 50% for PHP-Ia, PHP-Ib, or PHP-Ic<br />If mother clinically unaffected: presumed low<br />If <i>GNAS</i> inactivation alternation not identified in maternal leukocyte DNA: slightly > general population (i.e., possibility of <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>) <sup>5</sup></td></tr><tr><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">PHP-Ib</td></tr><tr><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">PHP-Ic</td></tr><tr><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">PPHP</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Not affected</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No further eval/testing</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Not <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a></td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Depends on father's genetic status</td></tr><tr><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">POH</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Typically not affected <sup>6</sup></td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_4" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">If father's eval normal, mol gen testing and/or clinical eval of mother may be appropriate.</td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_5" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Typically not <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a></td><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_6" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Unknown</td></tr><tr><td headers="hd_h_gnas-dis.T.disorders_of_gnas_inactivatio_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">OC</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">OC = osteoma cutis; PHP-Ia = pseudohypoparathyroidism Ia; PHP-Ib = pseudohypoparathyroidism Ib; PHP-Ic = pseudohypoparathyroidism Ic; POH = progressive osseous heteroplasia; PPHP = pseudopseudohypoparathyroidism; PTH = parathyroid hormone</p></div></dd><dt>1. </dt><dd><div id="gnas-dis.TF.3.1"><p class="no_margin">Although some probands diagnosed with a disorder of <i>GNAS</i> inactivation have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in other family members.</p></div></dd><dt>2. </dt><dd><div id="gnas-dis.TF.3.2"><p class="no_margin">If the parent is the individual in the family in whom the genetic alteration first occurred, the parent may have <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a> and may be mildly/minimally affected.</p></div></dd><dt>3. </dt><dd><div id="gnas-dis.TF.3.3"><p class="no_margin">The endocrine features of PHP-1a may in some cases become apparent after the development of findings of AHO, suggesting that an individual may be incorrectly diagnosed initially as PPHP if an AHO <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> occurs prior to the onset of endocrine abnormalities. In this case, maternal testing may identify a genetic or <a class="def" href="/books/n/gene/glossary/def-item/epigenetic/">epigenetic</a> cause.</p></div></dd><dt>4. </dt><dd><div id="gnas-dis.TF.3.4"><p class="no_margin"><a class="bk_pop" href="#gnas-dis.REF.elli.2014b.e724">Elli et al [2014b]</a> reported an individual with PHP-1b who inherited an <i>STX16</i> or other regulatory <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> element <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> from his asymptomatic mother whose deletion was on her paternally inherited <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>.</p></div></dd><dt>5. </dt><dd><div id="gnas-dis.TF.3.5"><p class="no_margin"><a class="bk_pop" href="#gnas-dis.REF.aldred.2000.e35">Aldred et al [2000]</a>, <a class="bk_pop" href="#gnas-dis.REF.fernandezrebollo.2010.765">Fernandez-Rebollo et al [2010]</a>, <a class="bk_pop" href="#gnas-dis.REF.ngai.2010.2784">Ngai et al [2010]</a></p></div></dd><dt>6. </dt><dd><div id="gnas-dis.TF.3.6"><p class="no_margin">POH/OC is more often inherited from the father; however, features of POH/OC are on occasion due to maternal inheritance.</p></div></dd></dl></div></div></div><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with a disorder of GNAS inactivation.</b> Each child of an individual with a disorder of <i>GNAS</i> inactivation has a 50% chance of inheriting the genetic alteration, except for persons with <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> PHP-1b, in which there may not be an underlying heritable variant. The <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of the offspring who inherit a <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> or <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> defect depends on the sex of the parent of origin (see <a href="/books/NBK459117/table/gnas-dis.T.disorder_of_gnas_inactivation/?report=objectonly" target="object" rid-ob="figobgnasdisTdisorderofgnasinactivation">Table 4</a>).</p><div id="gnas-dis.T.disorder_of_gnas_inactivation" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Disorder of <i>GNAS</i> Inactivation: Phenotypes for Offspring Based on the Sex of the Parent</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK459117/table/gnas-dis.T.disorder_of_gnas_inactivation/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gnas-dis.T.disorder_of_gnas_inactivation_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gnas-dis.T.disorder_of_gnas_inactivation_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sex of Parent</th><th id="hd_h_gnas-dis.T.disorder_of_gnas_inactivation_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Phenotypes for Which Offspring are at 50% Risk</th></tr></thead><tbody><tr><td headers="hd_h_gnas-dis.T.disorder_of_gnas_inactivation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Male</b>
|
||
</td><td headers="hd_h_gnas-dis.T.disorder_of_gnas_inactivation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PPHP<br />POH/OC</td></tr><tr><td headers="hd_h_gnas-dis.T.disorder_of_gnas_inactivation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Female</b>
|
||
</td><td headers="hd_h_gnas-dis.T.disorder_of_gnas_inactivation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PHP-Ia <sup>1</sup><br />PHP-Ib <sup>1</sup><br />PHP-Ic <sup>1</sup><br />POH/OC</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="gnas-dis.TF.4.1"><p class="no_margin">PHP type depends on the maternal <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a>.</p></div></dd></dl></div></div></div><p>Note regarding inheritance of PHP-Ib: Although females who inherit a PHP-Ib-related genetic alteration from their father (i.e., a paternally <a class="def" href="/books/n/gene/glossary/def-item/imprinted/">imprinted</a> PHP-Ib-related genetic alteration) will be unaffected, their offspring have a 50% risk of inheriting the now maternally imprinted PHP-Ib-related genetic alteration and being affected.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents: if a parent is affected, the parent's family members may be at risk.</p></div><div id="gnas-dis.Related_Genetic_Counseling_Issu"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#gnas-dis.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p><b>Considerations in families with an apparent <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</b> When neither parent of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely <i>de novo</i>. However, non-medical explanations including <a class="def" href="/books/n/gene/glossary/def-item/alternate-paternity/">alternate paternity</a> or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.</p><p>
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||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bk_pop" href="#gnas-dis.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="gnas-dis.Prenatal_Testing_and_Preimplant"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the mechanism of <i>GNAS</i> inactivation has been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk for a disorder of <i>GNAS</i> inactivation and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p><p>The <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> in offspring who inherit a <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> depends on the sex of the parent of origin (i.e., the parent from whom an individual inherited the <i>GNAS</i> pathogenic variant; see <a href="#gnas-dis.Risk_to_Family_Members">Risk to Family Members</a>, <b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with a disorder of <i>GNAS</i> inactivation</b>).</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="gnas-dis.Resources"><h2 id="_gnas-dis_Resources_">Resources</h2><p>
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||
<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>Metabolic Support UK</b>
|
||
</div><div>United Kingdom</div><div><b>Phone:</b> 0845 241 2173</div><div>
|
||
<a href="https://metabolicsupportuk.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">metabolicsupportuk.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>UCLA International Skeletal Dysplasia Registry (ISDR)</b>
|
||
</div><div><b>Phone:</b> 310-825-8998</div><div>
|
||
<a href="https://www.uclahealth.org/ortho/isdr" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">International Skeletal Dysplasia Registry</a>
|
||
</div></li></ul>
|
||
</div><div id="gnas-dis.Molecular_Genetics"><h2 id="_gnas-dis_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="gnas-dis.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Disorders of GNAS Inactivation: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK459117/table/gnas-dis.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gnas-dis.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_gnas-dis.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_gnas-dis.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_gnas-dis.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_gnas-dis.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_gnas-dis.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_gnas-dis.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_gnas-dis.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/2778" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>GNAS</i>
|
||
</a>
|
||
</td><td headers="hd_b_gnas-dis.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=2778" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">20q13<wbr style="display:inline-block"></wbr>.32</a>
|
||
</td><td headers="hd_b_gnas-dis.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P63092" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Guanine nucleotide-binding protein G(s) subunit alpha isoforms short</a>
|
||
</td><td headers="hd_b_gnas-dis.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://databases.lovd.nl/shared/genes/GNAS" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GNAS complex locus (GNAS) @ LOVD</a>
|
||
</td><td headers="hd_b_gnas-dis.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=GNAS" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GNAS</a>
|
||
</td><td headers="hd_b_gnas-dis.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=GNAS[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GNAS</a>
|
||
</td></tr><tr><td headers="hd_b_gnas-dis.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/8675" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>STX16</i>
|
||
</a>
|
||
</td><td headers="hd_b_gnas-dis.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=8675" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">20q13<wbr style="display:inline-block"></wbr>.32</a>
|
||
</td><td headers="hd_b_gnas-dis.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/O14662" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Syntaxin-16</a>
|
||
</td><td headers="hd_b_gnas-dis.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://databases.lovd.nl/shared/genes/STX16" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">STX16 database</a>
|
||
</td><td headers="hd_b_gnas-dis.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=STX16" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">STX16</a>
|
||
</td><td headers="hd_b_gnas-dis.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=STX16[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">STX16</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="gnas-dis.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="gnas-dis.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Disorders of GNAS Inactivation (<a href="/omim/103580,139320,166350,603233,603666,610540,612462,612463" 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/NBK459117/table/gnas-dis.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gnas-dis.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/103580" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">103580</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PSEUDOHYPOPARATHYROIDISM, TYPE IA; PHP1A</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/139320" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">139320</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GNAS COMPLEX LOCUS; GNAS</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/166350" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">166350</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OSSEOUS HETEROPLASIA, PROGRESSIVE; POH</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/603233" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">603233</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PSEUDOHYPOPARATHYROIDISM, TYPE IB; PHP1B</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/603666" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">603666</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SYNTAXIN 16; STX16</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/610540" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">610540</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GNAS COMPLEX LOCUS, ANTISENSE TRANSCRIPT 1; GNASAS1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/612462" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">612462</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PSEUDOHYPOPARATHYROIDISM, TYPE IC; PHP1C</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/612463" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">612463</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PSEUDOPSEUDOHYPOPARATHYROIDISM; PPHP</td></tr></tbody></table></div></div><div id="gnas-dis.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><b>The PHP-Ia, Ib, Ic</b>
|
||
<b>phenotypes</b> are associated with lack of expression/function of the protein Gsα (encoded by the maternal <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a>) as a result of one of the following:</p><ul><li class="half_rhythm"><div>An <a class="def" href="/books/n/gene/glossary/def-item/inactivating/">inactivating</a> <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a></div></li><li class="half_rhythm"><div>A genetic alteration in the <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> regulatory elements in the <i>GNAS</i> complex <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> or the nearby <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>, <i>STX16</i>, that prevents proper maternal imprint of the <i>GNAS</i> complex locus</div></li><li class="half_rhythm"><div>Isolated epimutations</div></li><li class="half_rhythm"><div>Paternal 20q disomy</div></li></ul><p><b>PPHP</b> is associated with lack of expression/function of Gsα encoded from the paternal <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> with an <a class="def" href="/books/n/gene/glossary/def-item/inactivating/">inactivating</a> <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. POH/OC is also most commonly associated with paternal <i>GNAS</i> pathogenic variants.</p><div id="gnas-dis.Gene_Structure"><h4>Gene Structure</h4><p><i>GNAS</i> is a complex transcriptional unit with multiple transcript variants through the use of alternative first exons, alternative <a class="def" href="/books/n/gene/glossary/def-item/splicing/">splicing</a> of downstream exons, antisense transcripts, and reciprocal <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a>. For detailed summaries of <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>, transcript, and protein isoform information see: <a class="figpopup" href="/books/NBK459117/figure/gnas-dis.F1/?report=objectonly" target="object" rid-figpopup="figgnasdisF1" rid-ob="figobgnasdisF1">Figure 1</a>; <a href="/books/NBK459117/#gnas-dis.molgen.TA">Table A</a>, <b>Gene</b>; <a class="bk_pop" href="#gnas-dis.REF.levine.2012.443">Levine [2012]</a>; <a class="bk_pop" href="#gnas-dis.REF.pignolo.2015.37">Pignolo et al [2015]</a>; <a class="bk_pop" href="#gnas-dis.REF.mantovani.2016.347">Mantovani et al [2016]</a>; and <a class="bk_pop" href="#gnas-dis.REF.tafaj.2017.347">Tafaj & Jüppner [2017]</a>.</p><p>Gsα is encoded by <i>GNAS</i> exons 1-13 from the transcript variant <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000516.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000516.5</a>, which is expressed from both maternal and paternal alleles in most cells. However, in some cells (e.g., pituitary somatotropes, proximal renal tubular cells, thyroid epithelial cells, and gonadal cells) Gsα is primarily expressed from the maternal <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>; preferential maternal expression may also occur in other tissues. While the Gsα promoter is not methylated, it appears that <a class="def" href="/books/n/gene/glossary/def-item/cis/"><i>cis</i></a>-acting elements that control tissue-specific paternal <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> of Gsα are located within the primary imprint region in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> A/B (also referred to as exon 1A) [<a class="bk_pop" href="#gnas-dis.REF.levine.2012.443">Levine 2012</a>] (see <a class="figpopup" href="/books/NBK459117/figure/gnas-dis.F1/?report=objectonly" target="object" rid-figpopup="figgnasdisF1" rid-ob="figobgnasdisF1">Figure 1</a>).</p></div><div id="gnas-dis.Pathogenic_Variants"><h4>Pathogenic Variants</h4><p><b>PHP-Ia and PHP-Ic and PPHP or POH/OC.</b> Although the <a class="def" href="/books/n/gene/glossary/def-item/inactivating/">inactivating</a> <i>GNAS</i> pathogenic variants observed in the phenotypes PHP-Ia and PHP-Ic and the phenotypes PPHP or POH/OC are similar, they differ in the parent of origin (<a href="/books/NBK459117/table/gnas-dis.T.phenotypes_and_genetic_mechan/?report=objectonly" target="object" rid-ob="figobgnasdisTphenotypesandgeneticmechan">Table 2</a>):</p><ul><li class="half_rhythm"><div>PHP-Ia and PHP-Ic result from lack of expression of the maternal <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a></div></li><li class="half_rhythm"><div>PPHP result from lack of expression of the paternal <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>.</div></li><li class="half_rhythm"><div>POH and OC can be associated with pathogenic variants in either the maternal or paternal <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>; however, paternal pathogenic variants are more common.</div></li></ul><p><b>PHP-Ib.</b> The genetic alteration differs in <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> cases and <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases (i.e., a single occurrence in a family) (<a href="/books/NBK459117/table/gnas-dis.T.phenotypes_and_genetic_mechan/?report=objectonly" target="object" rid-ob="figobgnasdisTphenotypesandgeneticmechan">Table 2</a>).</p><p>Familial PHP-Ib genetic alterations include:</p><ul><li class="half_rhythm"><div>A pathogenic <i>GNAS</i> variant in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 13 on the maternal <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>;</div></li><li class="half_rhythm"><div>Loss of <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> (<a class="def" href="/books/n/gene/glossary/def-item/methylation/">methylation</a>) at the maternal GNAS <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> A/B DMR (also referred to as exon 1A or <i>GNAS A/B</i>:TSS-DMR);</div></li><li class="half_rhythm"><div>Deletion of maternal <i>STX16</i> exons 3-5 or 4-6 [<a class="bk_pop" href="#gnas-dis.REF.bastepe.2003.1255">Bastepe et al 2003</a>, <a class="bk_pop" href="#gnas-dis.REF.linglart.2005.804">Linglart et al 2005</a>];</div></li><li class="half_rhythm"><div>Deletion of maternal NESP and/or NESP-AS [<a class="bk_pop" href="#gnas-dis.REF.bastepe.2005.25">Bastepe et al 2005</a>, <a class="bk_pop" href="#gnas-dis.REF.chillambhi.2010.3993">Chillambhi et al 2010</a>, <a class="bk_pop" href="#gnas-dis.REF.richard.2012.e863">Richard et al 2012</a>, <a class="bk_pop" href="#gnas-dis.REF.rezwan.2015.494">Rezwan et al 2015</a>];</div></li><li class="half_rhythm"><div>Deletion of maternal <i>STX16</i> [<a class="bk_pop" href="#gnas-dis.REF.elli.2014b.e724">Elli et al 2014b</a>, <a class="bk_pop" href="#gnas-dis.REF.tafaj.2017.347">Tafaj & Jüppner 2017</a>].</div></li></ul><p>Simplex PHP-Ib genetic alterations include:</p><ul><li class="half_rhythm"><div>GNAS <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> abnormalities that involve multiple DMRs [<a class="bk_pop" href="#gnas-dis.REF.mantovani.2012.716">Mantovani et al 2012</a>];</div></li><li class="half_rhythm"><div>Paternal <a class="def" href="/books/n/gene/glossary/def-item/uniparental-disomy/">uniparental disomy</a> for all or part of <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> 20 [<a class="bk_pop" href="#gnas-dis.REF.fernandezrebollo.2010.765">Fernandez-Rebollo et al 2010</a>, <a class="bk_pop" href="#gnas-dis.REF.linglart.2013.119">Linglart et al 2013</a>].</div></li></ul><p><b>General comments.</b> The most commonly found <i>GNAS</i> variants are frameshift, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, or <a class="def" href="/books/n/gene/glossary/def-item/splicing/">splicing</a>; they are expected to lead to untranslated proteins. Nonsense and single-nucleotide variants that alter translation initiation or <a class="def" href="/books/n/gene/glossary/def-item/mrna/">mRNA</a> splicing have also been documented [<a class="bk_pop" href="#gnas-dis.REF.elli.2013a.276">Elli et al 2013a</a>, <a class="bk_pop" href="#gnas-dis.REF.elli.2016.3657">Elli et al 2016</a>].</p><p>Heterozygous <i>GNAS</i> pathogenic variants in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 1 are the most common (18%). Only one individual has been described with a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in exon 3, which is alternatively spliced out of transcripts that encode a slightly smaller form of Gsα [<a class="bk_pop" href="#gnas-dis.REF.thiele.2007.1764">Thiele et al 2007</a>]. While pathogenic variants are distributed across <i>GNAS</i> [<a class="bk_pop" href="#gnas-dis.REF.mantovani.2016.347">Mantovani et al 2016</a>], exon 7 is a <a class="def" href="/books/n/gene/glossary/def-item/hot-spot/">hot spot</a> for the 4-bp <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> <a href="/books/NBK459117/table/gnas-dis.T.gnas_pathogenic_variants_disc/?report=objectonly" target="object" rid-ob="figobgnasdisTgnaspathogenicvariantsdisc">c.565_568delGACT</a> [<a class="bk_pop" href="#gnas-dis.REF.elli.2013a.276">Elli et al 2013a</a>].</p><p>Individuals with pathogenic variants in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 1 of <i>GNAS</i> have a higher prevalence of ectopic ossifications than other affected individuals [<a class="bk_pop" href="#gnas-dis.REF.elli.2013a.276">Elli et al 2013a</a>]. Truncating variants are associated with more ectopic ossifications than other types of pathogenic variants [<a class="bk_pop" href="#gnas-dis.REF.lemos.2015.11">Lemos & Thakker 2015</a>, <a class="bk_pop" href="#gnas-dis.REF.thiele.2015.111">Thiele et al 2015</a>].</p><div id="gnas-dis.T.gnas_pathogenic_variants_disc" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p><i>GNAS</i> Pathogenic Variants Discussed in This <i>GeneReview</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK459117/table/gnas-dis.T.gnas_pathogenic_variants_disc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__gnas-dis.T.gnas_pathogenic_variants_disc_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_gnas-dis.T.gnas_pathogenic_variants_disc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_gnas-dis.T.gnas_pathogenic_variants_disc_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_gnas-dis.T.gnas_pathogenic_variants_disc_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th></tr></thead><tbody><tr><td headers="hd_h_gnas-dis.T.gnas_pathogenic_variants_disc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.432+1G>A</td><td headers="hd_h_gnas-dis.T.gnas_pathogenic_variants_disc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_gnas-dis.T.gnas_pathogenic_variants_disc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000516.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000516<wbr style="display:inline-block"></wbr>.5</a>
|
||
</td></tr><tr><td headers="hd_h_gnas-dis.T.gnas_pathogenic_variants_disc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.493C>T</td><td headers="hd_h_gnas-dis.T.gnas_pathogenic_variants_disc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg165Cys</td><td headers="hd_h_gnas-dis.T.gnas_pathogenic_variants_disc_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000516.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000516<wbr style="display:inline-block"></wbr>.5</a>
|
||
<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000507.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000507<wbr style="display:inline-block"></wbr>.1</a>
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</td></tr><tr><td headers="hd_h_gnas-dis.T.gnas_pathogenic_variants_disc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.565_568delGACT</td><td headers="hd_h_gnas-dis.T.gnas_pathogenic_variants_disc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asp189MetfsTer14</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd><dt>1. </dt><dd><div id="gnas-dis.TF.5.1"><p class="no_margin">Variant descriptions are based on the RefSeq <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000516.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000516<wbr style="display:inline-block"></wbr>.5</a>. <a class="bk_pop" href="#gnas-dis.REF.thiele.2015.111">Thiele et al [2015]</a> detail the difference in variant numbering using this reference sequences versus an alternate sequence <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001077488.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_001077488<wbr style="display:inline-block"></wbr>.2</a>.</p></div></dd></dl></div></div></div></div><div id="gnas-dis.Normal_Gene_Product"><h4>Normal Gene Product</h4><p><i>GNAS</i> encodes the alpha subunit of the stimulatory guanine nucleotide-binding protein (Gsα), which binds and hydrolyzes GTP as a downstream effect following activation of a hormone receptor [<a class="bk_pop" href="#gnas-dis.REF.elli.2013b.411">Elli et al 2013b</a>].</p><p><i>GNAS</i> encodes for two protein <a class="def" href="/books/n/gene/glossary/def-item/isoforms/">isoforms</a> depending on whether <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 3 is included (52-kd) or excluded (45-kd).</p></div><div id="gnas-dis.Abnormal_Gene_Product"><h4>Abnormal Gene Product</h4><p>Haploinsufficiency of Gsα results in PHP-Ia and PHP-Ic (lack of expression of the maternal <i>GNAS</i> <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>) and PPHP (lack of expression of the paternal <i>GNAS</i> allele).</p><p>In PHP-Ib, the <a class="def" href="/books/n/gene/glossary/def-item/imprinting/">imprinting</a> defects lead to reduced expression of Gsα in a tissue-specific manner.</p><p>In PHP-Ic <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>GNAS</i> pathogenic variants do not affect the function of Gsα (in vitro activity is normal), but rather affect the coupling of Gsα to its receptors. In a few affected individuals, pathogenic variants in <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 13 were shown to affect receptor-mediated activation [<a class="bk_pop" href="#gnas-dis.REF.mantovani.2012.716">Mantovani et al 2012</a>]. The discussion of PHP-1c can be complicated: patients with Gs coupling defects in fact have PHP-1a and are misassigned due to the vagaries of the old ex vivo assay, which did not activate Gs via a receptor pathway. PHP-1c should be reserved for the rare persons (if they exist) who have PHP-1a and no observable Gs abnormality.</p></div></div></div><div id="gnas-dis.Chapter_Notes"><h2 id="_gnas-dis_Chapter_Notes_">Chapter Notes</h2><div id="gnas-dis.Author_Notes"><h3>Author Notes</h3><p>Dr Levine's <a href="https://www.chop.edu/doctors/levine-michael-a" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">web page</a></p></div><div id="gnas-dis.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>26 October 2017 (bp) Review posted live</div></li><li class="half_rhythm"><div>15 April 2015 (mal) Original submission</div></li></ul></div></div><div id="gnas-dis.References"><h2 id="_gnas-dis_References_">References</h2><div id="gnas-dis.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.ahrens.2001.4630">Ahrens W, Hiort O, Staedt P, Kirschner T, Marschke C, Kruse K. Analysis of the GNAS1 gene in Albright's hereditary osteodystrophy. <span><span class="ref-journal">J Clin Endocrinol Metab. </span>2001;<span class="ref-vol">86</span>:4630–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11600516" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11600516</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.aldred.2002.167">Aldred MA, Aftimos S, Hall C, Waters KS, Thakker RV, Trembath RC, Brueton L. Constitutional deletion of chromosome 20q in two patients affected with albright hereditary osteodystrophy. <span><span class="ref-journal">Am J Med Genet. </span>2002;<span class="ref-vol">113</span>:167–72.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12407707" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12407707</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.aldred.2000.e35">Aldred MA, Bagshaw RJ, Macdermot K, Casson D, Murch SH, Walker-Smith JA, Trembath RC. Germline mosaicism for a GNAS1 mutation and Albright hereditary osteodystrophy. <span><span class="ref-journal">J Med Genet. </span>2000;<span class="ref-vol">37</span>:E35. </span> [<a href="/pmc/articles/PMC1734481/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1734481</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11073544" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11073544</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.bastepe.2003.1255">Bastepe M, Fröhlich LF, Hendy GN, Indridason OS, Josse RG, Koshiyama H, Körkkö J, Nakamoto JM, Rosenbloom AL, Slyper AH, Sugimoto T, Tsatsoulis A, Crawford JD, Jüppner H. Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. <span><span class="ref-journal">J Clin Invest. </span>2003;<span class="ref-vol">112</span>:1255–63.</span> [<a href="/pmc/articles/PMC213493/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC213493</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14561710" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14561710</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.bastepe.2005.25">Bastepe M, Fröhlich LF, Linglart A, Abu-Zahra HS, Tojo K, Ward LM, Jüppner H. Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. <span><span class="ref-journal">Nat Genet. </span>2005;<span class="ref-vol">37</span>:25–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15592469" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15592469</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.bastepe.2004.14794">Bastepe M, Weinstein LS, Ogata N, Kawaguchi H, Jüppner H, Kronenberg HM, Chung UI. Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2004;<span class="ref-vol">101</span>:14794–9.</span> [<a href="/pmc/articles/PMC522030/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC522030</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15459318" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15459318</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.br_hin.2015.e623">Bréhin AC, Colson C, Maupetit-Méhouas S, Grybek V, Richard N, Linglart A, Kottler ML, Jüppner H. Loss of methylation at GNAS exon A/B is associated with increased intrauterine growth. <span><span class="ref-journal">J Clin Endocrinol Metab. </span>2015;<span class="ref-vol">100</span>:E623–31.</span> [<a href="/pmc/articles/PMC4399294/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4399294</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25603460" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25603460</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.chen.2017.500">Chen M, Shrestha YB, Podyma B, Cui Z, Naglieri B, Sun H, Ho T, Wilson EA, Li YQ, Gavrilova O, Weinstein LS. Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutations. <span><span class="ref-journal">J Clin Invest. </span>2017;<span class="ref-vol">127</span>:500–10.</span> [<a href="/pmc/articles/PMC5272175/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5272175</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27991864" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27991864</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.chillambhi.2010.3993">Chillambhi S, Turan S, Hwang DY, Chen HC, Jüppner H, Bastepe M. Deletion of the noncoding GNAS antisense transcript causes pseudohypoparathyroidism type Ib and biparental defects of GNAS methylation in cis. <span><span class="ref-journal">J Clin Endocrinol Metab. </span>2010;<span class="ref-vol">95</span>:3993–4002.</span> [<a href="/pmc/articles/PMC2913043/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2913043</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20444925" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20444925</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.dekelbab.2009.249">Dekelbab BH, Aughton DJ, Levine MA. Pseudohypoparathyroidism type 1a and morbid obesity in infancy. <span><span class="ref-journal">Endocr Pract. </span>2009;<span class="ref-vol">15</span>:249–53.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19364695" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19364695</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.de_sanctis.2007.97">de Sanctis L, Bellone J, Salerno M, Faleschini E, Caruso-Nicoletti M, Cicchetti M, Concolino D, Balsamo A, Buzi F, Ghizzoni L, de Sanctis C. GH secretion in a cohort of children with pseudohypoparathyroidism type Ia. <span><span class="ref-journal">J Endocrinol Invest. </span>2007;<span class="ref-vol">30</span>:97–103.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17392598" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17392598</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.elli.2013a.276">Elli FM, Barbieri AM, Bordogna P, Ferrari P, Bufo R, Ferrante E, Giardino E, Beck-Peccoz P, Spada A, Mantovani G. Screening for GNAS genetic and epigenetic alterations in progressive osseous heteroplasia: first Italian series. <span><span class="ref-journal">Bone. </span>2013a;<span class="ref-vol">56</span>:276–80.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23796510" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23796510</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.elli.2014a.e508">Elli FM, de Sanctis L, Bollati V, Tarantini L, Filopanti M, Barbieri AM, Peverelli E, Beck-Peccoz P, Spada A, Mantovani G. Quantitative analysis of methylation defects and correlation with clinical characteristics in patients with pseudohypoparathyroidism type I and GNAS epigenetic alterations. <span><span class="ref-journal">J Clin Endocrinol Metab. </span>2014a;<span class="ref-vol">99</span>:E508–17.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24423294" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24423294</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.elli.2013b.411">Elli FM, deSanctis L, Ceoloni B, Barbieri AM, Bordogna P, Beck-Peccoz P, Spada A, Mantovani G. 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Autosomal dominant pseudohypoparathyroidism type Ib: a novel inherited deletion ablating STX16 causes loss of imprinting at the A/B DMR. <span><span class="ref-journal">J Clin Endocrinol Metab. </span>2014b;<span class="ref-vol">99</span>:E724–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24438374" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24438374</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.elli.2016.3657">Elli FM, Linglart A, Garin I, de Sanctis L, Bordogna P, Grybek V, Pereda A, Giachero F, Verrua E, Hanna P, Mantovani G, Perez de Nanclares G. 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Albright's hereditary osteodystrophy: a review. <span><span class="ref-journal">Am J Med Genet. </span>1982;<span class="ref-vol">11</span>:11–29.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6278930" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6278930</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.furukawa.2011.161">Furukawa T, Kuboki Y, Tanji E, Yoshida S, Hatori T, Yamamoto M, Shibata N, Shimizu K, Kamatani N, Shiratori K. Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas. <span><span class="ref-journal">Sci Rep. </span>2011;<span class="ref-vol">1</span>:161.</span> [<a href="/pmc/articles/PMC3240977/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3240977</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22355676" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22355676</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.garin.2015.e681">Garin I, Elli FM, Linglart A, Silve C, de Sanctis L, Bordogna P, Pereda A, Clarke JT, Kannengiesser C, Coutant R, Tenebaum-Rakover Y, Admoni O, de Nanclares GP, Mantovani G. 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Increased prevalence of sleep apnea in children with pseudohypoparathyroidism Type 1a. <span><span class="ref-journal">Horm Res Paediatr. </span>2015;<span class="ref-vol">84</span>:1–5.</span> [<a href="/pmc/articles/PMC4540680/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4540680</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25925491" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25925491</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.lemos.2015.11">Lemos MC, Thakker RV. 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Case report and review of the literature. <span><span class="ref-journal">Pediatr Neurosurg. </span>2008;<span class="ref-vol">44</span>:337–40.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18552518" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18552518</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.wilson.2006.671">Wilson LC. Albright's hereditary osteodystrophy. <span><span class="ref-journal">J Pediatr Endocrinol Metab. </span>2006;<span class="ref-vol">19</span> Suppl 2:671–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16789633" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16789633</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="gnas-dis.REF.wilson.2002.273">Wilson LC, Hall CM. Albright's hereditary osteodystrophy and pseudohypoparathyroidism. <span><span class="ref-journal">Semin Musculoskelet Radiol. </span>2002;<span class="ref-vol">6</span>:273–83.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12541184" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12541184</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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