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<title>Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®) - PDQ Cancer Information Summaries - NCBI Bookshelf</title>
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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="author" content="PDQ Cancer Genetics Editorial Board" /><meta name="citation_inbook_title" content="PDQ Cancer Information Summaries [Internet]" /><meta name="citation_title" content="Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)" /><meta name="citation_publisher" content="National Cancer Institute (US)" /><meta name="citation_date" content="2016/06/24" /><meta name="citation_author" content="PDQ Cancer Genetics Editorial Board" /><meta name="citation_pmid" content="26389271" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK65830/" /><meta name="citation_keywords" content="neuroendocrine neoplasm" /><meta name="citation_keywords" content="endocrine cancer" /><meta name="citation_keywords" content="cancer genetics" /><meta name="citation_keywords" content="cancer genetics" /><meta name="citation_keywords" content="neuroendocrine neoplasm" /><meta name="citation_keywords" content="endocrine cancer" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Cancer Institute (US)" /><meta name="DC.Contributor" content="PDQ Cancer Genetics Editorial Board" /><meta name="DC.Date" content="2016/06/24" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK65830/" /><meta name="DC.Language" content="en" /><meta name="description" content="Expert-reviewed information summary about the genetics of endocrine and neuroendocrine neoplasias. This summary contains information about the MEN1 gene, the RET gene, genetic testing, and clinical interventions. Psychosocial issues associated with genetic testing and counseling of individuals who may have a hereditary medullary thyroid cancer syndrome are also discussed." /><meta name="og:title" content="Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)" /><meta name="og:type" content="book" /><meta name="og:description" content="Expert-reviewed information summary about the genetics of endocrine and neuroendocrine neoplasias. This summary contains information about the MEN1 gene, the RET gene, genetic testing, and clinical interventions. Psychosocial issues associated with genetic testing and counseling of individuals who may have a hereditary medullary thyroid cancer syndrome are also discussed." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK65830/" /><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-pdqcis-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/pdqcis/CDR0000062890/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK65830/" /><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><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>PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/pdqcis/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-pdqcis-lrg.png" alt="Cover of PDQ Cancer Information Summaries" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>PDQ Cancer Information Summaries [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK65830_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK65830_dtls__"><div>Bethesda (MD): <a href="http://www.cancer.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Cancer Institute (US)</a>; 2002-.</div></div><div class="half_rhythm"></div><div class="bk_noprnt"><form method="get" action="/books/n/pdqcis/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></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="_NBK65830_"><span class="title" itemprop="name">Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)</span></h1><div class="subtitle whole_rhythm">Health Professional Version</div><p class="contrib-group"><span itemprop="author">PDQ Cancer Genetics Editorial Board</span>.</p><p class="small">Published online: June 24, 2016.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p id="CDR0000062890__1005">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of endocrine and neuroendocrine neoplasias. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.</p><p id="CDR0000062890__1006">This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p></div><div id="CDR0000062890__286"><h2 id="_CDR0000062890__286_">Introduction</h2><p id="CDR0000062890__287">[<i>Note: Many of the medical and scientific terms used in this summary are found in the <a href="http://www.cancer.gov/publications/dictionaries/genetics-dictionary" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI Dictionary of Genetics Terms</a>. When a linked term is clicked, the definition will appear in a separate window.</i>]</p><p id="CDR0000062890__288">[<i>Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.</i>]</p><p id="CDR0000062890__817">There are several hereditary syndromes that involve endocrine or neuroendocrine glands, such as multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2 (MEN2), pheochromocytoma (PHEO), paraganglioma (PGL), Li-Fraumeni syndrome, familial adenomatous polyposis, and von Hippel-Lindau syndrome. This summary currently focuses on MEN1, MEN2, familial PHEO and PGL syndrome, and Carney-Stratakis (CSS) syndrome. Li-Fraumeni syndrome, familial adenomatous polyposis, Cowden syndrome, and von Hippel-Lindau syndrome are discussed in the PDQ summaries on <a href="/books/n/pdqcis/CDR0000062855/">Genetics of Breast and Gynecologic Cancers</a>; <a href="/books/n/pdqcis/CDR0000062863/">Genetics of Colorectal Cancer</a>; and <a href="/books/n/pdqcis/CDR0000574548/">Genetics of Kidney Cancer</a>.</p><p id="CDR0000062890__840"> The term <i>multiple endocrine neoplasia</i> is used to describe a group of heritable tumors of endocrine tissues that may be benign or malignant. They are typically classified into two main categories: MEN1 (also known as Wermer syndrome) and MEN2. Historically, MEN2 has been further stratified into the following three subtypes based on the presence or absence of certain endocrine tumors in the individual or family: MEN2A, familial medullary thyroid carcinoma, and MEN2B. The tumors usually manifest themselves by overproduction of hormones, tumor growth, or both. (Refer to the <a href="#CDR0000062890__760">MEN1</a> and <a href="#CDR0000062890__5">MEN2</a> sections of this summary for more information.)</p><p id="CDR0000062890__899">PGLs and PHEOs are rare tumors arising from chromaffin cells, which have the ability to synthesize, store, and secrete catecholamines and neuropeptides. In 2004, the World Health Organization characterized PHEOs as adrenal gland tumors and PGLs as extra-adrenal tumors.[<a class="bk_pop" href="#CDR0000062890_rl_286_1">1</a>] Either tumor may occur sporadically, as a manifestation of a hereditary syndrome, or as the sole tumor in familial PGL and PHEO syndrome. (Refer to the <a href="#CDR0000062890__850">Familial PHEO and PGL Syndrome</a> section of this summary for more information.)</p><p id="CDR0000062890__1052"><a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460124/" class="def">Affected</a> individuals with CSS have multifocal, locally aggressive gastrointestinal stromal tumors and multiple neck, intrathoracic, and intra-abdominal PGLs at relatively early ages.[<a class="bk_pop" href="#CDR0000062890_rl_286_2">2</a>-<a class="bk_pop" href="#CDR0000062890_rl_286_4">4</a>] Although similarly named, this syndrome is distinct from Carney Complex and Carney Triad. (Refer to the <a href="#CDR0000062890__972">CSS</a> section of this summary for more information.)</p><div id="CDR0000062890_rl_286"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062890_rl_286_1">DeLellis RA, Lloyd RV, Heitz PU, et al., eds.: Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press, 2004. World Health Organization classification of tumours, vol. 8.</div></li><li><div class="bk_ref" id="CDR0000062890_rl_286_2">Carney JA, Stratakis CA: Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet 108 (2): 132-9, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11857563" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11857563</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_286_3">McWhinney SR, Pasini B, Stratakis CA, et al.: Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med 357 (10): 1054-6, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17804857" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17804857</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_286_4">Pasini B, McWhinney SR, Bei T, et al.: Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 16 (1): 79-88, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/17667967" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17667967</span></a>]</div></li></ol></div></div><div id="CDR0000062890__760"><h2 id="_CDR0000062890__760_">Multiple Endocrine Neoplasia Type 1</h2><div id="CDR0000062890__763"><h3>Clinical Description</h3><p id="CDR0000062890__764">Multiple endocrine neoplasia type 1 (MEN1) (<a href="/omim/131100" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>) is an <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339338/" class="def">autosomal dominant</a> syndrome, with an estimated prevalence of about 1 in 30,000 individuals.[<a class="bk_pop" href="#CDR0000062890_rl_760_1">1</a>] The major endocrine features of MEN1 include the following:</p><ul id="CDR0000062890__805"><li class="half_rhythm"><div><a href="#CDR0000062890__765">Parathyroid tumors and primary hyperparathyroidism (PHPT)</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062890__767">Duodenopancreatic neuroendocrine tumors (NETs)</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000062890__769">Pituitary tumors</a>.</div></li></ul><p id="CDR0000062890__806">A clinical diagnosis of MEN1 is made when an individual has two of these three major endocrine tumors. <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460148/" class="def">Familial</a> MEN1 is defined as at least one MEN1 case plus at least one <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460150/" class="def">first-degree relative</a> (FDR) with one of these three tumors, or two FDRs with a germline mutation.[<a class="bk_pop" href="#CDR0000062890_rl_760_2">2</a>-<a class="bk_pop" href="#CDR0000062890_rl_760_4">4</a>] </p><p id="CDR0000062890__1067">Initial clinical presentation of symptoms typically occurs between the ages of 20 years and 30 years, although a diagnosis of MEN1 may not be confirmed for many more years. The age-related <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339344/" class="def">penetrance</a> of MEN1 is 45% to 73% by age 30 years, 82% by age 50 years, and 96% by age 70 years.[<a class="bk_pop" href="#CDR0000062890_rl_760_2">2</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_5">5</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_6">6</a>]</p></div><div id="CDR0000062890__765"><h3>Parathyroid Tumors and PHPT</h3><p id="CDR0000062890__766">The most common features and often the first presenting signs of MEN1 are parathyroid tumors, which result in PHPT. These tumors occur in 80% to 100% of patients by age 50 years.[<a class="bk_pop" href="#CDR0000062890_rl_760_2">2</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_7">7</a>-<a class="bk_pop" href="#CDR0000062890_rl_760_9">9</a>] Unlike the solitary adenoma seen in sporadic cases, MEN1-associated parathyroid tumors are typically multiglandular and often hyperplastic.[<a class="bk_pop" href="#CDR0000062890_rl_760_10">10</a>] The mean age at onset of PHPT in MEN1 is 20 to 25 years, in contrast to that in the general population, which is typically age 50 to 59 years. Parathyroid carcinoma in MEN1 is rare but has been described.[<a class="bk_pop" href="#CDR0000062890_rl_760_11">11</a>-<a class="bk_pop" href="#CDR0000062890_rl_760_14">14</a>]</p><p id="CDR0000062890__779">Individuals with MEN1-associated PHPT will have elevated parathyroid hormone (PTH) and calcium levels in the blood. The clinical manifestations of PHPT are mainly the result of hypercalcemia. Mild hypercalcemia may go undetected and have few or no symptoms. More severe hypercalcemia can result in the following:</p><ul id="CDR0000062890__807"><li class="half_rhythm"><div>Constipation.</div></li><li class="half_rhythm"><div>Nausea and vomiting.</div></li><li class="half_rhythm"><div>Dehydration</div></li><li class="half_rhythm"><div>Decreased appetite and abdominal pain.</div></li><li class="half_rhythm"><div>Anorexia.</div></li><li class="half_rhythm"><div>Diuresis.</div></li><li class="half_rhythm"><div>Kidney stones.</div></li><li class="half_rhythm"><div>Increased bone resorption with resultant increased risk of bone fracture.</div></li><li class="half_rhythm"><div>Lethargy.</div></li><li class="half_rhythm"><div>Depression.</div></li><li class="half_rhythm"><div>Confusion.</div></li><li class="half_rhythm"><div>Hypertension.</div></li><li class="half_rhythm"><div>Shortened QT interval.</div></li></ul><p id="CDR0000062890__808">Since MEN1-associated hypercalcemia is directly related to the presence of parathyroid tumors, surgical removal of these tumors may result in normalization of calcium and PTH levels and relief of symptoms; however, high recurrence rates following surgery have been reported in some series.[<a class="bk_pop" href="#CDR0000062890_rl_760_15">15</a>-<a class="bk_pop" href="#CDR0000062890_rl_760_17">17</a>] (Refer to the <a href="#CDR0000062890__777">Interventions</a> section of this summary for more information.) </p></div><div id="CDR0000062890__767"><h3>Duodenopancreatic NETs</h3><p id="CDR0000062890__768">Duodenopancreatic NETs are the second most common endocrine manifestation in MEN1, occurring in 30% to 80% of patients by age 40 years.[<a class="bk_pop" href="#CDR0000062890_rl_760_2">2</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_9">9</a>] </p><p id="CDR0000062890__791">Duodenopancreatic NETs seen in MEN1 include the following:</p><ul id="CDR0000062890__809"><li class="half_rhythm"><div>Gastrinomas (up to 70% penetrance).[<a class="bk_pop" href="#CDR0000062890_rl_760_18">18</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_19">19</a>]</div></li><li class="half_rhythm"><div>Nonfunctioning NETs (20% penetrance).</div></li><li class="half_rhythm"><div> Insulinomas (10%–20% penetrance).</div></li><li class="half_rhythm"><div>Vasoactive intestinal peptide tumors (VIPomas) (~1% penetrance).</div></li><li class="half_rhythm"><div>Glucagonomas (1%–5% penetrance).</div></li><li class="half_rhythm"><div>Somatostatinomas (~1% penetrance).</div></li></ul><p id="CDR0000062890__1068">Gastrinomas represent 50% of the gastrointestinal NETs in MEN1 and are the major cause of morbidity and mortality in MEN1 patients.[<a class="bk_pop" href="#CDR0000062890_rl_760_2">2</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_15">15</a>] Gastrinomas are usually multicentric, with small (<0.5 cm) foci throughout the duodenum.[<a class="bk_pop" href="#CDR0000062890_rl_760_18">18</a>] Most result in peptic ulcer disease (Zollinger-Ellison syndrome), and half are malignant at the time of diagnosis.[<a class="bk_pop" href="#CDR0000062890_rl_760_15">15</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_18">18</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_20">20</a>] </p><p id="CDR0000062890__810">Nonfunctioning duodenopancreatic NETs were originally thought to be relatively uncommon tumors in individuals with MEN1, with early penetrance estimates of 20%.[<a class="bk_pop" href="#CDR0000062890_rl_760_21">21</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_22">22</a>] With the advent of genetic testing and improved imaging techniques, however, their prevalence in MEN1 has increased, with one study showing a frequency as high as 55% by age 39 years in <i>MEN1</i> mutation carriers undergoing prospective endoscopic ultrasound of the pancreas.[<a class="bk_pop" href="#CDR0000062890_rl_760_23">23</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_24">24</a>] These tumors can be metastatic. One study of 108 <i>MEN1</i> mutation carriers with nonfunctioning duodenopancreatic NETs showed a positive correlation between tumor size and rate of metastasis and death, with tumors larger than 2 cm having significantly higher rates of metastasis than those smaller than 2 cm.[<a class="bk_pop" href="#CDR0000062890_rl_760_25">25</a>] (Refer to the <a href="#CDR0000062890__773">Molecular Genetics of MEN1</a> section of this summary for more information about <i>MEN1</i> gene mutations.) </p></div><div id="CDR0000062890__769"><h3>Pituitary Tumors</h3><p id="CDR0000062890__770">Approximately 15% to 50% of MEN1 patients will develop a pituitary tumor.[<a class="bk_pop" href="#CDR0000062890_rl_760_2">2</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_9">9</a>] Two-thirds are microadenomas (<1.0 cm in diameter), and the majority are prolactin-secreting.[<a class="bk_pop" href="#CDR0000062890_rl_760_26">26</a>] Other pituitary tumors can include somatotropinomas and corticotropinomas, or they may be nonfunctioning.</p></div><div id="CDR0000062890__771"><h3>Other MEN1-Associated Tumors</h3><p id="CDR0000062890__772">Other manifestations of MEN1 include carcinoids of the foregut (5%–10% of MEN1 patients). These are typically bronchial or thymic and are sometimes gastric. Skin lesions are also common and can include facial angiofibromas (up to 80% of MEN1 patients) and collagenomas (~75% of MEN1 patients).[<a class="bk_pop" href="#CDR0000062890_rl_760_27">27</a>] Lipomas (~30% of MEN1 patients) and adrenal cortical lesions (up to 50% of MEN1 patients), including cortical adenomas, diffuse or nodular hyperplasia, or rarely, carcinoma are also common.[<a class="bk_pop" href="#CDR0000062890_rl_760_28">28</a>-<a class="bk_pop" href="#CDR0000062890_rl_760_30">30</a>] The following manifestations have also been reported:[<a class="bk_pop" href="#CDR0000062890_rl_760_31">31</a>-<a class="bk_pop" href="#CDR0000062890_rl_760_33">33</a>]</p><ul id="CDR0000062890__814"><li class="half_rhythm"><div>Thyroid adenomas.</div></li><li class="half_rhythm"><div>Pheochromocytoma.</div></li><li class="half_rhythm"><div>Spinal ependymoma.</div></li><li class="half_rhythm"><div>Meningioma.</div></li><li class="half_rhythm"><div>Leiomyoma (e.g., esophageal, lung, and uterine).</div></li></ul></div><div id="CDR0000062890__794"><h3>Making the Diagnosis of MEN1</h3><p id="CDR0000062890__795">MEN1 is often difficult to diagnose in the absence of a significant family history or a positive genetic test for a mutation in the <i>MEN1</i> gene. One study of 560 individuals with MEN1 showed a significant delay between the time of the first presenting symptom and the diagnosis of MEN1.[<a class="bk_pop" href="#CDR0000062890_rl_760_34">34</a>] This time lapse is likely because some presenting symptoms of MEN1-associated tumors, such as amenorrhea, peptic ulcers, hypoglycemia, and nephrolithiasis, are not specific to MEN1.</p><p id="CDR0000062890__812">Furthermore, identification of an MEN1-associated tumor is not sufficient to make the clinical diagnosis of MEN1 and may not trigger a referral to an endocrinologist. The median time between the first presenting symptom and diagnosis of MEN1 ranges from 7.6 years to 12 years.[<a class="bk_pop" href="#CDR0000062890_rl_760_5">5</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_29">29</a>] Genetic testing alleviates some of this delay. Several studies have shown statistically significant differences in the age at MEN1 diagnosis between <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460211/" class="def">probands</a> and their family members. In one study, clinically symptomatic probands were diagnosed with MEN1 at a mean age of 47.5 years (standard deviation [SD] +/- 13.5 years), while family members were diagnosed at a mean age of 38.5 years (SD +/- 15.4 years; <i>P</i> < .001).[<a class="bk_pop" href="#CDR0000062890_rl_760_34">34</a>] In another study of 154 individuals with MEN1, probands were diagnosed at a mean age of 39.5 years (range: 18–74 years), compared with a mean age of 27 years (range: 14–56 years; <i>P <</i> .05) in family members diagnosed by predictive genetic testing.[<a class="bk_pop" href="#CDR0000062890_rl_760_35">35</a>] These findings underscore the importance of increased awareness of the signs and symptoms of MEN1-related tumors and the constellation of findings necessary to suspect the diagnosis. It also highlights the importance of genetic counseling and testing and communication among family members once a diagnosis of MEN1 is made. Figure 1 illustrates some of the challenges in identifying MEN1 in a family.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figCDR0000062890901" co-legend-rid="figlgndCDR0000062890901"><a href="/books/NBK65830.8/figure/CDR0000062890__901/?report=objectonly" target="object" title="Figure" class="img_link icnblk_img figpopup" rid-figpopup="figCDR0000062890901" rid-ob="figobCDR0000062890901"><img class="small-thumb" src="/books/NBK65830.8/bin/CDR0000749983.gif" src-large="/books/NBK65830.8/bin/CDR0000749983.jpg" alt="Figure 1" /></a><div class="icnblk_cntnt" id="figlgndCDR0000062890901"><h4 id="CDR0000062890__901"><a href="/books/NBK65830.8/figure/CDR0000062890__901/?report=objectonly" target="object" rid-ob="figobCDR0000062890901">Figure</a></h4><p class="float-caption no_bottom_margin">Figure 1. MEN1 pedigree. MEN1 can be very difficult to identify in a pedigree. The pedigree on the left was constructed based on self-report, and the pedigree on the right depicts the same family following a review of available medical records. This pedigree <a href="/books/NBK65830.8/figure/CDR0000062890__901/?report=objectonly" target="object" rid-ob="figobCDR0000062890901">(more...)</a></p></div></div><p id="CDR0000062890__796">Since many of the tumors in MEN1 are underdiagnosed or misdiagnosed, identifying an <i>MEN1</i> gene mutation in the proband early in the disease process can allow for early detection and treatment of tumors and earlier identification of at-risk family members. Many studies have been performed to determine the prevalence of <i>MEN1</i> gene mutations among patients with apparently sporadic MEN1-related tumors. For example, approximately one-third of patients with Zollinger-Ellison syndrome will carry an <i>MEN1</i> mutation.[<a class="bk_pop" href="#CDR0000062890_rl_760_36">36</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_37">37</a>] In individuals with apparently isolated PHPT or pituitary adenomas, the mutation prevalence is lower, on the order of 2% to 5%,[<a class="bk_pop" href="#CDR0000062890_rl_760_26">26</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_38">38</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_39">39</a>] but the prevalence is higher in individuals diagnosed with these tumors before age 30 years. Some authors suggest referral for genetics consultation and/or genetic testing for mutations in <i>MEN1</i> if one of the following conditions is present:[<a class="bk_pop" href="#CDR0000062890_rl_760_40">40</a>-<a class="bk_pop" href="#CDR0000062890_rl_760_42">42</a>]</p><ul id="CDR0000062890__813"><li class="half_rhythm"><div>Gastrinoma at any age in the individual or an FDR.</div></li><li class="half_rhythm"><div>Multifocal duodenopancreatic NETs at any age.</div></li><li class="half_rhythm"><div>PHPT before age 30 or 40 years.</div></li><li class="half_rhythm"><div>Multiglandular parathyroid adenomas/hyperplasia or recurrent PHPT.</div></li><li class="half_rhythm"><div>Presence of one of the three main MEN1 tumors plus one of the less common tumors/findings.</div></li><li class="half_rhythm"><div>Presence of two or more features (e.g., adrenal adenomas and carcinoid tumor).</div></li><li class="half_rhythm"><div>Combination of at least two of the following in one individual: parathyroid adenoma; thymic, bronchial, or foregut carcinoid tumor; duodenopancreatic NET; pituitary tumor; adrenal tumor.</div></li><li class="half_rhythm"><div>Parathyroid adenoma and a family history of hyperparathyroidism, pituitary
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adenoma, duodenopancreatic NET, or foregut carcinoid tumor.</div></li><li class="half_rhythm"><div>Multiple primary duodenopancreatic NETs in the same person.</div></li></ul></div><div id="CDR0000062890__773"><h3>Molecular Genetics of MEN1</h3><p id="CDR0000062890__797">The <i>MEN1</i> gene is located on chromosome 11q13 and encodes the protein menin.[<a class="bk_pop" href="#CDR0000062890_rl_760_3">3</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_43">43</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_44">44</a>] Over 1,300 mutations have been identified in the <i>MEN1</i> gene to date, and these are scattered across the entire coding region.[<a class="bk_pop" href="#CDR0000062890_rl_760_45">45</a>] Most (~65%) of these are nonsense or <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460152/" class="def">frameshift mutations</a>. The remainder are <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460164/" class="def">missense mutations</a> (20%), which lead to expression of an altered protein, <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000766216/" class="def">splice-site mutations</a> (9%), or partial- or whole-gene <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460141/" class="def">deletions</a> (1%–4%). There is currently no evidence of <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000660739/" class="def">genotype</a>-<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460203/" class="def">phenotype</a> correlations, and inter- and intra-familial variability is common.[<a class="bk_pop" href="#CDR0000062890_rl_760_46">46</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_47">47</a>] </p></div><div id="CDR0000062890__798"><h3>Genetic Testing and Differential Diagnosis</h3><p id="CDR0000062890__799">Genetic testing for <i>MEN1</i> mutations is recommended for individuals meeting <a href="/books/NBK65830.8/#CDR0000062890__805">clinical diagnostic criteria</a> and may be considered in a subset of the less common tumors. (Refer to the bulleted list in the <a href="/books/NBK65830.8/#CDR0000062890__813">Making the diagnosis of MEN1</a> section of this summary for more information.) For individuals meeting diagnostic criteria, the mutation detection rate is approximately 75% to 90%.[<a class="bk_pop" href="#CDR0000062890_rl_760_46">46</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_48">48</a>] Still, germline mutation yield ranged from 16% to 38% for apparently sporadic cases of parathyroid (15.8%), pancreatic islet (25.0%), or pituitary (37.5%) tumors, warranting consideration of genetic testing in these individuals because a diagnosis of MEN1 would prompt screening for other MEN1-related tumors.[<a class="bk_pop" href="#CDR0000062890_rl_760_49">49</a>] Many commercial laboratories currently offering <i>MEN1</i> testing use <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045671/" class="def">DNA</a> sequencing as their primary method. Several offer additional analysis for partial- or whole-gene deletion and/or duplication, although such mutations are rare and deletion/duplication testing is often reserved for individuals or families in which there is a very high clinical suspicion.</p><p id="CDR0000062890__800">Genetic testing for <i>MEN1</i> mutations can be used to distinguish between MEN1 and other forms of hereditary hyperparathyroidism, such as familial isolated hyperparathyroidism (FIHP) (<a href="/omim/145000" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>), hyperparathyroidism–jaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia (FHH). [<i>Note: The hyperparathyroidism in FHH is not primary hyperparathyroidism, which is seen in MEN1, HPT-JT and FIHP.</i>] HPT-JT, which is caused by <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460154/" class="def">germline</a> mutations in the <i>HRPT2</i> gene, is associated with PHPT, ossifying lesions of the maxilla and mandible, and renal lesions, usually bilateral renal cysts, hamartomas, and in some cases, Wilms tumor.[<a class="bk_pop" href="#CDR0000062890_rl_760_50">50</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_51">51</a>] Unlike MEN1, HPT-JT is associated with an increased risk of parathyroid carcinoma.[<a class="bk_pop" href="#CDR0000062890_rl_760_52">52</a>] FIHP, as its name suggests, is characterized by isolated PHPT with no additional endocrine features; in some families, FIHP is the initial diagnosis of what later develops into MEN1, HPT-JT, or FHH.[<a class="bk_pop" href="#CDR0000062890_rl_760_53">53</a>-<a class="bk_pop" href="#CDR0000062890_rl_760_55">55</a>] Approximately 20% of families with a clinical diagnosis of FIHP carry germline <i>MEN1</i> mutations.[<a class="bk_pop" href="#CDR0000062890_rl_760_54">54</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_57">57</a>] Mutations in the <i>calcium-sensing receptor</i> (<i>CaSR</i>) gene cause FHH, which can closely mimic the hyperparathyroidism in MEN1. Distinguishing between MEN1 and FHH can be critical in terms of management, as removal of the parathyroid glands in FHH does not correct the patient’s hyperparathyroidism and results in unnecessary surgery without relief of symptoms.[<a class="bk_pop" href="#CDR0000062890_rl_760_58">58</a>] Given the differential risks and management of these conditions and the increased risk of parathyroid carcinoma in HPT-JT, genetic diagnosis in a patient presenting with early-onset hyperparathyroidism may play an important role in the management of these patients and their families.[<a class="bk_pop" href="#CDR0000062890_rl_760_59">59</a>] Refer to Table 1 for a summary of the clinical features of MEN1 and other forms of hereditary hyperparathyroidism.</p><div id="CDR0000062890__862" class="table"><h3><span class="title">Table 1. Major Clinical Features of MEN1, FIHP, HPT-JT, and FHH</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65830.8/table/CDR0000062890__862/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062890__862_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Condition</th><th colspan="1" rowspan="1" style="vertical-align:top;">Gene(s)</th><th colspan="1" rowspan="1" style="vertical-align:top;">Major Clinical Features </th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">MEN1</td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>MEN1</i></td><td colspan="1" rowspan="1" style="vertical-align:top;">PHPT, pituitary adenomas, duodenopancreatic NETs [<a class="bk_pop" href="#CDR0000062890_rl_760_10">10</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">FIHP</td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>MEN1</i>, <i>HRPT2</i></td><td colspan="1" rowspan="1" style="vertical-align:top;">PHPT [<a class="bk_pop" href="#CDR0000062890_rl_760_53">53</a>-<a class="bk_pop" href="#CDR0000062890_rl_760_57">57</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">HPT-JT</td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>HRPT2</i></td><td colspan="1" rowspan="1" style="vertical-align:top;"> PHPT; osteomas of maxilla and mandible; renal cysts or hamartomas; and rarely, Wilms tumor and parathyroid carcinoma [<a class="bk_pop" href="#CDR0000062890_rl_760_50">50</a>-<a class="bk_pop" href="#CDR0000062890_rl_760_52">52</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">FHH</td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>CaSR</i></td><td colspan="1" rowspan="1" style="vertical-align:top;">Hyperparathyroidism (not primary) [<a class="bk_pop" href="#CDR0000062890_rl_760_58">58</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_60">60</a>]</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin"><i>CaSR</i> = <i>calcium-sensing receptor </i>gene; FHH = familial hypocalciuric hypercalcemia; FIHP = familial isolated hyperparathyroidism; HPT-JT = hyperparathyroidism–jaw tumor syndrome; <i>HRPT2</i> = <i>hyperparathyroidism 2</i> gene; MEN1 = multiple endocrine neoplasia type 1 (gene is italicized); NETs = neuroendocrine tumors; PHPT = primary hyperparathyroidism.</p></div></dd></dl></div></div></div></div><div id="CDR0000062890__775"><h3>Surveillance</h3><p id="CDR0000062890__776">Screening and surveillance for MEN1 may employ a combination of biochemical tests and imaging. Available recommendations are summarized in Table 2.[<a class="bk_pop" href="#CDR0000062890_rl_760_4">4</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_40">40</a>]</p><div id="CDR0000062890__857" class="table"><h3><span class="title">Table 2. Practice Guidelines for Surveillance of Multiple Endocrine Neoplasia Type 1 (MEN1)<sup>a</sup>
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</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65830.8/table/CDR0000062890__857/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062890__857_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Biochemical Test or Procedure</th><th colspan="1" rowspan="1" style="vertical-align:top;">Condition Screened For</th><th colspan="1" rowspan="1" style="vertical-align:top;">Age Screening Initiated (y) </th><th colspan="1" rowspan="1" style="vertical-align:top;">Frequency </th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Serum prolactin and/or insulin-like growth factor 1</td><td colspan="1" rowspan="1" style="vertical-align:top;">Pituitary tumors</td><td colspan="1" rowspan="1" style="vertical-align:top;">5</td><td colspan="1" rowspan="1" style="vertical-align:top;">Every 1 y</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Fasting total serum calcium and/or ionized calcium and PTH</td><td colspan="1" rowspan="1" style="vertical-align:top;">Parathyroid tumors and PHPT</td><td colspan="1" rowspan="1" style="vertical-align:top;">8 </td><td colspan="1" rowspan="1" style="vertical-align:top;">Every 1 y</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Fasting serum gastrin</td><td colspan="1" rowspan="1" style="vertical-align:top;">Duodenopancreatic gastrinoma </td><td colspan="1" rowspan="1" style="vertical-align:top;">20 </td><td colspan="1" rowspan="1" style="vertical-align:top;">Every 1 y</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Chromogranin A, pancreatic polypeptide, glucagon, and vasointestinal polypeptide</td><td colspan="1" rowspan="1" style="vertical-align:top;">Duodenopancreatic NETs</td><td colspan="1" rowspan="1" style="vertical-align:top;"><10 </td><td colspan="1" rowspan="1" style="vertical-align:top;">Every 1 y</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Fasting glucose and insulin</td><td colspan="1" rowspan="1" style="vertical-align:top;">Insulinoma</td><td colspan="1" rowspan="1" style="vertical-align:top;">5 </td><td colspan="1" rowspan="1" style="vertical-align:top;">Every 1 y</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Brain MRI<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">Pituitary tumors</td><td colspan="1" rowspan="1" style="vertical-align:top;">5 </td><td colspan="1" rowspan="1" style="vertical-align:top;">Every 3–5 y based on biochemical results</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Abdominal CT or MRI<sup>b</sup> [<a class="bk_pop" href="#CDR0000062890_rl_760_4">4</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">Duodenopancreatic NETs</td><td colspan="1" rowspan="1" style="vertical-align:top;">20</td><td colspan="1" rowspan="1" style="vertical-align:top;">Every 3–5 y based on biochemical results</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Abdominal CT, MRI, or endoscopic US<sup>b</sup> [<a class="bk_pop" href="#CDR0000062890_rl_760_40">40</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">Duodenopancreatic NETs</td><td colspan="1" rowspan="1" style="vertical-align:top;"><10</td><td colspan="1" rowspan="1" style="vertical-align:top;">Every 1 y</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">CT = computed tomography; MRI = magnetic resonance imaging; NETs = neuroendocrine tumors; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; US = ultrasound.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Adapted from Brandi et al. [<a class="bk_pop" href="#CDR0000062890_rl_760_4">4</a>] and Thakker et al. [<a class="bk_pop" href="#CDR0000062890_rl_760_40">40</a>].</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>b</sup>The recommendations for abdominal imaging differ between two published guidelines for the diagnosis and management of MEN1.[<a class="bk_pop" href="#CDR0000062890_rl_760_4">4</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_40">40</a>] There is weak evidence at this time to support annual imaging before age 10 years. Imaging before age 10 years does identify disease in a high proportion of patients, but it is not clear whether this impacts prognosis.[<a class="bk_pop" href="#CDR0000062890_rl_760_23">23</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_61">61</a>]</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>c</sup>The age to initiate screening and the screening frequency for pituitary tumors may be debatable because the clinical significance of small, nonfunctional tumors is unclear;[<a class="bk_pop" href="#CDR0000062890_rl_760_62">62</a>] further study may be warranted.</p></div></dd></dl></div></div></div></div><div id="CDR0000062890__777"><h3>Interventions</h3><p id="CDR0000062890__778">Surgical management of MEN1 is complex and controversial, given the multifocal and multiglandular nature of the disease and the high risk of tumor recurrence even after surgery. Establishing the diagnosis of MEN1 before making surgical decisions and referring affected individuals to a surgeon with experience in treating MEN1 can be critical in preventing unnecessary surgeries or inappropriate surgical approaches. </p><div id="CDR0000062890__802"><h4>Parathyroid tumors</h4><p id="CDR0000062890__803">Once evidence of parathyroid disease is established biochemically, the recommended course of action is surgical removal of the parathyroid glands. The timing and the extent of surgery, however, remain controversial.[<a class="bk_pop" href="#CDR0000062890_rl_760_63">63</a>] Preoperative genetic testing helps guide the extent of surgery and can increase the likelihood of successful initial surgery and lower the likelihood of recurrent disease if a mutation is detected.[<a class="bk_pop" href="#CDR0000062890_rl_760_59">59</a>] Some groups reserve surgical intervention for symptomatic patients, with continued annual biochemical screening for those who are asymptomatic. Once surgery is necessary, subtotal parathyroidectomy (removal of 3–3.5 glands) is often suggested as the initial treatment.[<a class="bk_pop" href="#CDR0000062890_rl_760_59">59</a>] However, the rate of recurrence is quite high (55%–66%), and reoperation is often necessary.[<a class="bk_pop" href="#CDR0000062890_rl_760_15">15</a>-<a class="bk_pop" href="#CDR0000062890_rl_760_17">17</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_59">59</a>] Total parathyroidectomy with autotransplantation of parathyroid tissue to the forearm is also an option. A benefit of this approach is the easier removal of recurrent disease from the forearm than from the neck. Although the likelihood of recurrence is lowered by more extensive surgery, this must be weighed against the risk of rendering the patient hypoparathyroid.[<a class="bk_pop" href="#CDR0000062890_rl_760_64">64</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_65">65</a>] Studies showing that concomitant bilateral cervical thymectomy decreases the rate of recurrence suggest that the thymus be removed at the initial operation.[<a class="bk_pop" href="#CDR0000062890_rl_760_64">64</a>] If the devastating complication of hypocalcemia occurs, management requires oral calcitriol and calcium supplementation. This daily drug dependence can be a major burden on patients. </p></div><div id="CDR0000062890__804"><h4>Duodenopancreatic NETs</h4><p id="CDR0000062890__882">The role of surgery for duodenopancreatic NETs in MEN1 is controversial, given postoperative morbidity, long-term complications, and low cure rates. The timing and extent of surgery depend on many factors, including severity of symptoms, extent of disease, type and location of tumor, risk of metastasis, and patient preference. Long-acting somatostatin analogs may have a role in early-stage MEN1 duodenopancreatic NETs.[<a class="bk_pop" href="#CDR0000062890_rl_760_66">66</a>] Initial study results suggest that the treatment is safe and that long-term suppression of tumor and hormonal activity can be seen in up to 10% of patients and stability of hormone hyperfunction in 80% of patients.[<a class="bk_pop" href="#CDR0000062890_rl_760_66">66</a>] The primary goal of surgery is to improve long-term survival by reducing symptoms associated with hormone excess and lowering the risk of distant metastasis.[<a class="bk_pop" href="#CDR0000062890_rl_760_20">20</a>] Surgery is commonly performed for most functional tumors and for nonfunctioning NETs when the tumor exceeds 2 to 3 cm because as the likelihood of distant metastases is high.[<a class="bk_pop" href="#CDR0000062890_rl_760_67">67</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_68">68</a>]
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While more-extensive surgical approaches (e.g., pancreatoduodenectomy) have been associated with higher cure rates and improved overall survival,[<a class="bk_pop" href="#CDR0000062890_rl_760_69">69</a>-<a class="bk_pop" href="#CDR0000062890_rl_760_71">71</a>] they also have higher rates of postoperative complications and long-term morbidity.[<a class="bk_pop" href="#CDR0000062890_rl_760_72">72</a>] Therefore, the risks and benefits should be carefully considered, and surgical decisions should be made on a case-by-case basis.</p><p id="CDR0000062890__883">Individuals with MEN1 who are diagnosed with NETs often have multiple tumors of various types throughout the pancreas and duodenum, some of which can be identified using magnetic resonance imaging or computed tomography. Many tumors, however, are too small to be detected using standard imaging techniques, and intra-arterial secretin stimulation testing and/or intraoperative ultrasound may be useful.[<a class="bk_pop" href="#CDR0000062890_rl_760_73">73</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_74">74</a>] Preoperative assessment using various biochemical and imaging modalities, intraoperative assessment of tumor burden, and resolution of hormonal hyper-secretion are critical and, in some series, have been associated with higher cure rates and longer disease-free intervals.[<a class="bk_pop" href="#CDR0000062890_rl_760_73">73</a>-<a class="bk_pop" href="#CDR0000062890_rl_760_76">76</a>]</p><p id="CDR0000062890__948">In the current era of effective treatment for hyperfunctional hormone excess states, most MEN1-related deaths are due to the malignant nature of duodenopancreatic NETs. A less common but important risk of death is from malignant thymic carcinoid tumors. Indicators of a poor MEN1 prognosis include elevated fasting serum gastrin, the presence of functional hormonal syndromes, liver or distant metastases, aggressive duodenopancreatic NET growth, large duodenopancreatic NET size, or the need for multiple parathyroidectomies. The most common cause of non-MEN1–related death in this patient cohort is from cardiovascular disease.[<a class="bk_pop" href="#CDR0000062890_rl_760_77">77</a>]</p></div><div id="CDR0000062890__878"><h4>Insulinomas</h4><p id="CDR0000062890__879">Medical management of insulinoma using diet and medication is often unsuccessful; the mainstay of treatment for this tumor is surgery.[<a class="bk_pop" href="#CDR0000062890_rl_760_40">40</a>] Insulinomas in MEN1 patients can be located throughout the pancreas, with a preponderance found in the distal gland,[<a class="bk_pop" href="#CDR0000062890_rl_760_78">78</a>-<a class="bk_pop" href="#CDR0000062890_rl_760_80">80</a>] and have a higher rate of metastasis than sporadic insulinoma.[<a class="bk_pop" href="#CDR0000062890_rl_760_81">81</a>] Surgery can range from enucleation of single or multiple large tumors to partial pancreatic resection, or both,[<a class="bk_pop" href="#CDR0000062890_rl_760_79">79</a>] to subtotal or total pancreatectomy.[<a class="bk_pop" href="#CDR0000062890_rl_760_78">78</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_79">79</a>] More-extensive surgical approaches are associated with a lower rate of recurrence [<a class="bk_pop" href="#CDR0000062890_rl_760_69">69</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_70">70</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_79">79</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_82">82</a>] but a higher rate of postoperative morbidity. Because insulinoma often occurs in conjunction with nonfunctioning pancreatic tumors, the selective intra-arterial calcium-injection test (SAS test) may be necessary to determine the source of insulin excess.[<a class="bk_pop" href="#CDR0000062890_rl_760_83">83</a>] Intraoperative monitoring of insulin/glucose can help determine whether insulin-secreting tumors have been successfully excised.[<a class="bk_pop" href="#CDR0000062890_rl_760_74">74</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_84">84</a>]</p></div><div id="CDR0000062890__880"><h4>Gastrinomas</h4><p id="CDR0000062890__881">Most MEN1-associated gastrinomas originate in the duodenum. These tumors are typically multifocal and cause hyper-secretion of gastrin, with resultant peptic ulcer disease (Zollinger-Ellison syndrome). The multifocal nature makes complete surgical resection difficult. It is critical to manage symptoms before considering any type of surgical intervention. Historically, some groups have recommended close observation of individuals with smaller tumors (<2.0 cm on imaging) who have relief of symptoms using medications (e.g., proton pump inhibitors or histamine-2 agonists);[<a class="bk_pop" href="#CDR0000062890_rl_760_85">85</a>] however, this approach may not be optimal for all patients.</p><p id="CDR0000062890__884">Several published series have shown a positive correlation between primary tumor size and rate of distant metastasis. One retrospective study showed that 61% of patients with tumors larger than 3 cm had liver metastases.[<a class="bk_pop" href="#CDR0000062890_rl_760_20">20</a>] In another series, 40% of patients with tumors larger than 3 cm had liver metastases.[<a class="bk_pop" href="#CDR0000062890_rl_760_86">86</a>] In contrast, both of these series showed significantly lower rates of liver metastases in individuals with tumors smaller than 3 cm (32% and 4.8%, respectively). On the basis of these and other data, many groups recommend surgery in individuals with nonmetastatic gastrinoma who have tumors larger than 2 cm.[<a class="bk_pop" href="#CDR0000062890_rl_760_40">40</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_71">71</a>]</p><p id="CDR0000062890__885">The type of surgery for gastrinoma depends on many factors. A Whipple procedure is typically discouraged as an initial surgery, given the high postoperative morbidity and long-term complications, such as diabetes mellitus and malabsorption. Less extensive surgeries have been described with varying results. At a minimum, duodenectomy with intraoperative palpation and/or ultrasound to locate and excise duodenal tumors and peri-pancreatic lymph node dissection are performed.[<a class="bk_pop" href="#CDR0000062890_rl_760_73">73</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_87">87</a>] Because most patients with gastrinoma will have concomitant NETs throughout the pancreas, some of which may be nonfunctional, some groups recommend resection of the distal pancreas and enucleation of tumors in the pancreatic head in addition to duodenal tumor excision.[<a class="bk_pop" href="#CDR0000062890_rl_760_73">73</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_87">87</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_88">88</a>]</p></div><div id="CDR0000062890__886"><h4>Nonfunctioning NETs</h4><p id="CDR0000062890__887">Approximately 50% of individuals with MEN1 will develop nonfunctioning NETs.[<a class="bk_pop" href="#CDR0000062890_rl_760_23">23</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_25">25</a>] These are often identified incidentally during assessment and exploration for functioning tumors. As with gastrinomas, the metastatic rate is correlated with larger tumor size;[<a class="bk_pop" href="#CDR0000062890_rl_760_25">25</a>] the presence of metastatic disease has been associated with earlier age at death than in those without duodenopancreatic NETs.[<a class="bk_pop" href="#CDR0000062890_rl_760_25">25</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_89">89</a>]</p></div><div id="CDR0000062890__888"><h4>Other duodenopancreatic NETs</h4><p id="CDR0000062890__889">Glucagonomas, VIPomas, and somatostatinomas are rare but often have higher rates of malignancy than other duodenopancreatic NETs.[<a class="bk_pop" href="#CDR0000062890_rl_760_90">90</a>] These are often treated with aggressive surgery.[<a class="bk_pop" href="#CDR0000062890_rl_760_81">81</a>]</p></div><div id="CDR0000062890__890"><h4>Pituitary tumors</h4><p id="CDR0000062890__891">Medical therapy to suppress hypersecretion is often the first line of therapy for MEN1-associated pituitary tumors. In one series of 136 patients, medical therapy was successful in approximately one-half of patients with secreting tumors (49 of 116, 42%), and successful suppression was correlated with smaller tumor size.[<a class="bk_pop" href="#CDR0000062890_rl_760_91">91</a>] Surgery is often necessary for patients who are resistant to this treatment. Radiation therapy is reserved for patients with incomplete surgical resection.[<a class="bk_pop" href="#CDR0000062890_rl_760_40">40</a>,<a class="bk_pop" href="#CDR0000062890_rl_760_92">92</a>]</p></div></div><div id="CDR0000062890_rl_760"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062890_rl_760_1">Agarwal SK, Ozawa A, Mateo CM, et al.: The MEN1 gene and pituitary tumours. Horm Res 71 (Suppl 2): 131-8, 2009. [<a href="/pmc/articles/PMC6413329/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6413329</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19407509" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19407509</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_2">Trump D, Farren B, Wooding C, et al.: Clinical studies of multiple endocrine neoplasia type 1 (MEN1) QJM 89 (9): 653-69, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8917740" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8917740</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_3">Chandrasekharappa SC, Guru SC, Manickam P, et al.: Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276 (5311): 404-7, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9103196" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9103196</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_4">Brandi ML, Gagel RF, Angeli A, et al.: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86 (12): 5658-71, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11739416" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11739416</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_5">Carty SE, Helm AK, Amico JA, et al.: The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type 1. Surgery 124 (6): 1106-13; discussion 1113-4, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9854591" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9854591</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_6">Goudet P, Dalac A, Le Bras M, et al.: MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d'étude des Tumeurs Endocrines. J Clin Endocrinol Metab 100 (4): 1568-77, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25594862" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25594862</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_7">Benson L, Ljunghall S, Akerström G, et al.: Hyperparathyroidism presenting as the first lesion in multiple endocrine neoplasia type 1. Am J Med 82 (4): 731-7, 1987. [<a href="https://pubmed.ncbi.nlm.nih.gov/2882676" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2882676</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_8">Brandi ML, Marx SJ, Aurbach GD, et al.: Familial multiple endocrine neoplasia type I: a new look at pathophysiology. Endocr Rev 8 (4): 391-405, 1987. [<a href="https://pubmed.ncbi.nlm.nih.gov/2891500" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2891500</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_9">Thakker RV: Multiple endocrine neoplasia type 1. In: DeGroot LJ, Besser M, Burger HG, eds.: Endocrinology. Volume 3. 3rd ed. Philadelphia, Pa: WB Saunders Co, 1995, pp 2815-31.</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_10">Chandrasekharappa SC, Teh BT: Clinical and molecular aspects of multiple endocrine neoplasia type 1. Front Horm Res 28: 50-80, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11443853" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11443853</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_11">del Pozo C, García-Pascual L, Balsells M, et al.: Parathyroid carcinoma in multiple endocrine neoplasia type 1. Case report and review of the literature. Hormones (Athens) 10 (4): 326-31, 2011 Oct-Dec. [<a href="https://pubmed.ncbi.nlm.nih.gov/22281890" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22281890</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_12">Agha A, Carpenter R, Bhattacharya S, et al.: Parathyroid carcinoma in multiple endocrine neoplasia type 1 (MEN1) syndrome: two case reports of an unrecognised entity. J Endocrinol Invest 30 (2): 145-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17392605" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17392605</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_13">Shih RY, Fackler S, Maturo S, et al.: Parathyroid carcinoma in multiple endocrine neoplasia type 1 with a classic germline mutation. Endocr Pract 15 (6): 567-72, 2009 Sep-Oct. [<a href="https://pubmed.ncbi.nlm.nih.gov/19491073" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19491073</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_14">Sato M, Miyauchi A, Namihira H, et al.: A newly recognized germline mutation of MEN1 gene identified in a patient with parathyroid adenoma and carcinoma. Endocrine 12 (3): 223-6, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10963041" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10963041</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_15">Norton JA, Venzon DJ, Berna MJ, et al.: Prospective study of surgery for primary hyperparathyroidism (HPT) in multiple endocrine neoplasia-type 1 and Zollinger-Ellison syndrome: long-term outcome of a more virulent form of HPT. Ann Surg 247 (3): 501-10, 2008. [<a href="/pmc/articles/PMC2717476/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2717476</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18376196" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18376196</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_16">Hellman P, Skogseid B, Oberg K, et al.: Primary and reoperative parathyroid operations in hyperparathyroidism of multiple endocrine neoplasia type 1. Surgery 124 (6): 993-9, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9854574" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9854574</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_17">Schreinemakers JM, Pieterman CR, Scholten A, et al.: The optimal surgical treatment for primary hyperparathyroidism in MEN1 patients: a systematic review. World J Surg 35 (9): 1993-2005, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21713580" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21713580</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_18">Pipeleers-Marichal M, Somers G, Willems G, et al.: Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome. N Engl J Med 322 (11): 723-7, 1990. [<a href="https://pubmed.ncbi.nlm.nih.gov/1968616" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1968616</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_19">MacFarlane MP, Fraker DL, Alexander HR, et al.: Prospective study of surgical resection of duodenal and pancreatic gastrinomas in multiple endocrine neoplasia type 1. Surgery 118 (6): 973-9; discussion 979-80, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7491542" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7491542</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_20">Weber HC, Venzon DJ, Lin JT, et al.: Determinants of metastatic rate and survival in patients with Zollinger-Ellison syndrome: a prospective long-term study. Gastroenterology 108 (6): 1637-49, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7768367" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7768367</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_21">Marx SJ: Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 343 (25): 1863-75, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11117980" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11117980</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_22">Skogseid B, Rastad J, Oberg K: Multiple endocrine neoplasia type 1. Clinical features and screening. Endocrinol Metab Clin North Am 23 (1): 1-18, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7913018" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7913018</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_23">Thomas-Marques L, Murat A, Delemer B, et al.: Prospective endoscopic ultrasonographic evaluation of the frequency of nonfunctioning pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1. Am J Gastroenterol 101 (2): 266-73, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16454829" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16454829</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_24">Tonelli F, Giudici F, Fratini G, et al.: Pancreatic endocrine tumors in multiple endocrine neoplasia type 1 syndrome: review of literature. Endocr Pract 17 (Suppl 3): 33-40, 2011 Jul-Aug. [<a href="https://pubmed.ncbi.nlm.nih.gov/21550956" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21550956</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_25">Triponez F, Dosseh D, Goudet P, et al.: Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Ann Surg 243 (2): 265-72, 2006. [<a href="/pmc/articles/PMC1448903/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1448903</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16432361" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16432361</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_26">Corbetta S, Pizzocaro A, Peracchi M, et al.: Multiple endocrine neoplasia type 1 in patients with recognized pituitary tumours of different types. Clin Endocrinol (Oxf) 47 (5): 507-12, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9425388" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9425388</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_27">Darling TN, Skarulis MC, Steinberg SM, et al.: Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. Arch Dermatol 133 (7): 853-7, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9236523" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9236523</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_28">Machens A, Schaaf L, Karges W, et al.: Age-related penetrance of endocrine tumours in multiple endocrine neoplasia type 1 (MEN1): a multicentre study of 258 gene carriers. Clin Endocrinol (Oxf) 67 (4): 613-22, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17590169" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17590169</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_29">Pieterman CR, Schreinemakers JM, Koppeschaar HP, et al.: Multiple endocrine neoplasia type 1 (MEN1): its manifestations and effect of genetic screening on clinical outcome. Clin Endocrinol (Oxf) 70 (4): 575-81, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/18616711" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18616711</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_30">Waldmann J, Bartsch DK, Kann PH, et al.: Adrenal involvement in multiple endocrine neoplasia type 1: results of 7 years prospective screening. Langenbecks Arch Surg 392 (4): 437-43, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17235589" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17235589</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_31">Gibril F, Schumann M, Pace A, et al.: Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. Medicine (Baltimore) 83 (1): 43-83, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/14747767" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14747767</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_32">McKeeby JL, Li X, Zhuang Z, et al.: Multiple leiomyomas of the esophagus, lung, and uterus in multiple endocrine neoplasia type 1. Am J Pathol 159 (3): 1121-7, 2001. [<a href="/pmc/articles/PMC1850469/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1850469</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11549605" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11549605</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_33">Vortmeyer AO, Lubensky IA, Skarulis M, et al.: Multiple endocrine neoplasia type 1: atypical presentation, clinical course, and genetic analysis of multiple tumors. Mod Pathol 12 (9): 919-24, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10496602" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10496602</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_34">Yamazaki M, Suzuki S, Kosugi S, et al.: Delay in the diagnosis of multiple endocrine neoplasia type 1: typical symptoms are frequently overlooked. Endocr J 59 (9): 797-807, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22673601" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22673601</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_35">Lourenço DM Jr, Toledo RA, Coutinho FL, et al.: The impact of clinical and genetic screenings on the management of the multiple endocrine neoplasia type 1. Clinics (Sao Paulo) 62 (4): 465-76, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17823710" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17823710</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_36">Roy PK, Venzon DJ, Shojamanesh H, et al.: Zollinger-Ellison syndrome. Clinical presentation in 261 patients. Medicine (Baltimore) 79 (6): 379-411, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11144036" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11144036</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_37">Bardram L, Stage JG: Frequency of endocrine disorders in patients with the Zollinger-Ellison syndrome. Scand J Gastroenterol 20 (2): 233-8, 1985. [<a href="https://pubmed.ncbi.nlm.nih.gov/3887554" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3887554</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_38">Uchino S, Noguchi S, Sato M, et al.: Screening of the Men1 gene and discovery of germ-line and somatic mutations in apparently sporadic parathyroid tumors. Cancer Res 60 (19): 5553-7, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11034102" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11034102</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_39">Scheithauer BW, Laws ER Jr, Kovacs K, et al.: Pituitary adenomas of the multiple endocrine neoplasia type I syndrome. Semin Diagn Pathol 4 (3): 205-11, 1987. [<a href="https://pubmed.ncbi.nlm.nih.gov/2890193" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2890193</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_40">Thakker RV, Newey PJ, Walls GV, et al.: Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 97 (9): 2990-3011, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22723327" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22723327</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_41">Newey PJ, Thakker RV: Role of multiple endocrine neoplasia type 1 mutational analysis in clinical practice. Endocr Pract 17 (Suppl 3): 8-17, 2011 Jul-Aug. [<a href="https://pubmed.ncbi.nlm.nih.gov/21454234" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21454234</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_42">Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25394175" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25394175</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_43">Larsson C, Skogseid B, Oberg K, et al.: Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 332 (6159): 85-7, 1988. [<a href="https://pubmed.ncbi.nlm.nih.gov/2894610" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2894610</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_44">Bassett JH, Forbes SA, Pannett AA, et al.: Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet 62 (2): 232-44, 1998. [<a href="/pmc/articles/PMC1376903/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1376903</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/9463336" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9463336</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_45">Lemos MC, Thakker RV: Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat 29 (1): 22-32, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/17879353" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17879353</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_46">Giraud S, Zhang CX, Serova-Sinilnikova O, et al.: Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet 63 (2): 455-67, 1998. [<a href="/pmc/articles/PMC1377295/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1377295</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/9683585" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9683585</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_47">Wautot V, Vercherat C, Lespinasse J, et al.: Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein. Hum Mutat 20 (1): 35-47, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12112656" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12112656</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_48">Agarwal SK, Kester MB, Debelenko LV, et al.: Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet 6 (7): 1169-75, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9215689" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9215689</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_49">Klein RD, Salih S, Bessoni J, et al.: Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med 7 (2): 131-8, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15714081" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15714081</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_50">Teh BT, Farnebo F, Kristoffersson U, et al.: Autosomal dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomas and cystic kidney disease: linkage to 1q21-q32 and loss of the wild type allele in renal hamartomas. J Clin Endocrinol Metab 81 (12): 4204-11, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8954016" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8954016</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_51">Carpten JD, Robbins CM, Villablanca A, et al.: HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet 32 (4): 676-80, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12434154" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12434154</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_52">Marx SJ: Multiple endocrine neoplasia type 1. In: Vogelstein B, Kinzler KW, eds.: The Genetic Basis of Human Cancer. New York, NY: McGraw-Hill, 1998, pp 489-506.</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_53">Warner J, Epstein M, Sweet A, et al.: Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J Med Genet 41 (3): 155-60, 2004. [<a href="/pmc/articles/PMC1735699/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1735699</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14985373" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14985373</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_54">Mizusawa N, Uchino S, Iwata T, et al.: Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism-jaw tumour syndrome. Clin Endocrinol (Oxf) 65 (1): 9-16, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16817812" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16817812</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_55">Cetani F, Pardi E, Borsari S, et al.: Molecular pathogenesis of primary hyperparathyroidism. J Endocrinol Invest 34 (7 Suppl): 35-9, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21985978" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21985978</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_56">Miedlich S, Lohmann T, Schneyer U, et al.: Familial isolated primary hyperparathyroidism--a multiple endocrine neoplasia type 1 variant? Eur J Endocrinol 145 (2): 155-60, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11454510" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11454510</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_57">Cetani F, Pardi E, Ambrogini E, et al.: Genetic analyses in familial isolated hyperparathyroidism: implication for clinical assessment and surgical management. Clin Endocrinol (Oxf) 64 (2): 146-52, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16430712" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16430712</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_58">Raue F, Frank-Raue K: Primary hyperparathyroidism--what the nephrologist should know--an update. Nephrol Dial Transplant 22 (3): 696-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17138574" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17138574</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_59">Romero Arenas MA, Morris LF, Rich TA, et al.: Preoperative multiple endocrine neoplasia type 1 diagnosis improves the surgical outcomes of pediatric patients with primary hyperparathyroidism. J Pediatr Surg 49 (4): 546-50, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24726110" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24726110</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_60">Christensen SE, Nissen PH, Vestergaard P, et al.: Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes 18 (6): 359-70, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21986511" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21986511</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_61">Langer P, Kann PH, Fendrich V, et al.: Prospective evaluation of imaging procedures for the detection of pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1. World J Surg 28 (12): 1317-22, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15517479" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15517479</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_62">de Laat JM, Dekkers OM, Pieterman CR, et al.: Long-Term Natural Course of Pituitary Tumors in Patients With MEN1: Results From the DutchMEN1 Study Group (DMSG). J Clin Endocrinol Metab 100 (9): 3288-96, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/26126205" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26126205</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_63">Hubbard JG, Sebag F, Maweja S, et al.: Primary hyperparathyroidism in MEN 1--how radical should surgery be? Langenbecks Arch Surg 386 (8): 553-7, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11914930" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11914930</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_64">Pieterman CR, van Hulsteijn LT, den Heijer M, et al.: Primary hyperparathyroidism in MEN1 patients: a cohort study with longterm follow-up on preferred surgical procedure and the relation with genotype. Ann Surg 255 (6): 1171-8, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22470073" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22470073</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_65">Lairmore TC, Govednik CM, Quinn CE, et al.: A randomized, prospective trial of operative treatments for hyperparathyroidism in patients with multiple endocrine neoplasia type 1. Surgery 156 (6): 1326-34; discussion 1334-5, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/25262224" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25262224</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_66">Ramundo V, Del Prete M, Marotta V, et al.: Impact of long-acting octreotide in patients with early-stage MEN1-related duodeno-pancreatic neuroendocrine tumours. Clin Endocrinol (Oxf) 80 (6): 850-5, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24443791" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24443791</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_67">Triponez F, Goudet P, Dosseh D, et al.: Is surgery beneficial for MEN1 patients with small (< or = 2 cm), nonfunctioning pancreaticoduodenal endocrine tumor? An analysis of 65 patients from the GTE. World J Surg 30 (5): 654-62; discussion 663-4, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16680582" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16680582</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_68">Bettini R, Partelli S, Boninsegna L, et al.: Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. Surgery 150 (1): 75-82, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21683859" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21683859</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_69">Bartsch DK, Langer P, Wild A, et al.: Pancreaticoduodenal endocrine tumors in multiple endocrine neoplasia type 1: surgery or surveillance? Surgery 128 (6): 958-66, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11114630" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11114630</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_70">Bartsch DK, Fendrich V, Langer P, et al.: Outcome of duodenopancreatic resections in patients with multiple endocrine neoplasia type 1. Ann Surg 242 (6): 757-64, discussion 764-6, 2005. [<a href="/pmc/articles/PMC1409888/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1409888</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16327485" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16327485</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_71">Norton JA, Jensen RT: Role of surgery in Zollinger-Ellison syndrome. J Am Coll Surg 205 (4 Suppl): S34-7, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17916516" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17916516</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_72">Lopez CL, Waldmann J, Fendrich V, et al.: Long-term results of surgery for pancreatic neuroendocrine neoplasms in patients with MEN1. Langenbecks Arch Surg 396 (8): 1187-96, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21805182" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21805182</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_73">Imamura M, Komoto I, Ota S, et al.: Biochemically curative surgery for gastrinoma in multiple endocrine neoplasia type 1 patients. World J Gastroenterol 17 (10): 1343-53, 2011. [<a href="/pmc/articles/PMC3068271/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3068271</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21455335" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21455335</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_74">Tonelli F, Fratini G, Nesi G, et al.: Pancreatectomy in multiple endocrine neoplasia type 1-related gastrinomas and pancreatic endocrine neoplasias. Ann Surg 244 (1): 61-70, 2006. [<a href="/pmc/articles/PMC1570585/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1570585</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16794390" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16794390</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_75">Lewis MA, Thompson GB, Young WF Jr: Preoperative assessment of the pancreas in multiple endocrine neoplasia type 1. World J Surg 36 (6): 1375-81, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22382771" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22382771</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_76">van Asselt SJ, Brouwers AH, van Dullemen HM, et al.: EUS is superior for detection of pancreatic lesions compared with standard imaging in patients with multiple endocrine neoplasia type 1. Gastrointest Endosc 81 (1): 159-167.e2, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25527055" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25527055</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_77">Ito T, Igarashi H, Uehara H, et al.: Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors. Medicine (Baltimore) 92 (3): 135-81, 2013. [<a href="/pmc/articles/PMC3727638/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3727638</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23645327" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23645327</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_78">O'Riordain DS, O'Brien T, van Heerden JA, et al.: Surgical management of insulinoma associated with multiple endocrine neoplasia type I. World J Surg 18 (4): 488-93; discussion 493-4, 1994 Jul-Aug. [<a href="https://pubmed.ncbi.nlm.nih.gov/7725733" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7725733</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_79">Crippa S, Zerbi A, Boninsegna L, et al.: Surgical management of insulinomas: short- and long-term outcomes after enucleations and pancreatic resections. Arch Surg 147 (3): 261-6, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22430908" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22430908</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_80">Sakurai A, Yamazaki M, Suzuki S, et al.: Clinical features of insulinoma in patients with multiple endocrine neoplasia type 1: analysis of the database of the MEN Consortium of Japan. Endocr J 59 (10): 859-66, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22785103" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22785103</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_81">Akerström G, Stålberg P: Surgical management of MEN-1 and -2: state of the art. Surg Clin North Am 89 (5): 1047-68, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19836484" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19836484</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_82">Vezzosi D, Cardot-Bauters C, Bouscaren N, et al.: Long-term results of the surgical management of insulinoma patients with MEN1: a Groupe d'étude des Tumeurs Endocrines (GTE) retrospective study. Eur J Endocrinol 172 (3): 309-19, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25538206" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25538206</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_83">Grant CS: Insulinoma. Best Pract Res Clin Gastroenterol 19 (5): 783-98, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16253900" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16253900</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_84">Giudici F, Nesi G, Brandi ML, et al.: Surgical management of insulinomas in multiple endocrine neoplasia type 1. Pancreas 41 (4): 547-53, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22228047" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22228047</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_85">Mignon M, Cadiot G: Diagnostic and therapeutic criteria in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1. J Intern Med 243 (6): 489-94, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9681847" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9681847</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_86">Cadiot G, Vuagnat A, Doukhan I, et al.: Prognostic factors in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1. Groupe d'Etude des Néoplasies Endocriniennes Multiples (GENEM and groupe de Recherche et d'Etude du Syndrome de Zollinger-Ellison (GRESZE). Gastroenterology 116 (2): 286-93, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/9922308" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9922308</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_87">Dickson PV, Rich TA, Xing Y, et al.: Achieving eugastrinemia in MEN1 patients: both duodenal inspection and formal lymph node dissection are important. Surgery 150 (6): 1143-52, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/22136834" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22136834</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_88">Akerström G, Stålberg P, Hellman P: Surgical management of pancreatico-duodenal tumors in multiple endocrine neoplasia syndrome type 1. Clinics (Sao Paulo) 67 (Suppl 1): 173-8, 2012. [<a href="/pmc/articles/PMC3328819/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3328819</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22584725" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22584725</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_89">Goudet P, Murat A, Binquet C, et al.: Risk factors and causes of death in MEN1 disease. A GTE (Groupe d'Etude des Tumeurs Endocrines) cohort study among 758 patients. World J Surg 34 (2): 249-55, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/19949948" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19949948</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_90">Lévy-Bohbot N, Merle C, Goudet P, et al.: Prevalence, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas, and somatostatinomas: study from the GTE (Groupe des Tumeurs Endocrines) registry. Gastroenterol Clin Biol 28 (11): 1075-81, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15657529" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15657529</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_91">Vergès B, Boureille F, Goudet P, et al.: Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J Clin Endocrinol Metab 87 (2): 457-65, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11836268" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11836268</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_760_92">Pieterman CR, Vriens MR, Dreijerink KM, et al.: Care for patients with multiple endocrine neoplasia type 1: the current evidence base. Fam Cancer 10 (1): 157-71, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21061174" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21061174</span></a>]</div></li></ol></div></div><div id="CDR0000062890__5"><h2 id="_CDR0000062890__5_">Multiple Endocrine Neoplasia Type 2</h2><div id="CDR0000062890__11"><h3>Clinical Description</h3><p id="CDR0000062890__12">The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN2) are medullary thyroid cancer (MTC); its precursor, C-cell
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hyperplasia (CCH); pheochromocytoma (PHEO); and parathyroid adenomas and/or hyperplasia.
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MEN2-associated MTC is often bilateral and/or multifocal and arises in the background of CCH. In contrast, <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339347/" class="def">sporadic</a> MTC is typically unilateral and/or unifocal. Because approximately 75% to 80% of sporadic cases also have associated CCH, this histopathologic feature cannot be used as a predictor of <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460148/" class="def">familial</a> disease.[<a class="bk_pop" href="#CDR0000062890_rl_5_1">1</a>] Metastatic spread of MTC to regional lymph nodes (i.e.,
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parathyroid, paratracheal, jugular chain, and upper mediastinum) or to distant
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sites, such as the liver, is common in patients who
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present with a palpable thyroid mass or diarrhea.[<a class="bk_pop" href="#CDR0000062890_rl_5_2">2</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_3">3</a>] Although
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PHEOs rarely metastasize, they can be clinically significant in cases of intractable
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hypertension or anesthesia-induced hypertensive crises. Parathyroid
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abnormalities in MEN2 can range from benign parathyroid adenomas or multigland hyperplasia to clinically evident
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hyperparathyroidism with hypercalcemia and renal stones.
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</p><p id="CDR0000062890__298">Historically, individuals and families with MEN2 were classified into one of the following three clinical subtypes based on the presence or absence of certain endocrine tumors in the individual or family:</p><ol id="CDR0000062890__757"><li class="half_rhythm"><div>MEN2A (<a href="/omim/171400" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>).</div></li><li class="half_rhythm"><div> Familial medullary thyroid carcinoma (FMTC) (<a href="/omim/155240" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>).</div></li><li class="half_rhythm"><div>MEN2B (<a href="/omim/162300" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>).</div></li></ol><p id="CDR0000062890__758">Current stratification is moving away from a solely phenotype-based classification and more toward one that is based on <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000660739/" class="def">genotype</a> (i.e., the <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000046063/" class="def">mutation</a>) and <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460203/" class="def">phenotype</a>.[<a class="bk_pop" href="#CDR0000062890_rl_5_4">4</a>]</p><p id="CDR0000062890__1053">The prevalence of MEN2 has been estimated to be approximately 1 in 35,000 individuals.[<a class="bk_pop" href="#CDR0000062890_rl_5_5">5</a>] The vast majority of MEN2 cases are MEN2A. </p><p id="CDR0000062890__751">Clinical findings in the three MEN2 subtypes are summarized in <a class="figpopup" href="/books/NBK65830.8/table/CDR0000062890__259/?report=objectonly" target="object" rid-figpopup="figCDR0000062890259" rid-ob="figobCDR0000062890259">Table 3</a>. All three subtypes confer a high risk of MTC; MEN2A and MEN2B confer an increased risk of
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PHEO, and MEN2A has an increased risk of parathyroid hyperplasia
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and/or adenoma. Classifying a patient or family by MEN2 subtype is useful in
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determining prognosis and management.
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</p><div id="CDR0000062890__259" class="table"><h3><span class="title">Table 3. Percentage of Patients with Clinical Features of MEN2 by Subtype</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65830.8/table/CDR0000062890__259/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062890__259_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Subtype </th><th colspan="1" rowspan="1" style="vertical-align:top;">Medullary Thyroid
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Carcinoma (%)<sup>a</sup></th><th colspan="1" rowspan="1" style="vertical-align:top;">Pheochromocytoma (%)<sup>a</sup></th><th colspan="1" rowspan="1" style="vertical-align:top;">Parathyroid Disease (%)<sup>a</sup></th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">MEN2A </td><td colspan="1" rowspan="1" style="vertical-align:top;">95</td><td colspan="1" rowspan="1" style="vertical-align:top;">50 </td><td colspan="1" rowspan="1" style="vertical-align:top;">15–30</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">FMTC </td><td colspan="1" rowspan="1" style="vertical-align:top;">~100</td><td colspan="1" rowspan="1" style="vertical-align:top;">0 </td><td colspan="1" rowspan="1" style="vertical-align:top;">0 </td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">MEN2B </td><td colspan="1" rowspan="1" style="vertical-align:top;">100</td><td colspan="1" rowspan="1" style="vertical-align:top;">50 </td><td colspan="1" rowspan="1" style="vertical-align:top;">Uncommon</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">FMTC = familial medullary thyroid carcinoma; MEN2 = multiple endocrine neoplasia type 2. </p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Percentages based on observations in referral populations.[<a class="bk_pop" href="#CDR0000062890_rl_5_6">6</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_10">10</a>]</p></div></dd></dl></div></div></div></div><div id="CDR0000062890__18"><h3>MTC and CCH</h3><p id="CDR0000062890__19">MTC originates in calcitonin-producing cells (C-cells) of the thyroid gland.
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MTC is diagnosed when nests of C-cells extend beyond the basement
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membrane and infiltrate and destroy thyroid follicles. CCH
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is diagnosed histologically by the presence of an increased number of diffusely
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scattered or clustered C-cells.[<a class="bk_pop" href="#CDR0000062890_rl_5_11">11</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_12">12</a>] Individuals with <i>RET</i> (<i>REarranged during Transfection</i>) mutations and CCH are at substantially increased risk of progressing to MTC, although such progression is not universal.[<a class="bk_pop" href="#CDR0000062890_rl_5_13">13</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_14">14</a>] MTC and CCH
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are suspected in the presence of an elevated plasma calcitonin concentration.
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</p><p id="CDR0000062890__328">A study of 10,864 patients with nodular thyroid disease found 44 (1 of every 250) cases of MTC after stimulation with calcitonin, none of which were clinically suspected. Consequently, half of these patients had no evidence of MTC on fine-needle biopsy and thus might not have undergone surgery without the positive calcitonin stimulation test.[<a class="bk_pop" href="#CDR0000062890_rl_5_15">15</a>] CCH associated with a positive calcitonin stimulation test occurs in
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about 5% of the general population; therefore, the plasma calcitonin responses to
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stimulation do not always distinguish CCH from small MTC and cannot always distinguish between <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460132/" class="def">carriers</a> and <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000556483/" class="def">noncarriers</a> in an MEN2 family.[<a class="bk_pop" href="#CDR0000062890_rl_5_13">13</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_14">14</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_16">16</a>]</p><p id="CDR0000062890__20">MTC accounts for 2% to 3% of new cases of thyroid cancer diagnosed annually in
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the United States,[<a class="bk_pop" href="#CDR0000062890_rl_5_17">17</a>] although this figure may be an underrepresentation of true incidence because of changes in diagnostic techniques. The total number of new cases of MTC diagnosed annually in the United States is
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between 1,000 and 1,200, about 75% of which are sporadic (i.e., they
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occur in the absence of a <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000302456/" class="def">family history</a> of either MTC or other endocrine
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abnormalities seen in MEN2). The peak incidence of the sporadic form is in the
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fifth and sixth decades of life.[<a class="bk_pop" href="#CDR0000062890_rl_5_2">2</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_18">18</a>] A study in the
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United Kingdom estimated the incidence of MTC at 20 to 25 new cases per year
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among a population of 55 million.[<a class="bk_pop" href="#CDR0000062890_rl_5_8">8</a>]</p><p id="CDR0000062890__329"> In the absence of a positive family
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history, MEN2 may be suspected when MTC occurs at an early age or is
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bilateral or multifocal. While small series of apparently sporadic MTC cases have suggested a higher prevalence of <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460154/" class="def">germline</a>
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<i>RET</i> mutations,[<a class="bk_pop" href="#CDR0000062890_rl_5_19">19</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_20">20</a>] larger series indicate a prevalence range of 1% to 7%.[<a class="bk_pop" href="#CDR0000062890_rl_5_21">21</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_22">22</a>] On the basis of these data, <i>RET</i>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045693/" class="def">gene</a> mutation testing it is widely recommended for all cases of MTC.[<a class="bk_pop" href="#CDR0000062890_rl_5_23">23</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>]</p><p id="CDR0000062890__756"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531825/" class="def">Level of evidence (Screening): 3</a></p><div id="CDR0000062890__818"><h4>Natural history of MTC</h4><p id="CDR0000062890__819">Thyroid cancer represents approximately 4% of new malignancies occurring annually in the
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United States, with an estimated 64,300 cancer diagnoses and 1,980
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cancer deaths per year.[<a class="bk_pop" href="#CDR0000062890_rl_5_27">27</a>] Of these cancer diagnoses, 2% to 3% are MTC.[<a class="bk_pop" href="#CDR0000062890_rl_5_17">17</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_28">28</a>]</p><p id="CDR0000062890__820">MTC arises from the parafollicular calcitonin-secreting cells of the thyroid
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gland. MTC occurs in <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339347/" class="def">sporadic</a> and <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460148/" class="def">familial</a> forms and may be preceded by
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CCH, although CCH is a relatively common abnormality in
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middle-aged adults.[<a class="bk_pop" href="#CDR0000062890_rl_5_11">11</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_12">12</a>]</p><p id="CDR0000062890__821">Average survival for MTC is lower than that for more common
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thyroid cancers (e.g., 83% 5-year survival for MTC compared with 90% to 94% 5-year
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survival for papillary and follicular thyroid cancer).[<a class="bk_pop" href="#CDR0000062890_rl_5_28">28</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_29">29</a>] Survival is
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correlated with stage at diagnosis, and decreased survival in MTC can be
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accounted for in part by a high proportion of late-stage diagnosis.[<a class="bk_pop" href="#CDR0000062890_rl_5_28">28</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_30">30</a>]</p><p id="CDR0000062890__822">In addition to early stage at diagnosis, other factors associated with improved
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survival in MTC include smaller tumor size, younger age at diagnosis, familial
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versus sporadic form, and diagnosis by biochemical screening (i.e., screening for
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calcitonin elevation) versus symptoms.[<a class="bk_pop" href="#CDR0000062890_rl_5_30">30</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_33">33</a>]</p><p id="CDR0000062890__823">A Surveillance, Epidemiology, and End Results population-based study of 1,252 MTC patients found that survival varied by extent of local disease. For example, the 10-year survival rates ranged from 95.6% for those with disease confined to the thyroid gland to 40% for those with distant metastases.[<a class="bk_pop" href="#CDR0000062890_rl_5_31">31</a>]</p></div><div id="CDR0000062890__824"><h4>Hereditary MTC</h4><p id="CDR0000062890__825">While most MTC cases are sporadic, approximately 20% to 25% are hereditary because of mutations in the <i>RET</i> proto-oncogene.[<a class="bk_pop" href="#CDR0000062890_rl_5_34">34</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_36">36</a>] Mutations in the <i>RET</i> gene cause MEN2, an <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339338/" class="def">autosomal dominant</a> disorder associated with a high lifetime risk of MTC. Multiple endocrine neoplasia type 1 (MEN1) (<a href="/omim/131100" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>) is an autosomal dominant endocrinopathy that is genetically and clinically distinct
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from MEN2; however, the similar nomenclature for MEN1 and MEN2 may cause
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confusion. There is no increased risk of thyroid cancer for MEN1. (Refer to the <a href="#CDR0000062890__760">MEN1</a> section of this summary for more information.)</p></div></div><div id="CDR0000062890__21"><h3>MEN2-Related PHEO</h3><p id="CDR0000062890__22">PHEOs (<a href="/omim/171300" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>) arise from the catecholamine-producing chromaffin cells of the adrenal medulla. They are a relatively rare tumor and are suspected among patients with refractory hypertension or
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when biochemical screening reveals elevated excretion of catecholamines and
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catecholamine metabolites (i.e., norepinephrine, epinephrine, metanephrine, and
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vanillylmandelic acid) in 24-hour urine collections or plasma. In the past, measurement of urinary catecholamines was considered the preferred biochemical screening method. However, given that catecholamines are only released intermittently and are metabolized in the adrenal medulla into metanephrine and normetanephrine, the measurement of urine or plasma fractionated metanephrines has become the gold standard.[<a class="bk_pop" href="#CDR0000062890_rl_5_37">37</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_42">42</a>] When biochemical screening in an individual who has or is at risk of MEN2 suggests PHEO, localization studies, such as magnetic resonance imaging (MRI) or computed tomography, can be performed.[<a class="bk_pop" href="#CDR0000062890_rl_5_43">43</a>] Confirmation of the diagnosis can be made using I<sup>131</sup>-metaiodobenzylguanidine scintigraphy or positron emission tomography imaging.[<a class="bk_pop" href="#CDR0000062890_rl_5_14">14</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_43">43</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_45">45</a>]
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</p><p id="CDR0000062890__243">A diagnosis of MEN2 is often considered in individuals with bilateral PHEO, those with an early age of onset (age <35 years), and those with a personal and/or family history of MTC or hyperparathyroidism. However, MEN2 is not the only genetic disorder that includes a predisposition to PHEO. Other disorders include neurofibromatosis type 1 (NF1), von Hippel-Lindau disease (VHL),[<a class="bk_pop" href="#CDR0000062890_rl_5_46">46</a>] and the hereditary paraganglioma syndromes.[<a class="bk_pop" href="#CDR0000062890_rl_5_47">47</a>] (Refer to the <a href="/books/n/pdqcis/CDR0000574548/#CDR0000574548__29">von Hippel-Lindau Syndrome</a> section in the PDQ summary on the <a href="/books/n/pdqcis/CDR0000574548/">Genetics of Kidney Cancer</a> for more information about VHL.) A large European consortium that included 271 patients from Germany,[<a class="bk_pop" href="#CDR0000062890_rl_5_48">48</a>] 314 patients from France,[<a class="bk_pop" href="#CDR0000062890_rl_5_49">49</a>] and 57 patients from Italy (total = 642) with apparently sporadic PHEO analyzed the known PHEO/functional paraganglioma <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460209/" class="def">susceptibility genes</a> (<i>NF1</i>, <i>RET</i>, <i>VHL</i>, <i>SDHB</i>, and <i>SDHD</i>).[<a class="bk_pop" href="#CDR0000062890_rl_5_50">50</a>] The diagnosis of NF1 in this series was made clinically, while all other conditions were diagnosed based on the presence of a germline mutation in the causative gene. The disease was associated with a positive family history in 166 (25.9%) patients; germline mutations were detected in <i>RET</i> (n = 31), <i>VHL</i> (n = 56), <i>NF1</i> (n = 14), <i>SDHB</i> (n = 34), or <i>SDHD</i> (n = 31). Rigorous clinical evaluation and <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000044868/" class="def">pedigree</a> analysis either before or after testing revealed that of those with a positive family history and/or a syndromic presentation, 58.4% carried a mutation, compared with 12.7% who were nonsyndromic and/or had no family history. Of the 31 individuals with a germline <i>RET</i> mutation, 28 (90.3%) had a positive family history and/or syndromic presentation, suggesting that most individuals with <i>RET</i> mutations and PHEO will have a positive family history or other manifestations of the disease.</p></div><div id="CDR0000062890__299"><h3>Primary Hyperparathyroidism (PHPT)</h3><p id="CDR0000062890__322">PHPT is the third most common endocrine disorder in the general population. The incidence increases with age with the vast majority of cases occurring after the sixth decade of life. Approximately 80% of cases are the results of a single adenoma.[<a class="bk_pop" href="#CDR0000062890_rl_5_51">51</a>] PHPT can also be seen as a component tumor in several different hereditary syndromes, including the following:</p><ul id="CDR0000062890__323"><li class="half_rhythm"><div>MEN1.</div></li><li class="half_rhythm"><div>Hyperparathyroidism-Jaw Tumor syndrome.</div></li><li class="half_rhythm"><div>Familial Isolated Hyperparathyroidism.</div></li><li class="half_rhythm"><div>MEN2.[<a class="bk_pop" href="#CDR0000062890_rl_5_52">52</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_54">54</a>]</div></li></ul><p id="CDR0000062890__324">Hereditary PHPT is typically multiglandular, presents earlier in life, and can have histologic evidence of both adenoma and glandular hyperplasia.</p></div><div id="CDR0000062890__23"><h3>Clinical Diagnosis of MEN2 Subtypes</h3><p id="CDR0000062890__24">The diagnosis of the three MEN2 clinical subtypes relies on a combination of clinical
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findings, family history, and molecular genetic testing of the <i>RET</i> gene
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(chromosomal region 10q11.2).
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</p><div id="CDR0000062890__112"><h4>MEN2A</h4><p id="CDR0000062890__26">MEN2A is diagnosed clinically by the occurrence of two or more specific
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endocrine tumors (MTC, PHEO, or parathyroid adenoma and/or hyperplasia) in
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a single individual or in close relatives.
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</p><p id="CDR0000062890__27">The MEN2A subtype makes up about 60% to 90% of MEN2 cases. The MEN2A subtype
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was initially called Sipple syndrome.[<a class="bk_pop" href="#CDR0000062890_rl_5_55">55</a>] Since genetic testing for <i>RET</i>
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mutations has become available, it has become apparent that about 95% of individuals
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with MEN2A will develop MTC; about 50% will develop PHEO; and
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about 15% to 30% will develop hyperparathyroidism.[<a class="bk_pop" href="#CDR0000062890_rl_5_14">14</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_58">58</a>]
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</p><p id="CDR0000062890__28">MTC is generally the first manifestation of MEN2A. In asymptomatic at-risk individuals, stimulation testing may reveal elevated plasma calcitonin
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levels and the presence of CCH or MTC.[<a class="bk_pop" href="#CDR0000062890_rl_5_14">14</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_57">57</a>] In families with MEN2A,
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the biochemical manifestations of MTC generally appear between the ages of 5
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and 25 years (mean 15 years).[<a class="bk_pop" href="#CDR0000062890_rl_5_14">14</a>] If presymptomatic screening is not performed, MTC
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typically presents as a neck mass or neck pain at about age 5 to 20 years.
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More than 50% of such patients have cervical lymph node metastases.[<a class="bk_pop" href="#CDR0000062890_rl_5_2">2</a>]
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Diarrhea, the most frequent systemic symptom, occurs in patients with a plasma
|
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calcitonin level of greater than 10 ng/mL and implies a poor prognosis.[<a class="bk_pop" href="#CDR0000062890_rl_5_2">2</a>] Up to
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30% of patients with MTC present with diarrhea and advanced disease.[<a class="bk_pop" href="#CDR0000062890_rl_5_59">59</a>]
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</p><p id="CDR0000062890__29">MEN2-associated PHEOs are more often bilateral, multifocal, and associated with extratumoral medullary hyperplasia.[<a class="bk_pop" href="#CDR0000062890_rl_5_60">60</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_62">62</a>] They also have an earlier age of onset and are less likely to be malignant than their sporadic counterparts.[<a class="bk_pop" href="#CDR0000062890_rl_5_60">60</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_63">63</a>] MEN2-associated PHEOs usually present after MTC, typically with intractable
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hypertension.[<a class="bk_pop" href="#CDR0000062890_rl_5_7">7</a>]
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</p><p id="CDR0000062890__138">Unlike the PHPT seen in MEN1, hyperparathyroidism in individuals with MEN2 is typically asymptomatic or associated with only mild elevations in calcium.[<a class="bk_pop" href="#CDR0000062890_rl_5_59">59</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_64">64</a>] A series of 56 patients with MEN2-related hyperparathyroidism has been reported by the French Calcitonin Tumors Study Group.[<a class="bk_pop" href="#CDR0000062890_rl_5_64">64</a>] The median age at diagnosis was 38 years, documenting that this disorder is rarely the first manifestation of MEN2. This is in sharp contrast to MEN1, in which the vast majority of patients (87%–99%) initially present with primary hyperparathyroidism.[<a class="bk_pop" href="#CDR0000062890_rl_5_65">65</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_67">67</a>] Parathyroid abnormalities were found concomitantly with surgery for medullary thyroid carcinoma in 43 patients (77%). Two-thirds of the patients were asymptomatic. Among the 53 parathyroid glands removed surgically, there were 24 single adenomas, four double adenomas, and 25 hyperplastic glands. </p><p id="CDR0000062890__30">A small number of families with MEN2A have pruritic skin lesions known as <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000763035/" class="def">cutaneous lichen amyloidosis</a>. This lichenoid
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skin lesion is located over the upper portion of the back and may appear before
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the onset of MTC.[<a class="bk_pop" href="#CDR0000062890_rl_5_68">68</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_69">69</a>]
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</p><p id="CDR0000062890__900">Figure 2 depicts some of the classic manifestations of MEN2A in a family.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figCDR0000062890902" co-legend-rid="figlgndCDR0000062890902"><a href="/books/NBK65830.8/figure/CDR0000062890__902/?report=objectonly" target="object" title="Figure" class="img_link icnblk_img figpopup" rid-figpopup="figCDR0000062890902" rid-ob="figobCDR0000062890902"><img class="small-thumb" src="/books/NBK65830.8/bin/CDR0000749985.gif" src-large="/books/NBK65830.8/bin/CDR0000749985.jpg" alt="Figure 2" /></a><div class="icnblk_cntnt" id="figlgndCDR0000062890902"><h4 id="CDR0000062890__902"><a href="/books/NBK65830.8/figure/CDR0000062890__902/?report=objectonly" target="object" rid-ob="figobCDR0000062890902">Figure</a></h4><p class="float-caption no_bottom_margin">Figure 2. MEN2A pedigree. This pedigree shows some of the classic features of a family with a deleterious <i>RET</i> mutation across four generations, including affected family members with medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism. <a href="/books/NBK65830.8/figure/CDR0000062890__902/?report=objectonly" target="object" rid-ob="figobCDR0000062890902">(more...)</a></p></div></div><p id="CDR0000062890__989">In a child, the presence of oral and ocular neuromas and/or a tall and lanky appearance may warrant further investigation.[<a class="bk_pop" href="#CDR0000062890_rl_5_70">70</a>] Some authors have recommended referral to genetic counseling for an individual with medullary thyroid cancer or any of the following features:[<a class="bk_pop" href="#CDR0000062890_rl_5_70">70</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_71">71</a>]</p><ul id="CDR0000062890__990"><li class="half_rhythm"><div>Benign oral and submucosal neuromas.</div></li><li class="half_rhythm"><div>Elongated face and large lips.</div></li><li class="half_rhythm"><div>Ganglioneuromatosis.</div></li><li class="half_rhythm"><div>Inability to cry tears (biologic mechanism unknown).</div></li></ul></div><div id="CDR0000062890__113"><h4>Familial medullary thyroid carcinoma (FMTC)</h4><p id="CDR0000062890__32">The FMTC subtype makes up 5% to 35% of MEN2 cases and is defined as families with four or more cases of MTC in the absence of
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PHEO or parathyroid adenoma/hyperplasia.[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>] Families with two or three cases of MTC and incompletely documented screening for
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PHEO and parathyroid disease may actually represent MEN2A; it has been
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suggested that these families should be considered unclassified.[<a class="bk_pop" href="#CDR0000062890_rl_5_8">8</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_72">72</a>] Misclassification of families with MEN2A as having FMTC (because of too-small family size or later onset of other manifestations of MEN2A) may result in overlooking the risk of PHEO, a disease with significant morbidity and mortality. For this reason, there is debate about whether FMTC represents a separate entity or is a variation of MEN2A in which there is a lack of or delay in the onset of the other (nonthyroidal) manifestations of the MEN2A syndrome.[<a class="bk_pop" href="#CDR0000062890_rl_5_73">73</a>] Some authors recommended,[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>] therefore, that patients thought to have pure FMTC also be screened for PHEO and hyperparathyroidism. (Refer to the <a href="#CDR0000062890__121">Screening of at-risk individuals for pheochromocytoma</a> and <a href="#CDR0000062890__122">Screening of at-risk individuals for hyperparathyroidism</a> sections of this summary for more information.)</p></div><div id="CDR0000062890__114"><h4>MEN2B</h4><p id="CDR0000062890__35">MEN2B is diagnosed clinically by the presence of mucosal neuromas of the lips
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and tongue, medullated corneal nerve fibers, distinctive <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000763033/" class="def">facies</a> with
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enlarged lips, an asthenic Marfanoid body habitus, and MTC.[<a class="bk_pop" href="#CDR0000062890_rl_5_74">74</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_76">76</a>]
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</p><p id="CDR0000062890__36">The MEN2B subtype makes up about 5% of MEN2 cases. The MEN2B subtype was
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initially called mucosal neuroma syndrome or Wagenmann-Froboese syndrome.[<a class="bk_pop" href="#CDR0000062890_rl_5_77">77</a>]
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MEN2B is characterized by the early development of an aggressive form of MTC
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in all patients.[<a class="bk_pop" href="#CDR0000062890_rl_5_77">77</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_78">78</a>] Patients with MEN2B who do not undergo thyroidectomy
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at an early age (at approximately age 1 year) are likely to develop metastatic MTC at
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an early age. Before intervention with early risk-reducing thyroidectomy, the
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average age at death in patients with MEN2B was 21 years. PHEOs
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occur in about 50% of MEN2B cases; about half are multiple and often bilateral.
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Clinically apparent parathyroid disease is very uncommon.[<a class="bk_pop" href="#CDR0000062890_rl_5_6">6</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_79">79</a>] Patients with MEN2B may be identified in infancy or early childhood by a
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distinctive facial appearance and the presence of mucosal neuromas on the
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anterior dorsal surface of the tongue, palate, or pharynx. The lips become
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prominent over time, and submucosal nodules may be present on the vermilion
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border of the lips. Neuromas of the eyelids may cause thickening and eversion
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of the upper eyelid margins. Prominent thickened corneal nerves may be seen by
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slit lamp examination.
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</p><p id="CDR0000062890__38">About 40% of patients have diffuse ganglioneuromatosis of the gastrointestinal
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tract. Associated symptoms include abdominal distension, megacolon,
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constipation, and diarrhea.
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About 75% of patients have a Marfanoid habitus, often with kyphoscoliosis or
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lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle
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wasting and weakness can also be seen.[<a class="bk_pop" href="#CDR0000062890_rl_5_75">75</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_76">76</a>]</p></div></div><div id="CDR0000062890__42"><h3>Genetically Related Disorder</h3><div id="CDR0000062890__116"><h4>Hirschsprung disease (HSCR)</h4><p id="CDR0000062890__44">HSCR (<a href="/omim/142623" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>), a disorder of the enteric plexus of the colon that
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typically results in enlargement of the bowel and constipation or obstipation
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in neonates, is observed in a small number of individuals with MEN2A, FMTC, or very rarely, MEN2B.[<a class="bk_pop" href="#CDR0000062890_rl_5_80">80</a>] Up to 40% of familial cases of HSCR and 3% to 7% of sporadic cases are associated with germline mutations in the <i>RET</i>
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proto-oncogene and are designated HSCR1.[<a class="bk_pop" href="#CDR0000062890_rl_5_81">81</a>
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,<a class="bk_pop" href="#CDR0000062890_rl_5_82">82</a>] Some of these <i>RET</i> mutations are
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located in <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460135/" class="def">codons</a> that lead to the development of MEN2A or FMTC (i.e., codons 609, 618, and 620).[<a class="bk_pop" href="#CDR0000062890_rl_5_80">80</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_83">83</a>]</p><p id="CDR0000062890__45">In a study of 44 families, seven families (16%) had <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460139/" class="def">cosegregation</a> of MEN2A and HSCR1. The
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probability that individuals in a family with MEN2A and an <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460146/" class="def">exon</a> 10 Cys
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mutation would manifest HSCR1 was estimated to be 6% in one series.[<a class="bk_pop" href="#CDR0000062890_rl_5_81">81</a>] Furthermore, in a multicenter international <i>RET</i> mutation consortium study, 6 of 62 <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460158/" class="def">kindreds</a> carrying either the C618R or C620R mutation also had HSCR.[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>]</p><p id="CDR0000062890__222">A novel analytic approach employing family-based association studies coupled with comparative and functional genomic analysis revealed that a common <i>RET</i> variant within a conserved enhancer-like sequence in <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000660737/" class="def">intron</a> 1 makes a 20-fold greater contribution to HSCR compared with all known <i>RET</i> mutations.[<a class="bk_pop" href="#CDR0000062890_rl_5_84">84</a>] This mutation has low <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339344/" class="def">penetrance</a> and different genetic effects in males and females. Transmission to sons and daughters leads to a 5.7-fold and 2.1-fold increase in susceptibility, respectively. This finding is consistent with the greater incidence of HSCR in males. Demonstrating this strong relationship between a common noncoding mutation in <i>RET</i> and the risk of HSCR also accounts for previous failures to detect coding mutations in <i>RET</i>-linked families.</p></div></div><div id="CDR0000062890__48"><h3>Molecular Genetics of MEN2</h3><p id="CDR0000062890__49">MEN2 syndromes are the result of inherited mutations in the <i>RET</i> gene, located on
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chromosome region 10q11.2.[<a class="bk_pop" href="#CDR0000062890_rl_5_85">85</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_87">87</a>] The <i>RET</i> gene is a proto-oncogene composed of 21
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exons over 55 kilobase of genomic material.[<a class="bk_pop" href="#CDR0000062890_rl_5_88">88</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_89">89</a>] </p><p id="CDR0000062890__50"><i>RET</i> encodes a receptor tyrosine kinase with extracellular, transmembrane, and
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intracellular <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460145/" class="def">domains</a>. Details of <i>RET</i> receptor and ligand interaction in this signaling pathway have been reviewed.[<a class="bk_pop" href="#CDR0000062890_rl_5_90">90</a>] Briefly, the extracellular domain consists of a calcium-binding
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cadherin-like region and a cysteine-rich region that interacts with one of four ligands identified to date. These ligands, e.g., glial cell line–derived neurotrophic factor (GDNF), neurturin, persephin, and artemin, also interact with one of four coreceptors in the GDNF-family receptor–alpha family.[<a class="bk_pop" href="#CDR0000062890_rl_5_90">90</a>] The tyrosine kinase catalytic core is
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located in the intracellular domain, which causes downstream signaling events
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through a variety of second messenger molecules. Normal tissues contain
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transcripts of several lengths.[<a class="bk_pop" href="#CDR0000062890_rl_5_91">91</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_93">93</a>]
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</p><div id="CDR0000062890__118"><h4>Genetic testing</h4><p id="CDR0000062890__301">MEN2 is a well-defined hereditary cancer syndrome for which genetic testing is considered an important part of the management for at-risk family members. It meets the criteria related to indications for genetic testing for cancer susceptibility outlined by the American Society of Clinical Oncology in its most recent genetic testing policy statement.[<a class="bk_pop" href="#CDR0000062890_rl_5_94">94</a>] At-risk individuals are defined as <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460150/" class="def">first-degree relatives</a>
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(parents, siblings, and children) of a person known to have MEN2. Testing
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allows the identification of people with asymptomatic MEN2 who can be offered
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risk-reducing thyroidectomy and biochemical screening as preventive measures.
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A negative mutation analysis in at-risk relatives, however, is <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460156/" class="def">informative</a> only after a disease-causing mutation has been identified in an <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460124/" class="def">affected</a> relative. (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000062865/">Cancer Genetics Risk Assessment and Counseling</a> for more information.) Because early detection of at-risk individuals affects medical management,
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testing of children who have no symptoms is considered beneficial.[<a class="bk_pop" href="#CDR0000062890_rl_5_94">94</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_95">95</a>] (Refer to the <a href="#CDR0000062890__305">Genotype-Phenotype Correlations and Risk Stratification</a> section of this summary for more information about clinical management of at-risk individuals.)</p><p id="CDR0000062890__302"><a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000561402/" class="def">Germline DNA</a> testing for <i>RET</i> mutations is generally recommended to all individuals with a diagnosis of MTC, regardless of whether there is a personal or family history suggestive of MEN2.[<a class="bk_pop" href="#CDR0000062890_rl_5_24">24</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_96">96</a>] Approximately 95% of patients with MEN2A or MEN2B will have an identifiable germline <i>RET</i> mutation.[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>] For FMTC, the detection rate is slightly lower at 88%.[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>] Between 1% and 10% of individuals with apparently sporadic MTC will carry a germline <i>RET</i> mutation, underscoring the importance of testing all individuals diagnosed with MTC.[<a class="bk_pop" href="#CDR0000062890_rl_5_19">19</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_22">22</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_97">97</a>]</p><p id="CDR0000062890__316">There is no evidence for the involvement of other genetic <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460162/" class="def">loci</a>, and all mutation-negative families analyzed to date have demonstrated <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460161/" class="def">linkage</a> to the <i>RET</i> gene. For families that do not have a detectable mutation, clinical recommendations can be based on the clinical features in the affected individual and in the family.</p><p id="CDR0000062890__317">There is considerable diversity in the techniques used and the approach to <i>RET</i> mutation testing among the various laboratories that perform this procedure. Methods used to detect mutations in <i>RET</i> include
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000044798/" class="def">polymerase chain reaction</a> (PCR) followed by restriction enzyme digestion of PCR products, <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000671177/" class="def">heteroduplex analysis</a>,
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000681112/" class="def">single-stranded conformation polymorphism analysis</a>, denaturing high-performance liquid chromatography, and DNA sequencing.[<a class="bk_pop" href="#CDR0000062890_rl_5_98">98</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_101">101</a>] Most testing laboratories, at a minimum, offer testing using a targeted exon approach; that is, the laboratories look for mutations in the exons that are most commonly found to carry mutations (exons 10, 11, 13, 14, 15 and 16). Other laboratories offer testing for all exons. If targeted exon testing in a family with a high clinical suspicion for MEN2 is normal, sequencing of the remaining exons can then be performed. </p><p id="CDR0000062890__304">These differences in mutation detection method and targeted versus full gene testing represent important considerations for selecting a laboratory to perform a test and in interpreting the test result. (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000062865/">Cancer Genetics Risk Assessment and Counseling</a> for more information about clinical validity.)</p></div></div><div id="CDR0000062890__305"><h3>Genotype-Phenotype Correlations and Risk Stratification</h3><p id="CDR0000062890__306"><a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000660739/" class="def">Genotype</a>-<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460203/" class="def">phenotype</a> correlations in MEN2 are well-established and have long been used to guide clinicians in making medical management recommendations. Several groups have developed mutation-stratification tables based on clinical phenotype, age of onset, and aggressiveness of MTC.[<a class="bk_pop" href="#CDR0000062890_rl_5_24">24</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_72">72</a>] This classification strategy was first put forth after the Seventh International Workshop on MEN in 2001, which provided guidelines for the age of genetic testing and prophylactic thyroidectomy.[<a class="bk_pop" href="#CDR0000062890_rl_5_24">24</a>] This stratification was revised by the American Thyroid Association (ATA).[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>] The original classification scheme provided three levels of risk based on the genetic mutation of an individual. The new guidelines by the ATA added a fourth category for codon 634 mutations, in recognition of their aggressive clinical course. The specific mutations and their ATA classification are summarized in <a class="figpopup" href="/books/NBK65830.8/table/CDR0000062890__749/?report=objectonly" target="object" rid-figpopup="figCDR0000062890749" rid-ob="figobCDR0000062890749">Table 4</a> and <a class="figpopup" href="/books/NBK65830.8/table/CDR0000062890__748/?report=objectonly" target="object" rid-figpopup="figCDR0000062890748" rid-ob="figobCDR0000062890748">Table 5</a> below. The ATA's classification scheme has not been prospectively validated as a basis for clinical decision-making.</p><p id="CDR0000062890__714">ATA-level D mutations are the most aggressive and carry the highest risk of developing MTC.[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>] These mutations, which are typically seen in MEN2B, are associated with the youngest age at disease onset and the highest risk of mortality. ATA-level C mutations (codon 634) are associated with a slightly lower risk, yet the MTC in patients with these mutations is still quite aggressive and may present at an early age. ATA-level A and level B mutations are associated with a lower risk of aggressive MTC relative to the risk seen in level C and level D mutation carriers. However, the risk of MTC is still substantially elevated over the general population risk and consideration of risk-reducing thyroidectomy is warranted.[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>]</p><p id="CDR0000062890__716">A European multicenter study of 207 <i>RET</i> mutation carriers supported previous suggestions that some mutations are associated with early-onset disease. For example, this study found that individuals with the C634Y mutation developed MTC at a significantly younger age (mean 3.2 years; 95% confidence interval [CI], 1.2–5.4) than individuals with the C634R mutation (mean 6.9 years; 95% CI, 4.9–8.8). In the former group of patients, risk-reducing thyroidectomy warrants consideration before the age of 5 years. Although limited by small numbers, the same study did not support a need for risk-reducing thyroidectomy in asymptomatic carriers of mutations in codons 609, 630, 768, 790, 791, 804, or 891 before the age of 10 years or for central lymph node dissection before the age of 20 years.[<a class="bk_pop" href="#CDR0000062890_rl_5_102">102</a>] Some authors suggest using these differences as the basis for decisions on the timing of risk-reducing thyroidectomy and the extent of surgery.[<a class="bk_pop" href="#CDR0000062890_rl_5_24">24</a>] Two other studies have found conflicting results suggesting that the C634R mutation is associated with a higher penetrance of MTC-related PHEO and hyperparathyroidism and a higher likelihood of lymph node and distant metastases at an earlier age than is C634Y.[<a class="bk_pop" href="#CDR0000062890_rl_5_103">103</a>] Additional studies in larger populations are needed to further clarify this issue. Others have advocated using basal and stimulated calcitonin levels as a basis for determining the appropriate timing of thyroidectomy.[<a class="bk_pop" href="#CDR0000062890_rl_5_104">104</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_105">105</a>]</p><p id="CDR0000062890__1054"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531818/" class="def">Level of evidence (calcitonin level as a basis for the timing of thyroidectomy): 4aii</a></p><p id="CDR0000062890__308">Mutations 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC.[<a class="bk_pop" href="#CDR0000062890_rl_5_106">106</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_110">110</a>] Approximately 95% of individuals with MEN2B will have the M918T mutation.[<a class="bk_pop" href="#CDR0000062890_rl_5_106">106</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_108">108</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_111">111</a>] As discussed above, 50% of individuals with MEN2B will develop PHEO but PHPT is rare. In addition to mutations at codons 883 and 918, some individuals with an MEN2B-like phenotype have been found to carry two germline mutations.[<a class="bk_pop" href="#CDR0000062890_rl_5_112">112</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_116">116</a>] It is likely that as testing for <i>RET</i> becomes more common in clinical practice, additional double mutation phenotypes will be described. </p><p id="CDR0000062890__309">Mutations at codon 634 (ATA-level C) are by far the most frequent finding in families with MEN2A. One study of 477 <i>RET</i> carriers showed that 52.1% had the C634R mutation, 26.0% carried the C634Y mutation, and 9.1% had the C634G mutation.[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>] In general, mutations at codon 634 are associated with PHEOs and PHPT.[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_117">117</a>] Until recently, MEN2A with cutaneous lichen amyloidosis had been seen almost exclusively in patients with mutations at codon 634.[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_58">58</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_118">118</a>] However, a recent report described MTC and cutaneous lichen amyloidosis in an individual previously thought to have FMTC due to a codon 804 mutation.[<a class="bk_pop" href="#CDR0000062890_rl_5_119">119</a>] Codon 634 mutations have also been described in FMTC but are almost exclusively C634Y.[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>]</p><p id="CDR0000062890__310">In summary, ATA-level D and level C mutations confer the highest risk of MTC (about 95% lifetime risk) with a more aggressive disease course. There is an increased risk of PHEO (up to 50%).[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_120">120</a>] Individuals with codon 634 mutations (but not codon 883 or 918 mutations) also have an increased risk of PHPT.[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>] </p><p id="CDR0000062890__738">ATA-level B mutations, located in exon 10 of the <i>RET</i> gene, include mutations at codons 609, 611, 618, 620, and 630. These mutations involve cysteine residues in the extracellular domain of the RET protein and have been seen in families with MEN2A and those with MTC only (FMTC).[<a class="bk_pop" href="#CDR0000062890_rl_5_21">21</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_72">72</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_121">121</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_125">125</a>] The risk of MTC in individuals with ATA-level B mutations is approximately 95% to 100%; the risk of PHEO and hyperparathyroidism is lower than that seen in ATA-level A mutations. In a large series of 518 <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460211/" class="def">probands</a> with MTC undergoing <i>RET</i> testing, most individuals with codon 609, 611, 618, 620, or 630 mutations had only MTC and no other features suggestive of MEN2. The authors attributed this to the relatively short follow-up time, incomplete screening of family members, or the method of ascertainment (population-based).[<a class="bk_pop" href="#CDR0000062890_rl_5_34">34</a>] Another large study of 390 exon 10 mutation carriers showed an age-related risk of PHEO for individuals carrying any exon 10 mutation of 23.1% by age 50 years and 33% by age 60 years. Overall prevalence of PHEO was 17%. This study reported a 3.9% risk of developing hyperparathyroidism by age 60 years.[<a class="bk_pop" href="#CDR0000062890_rl_5_126">126</a>]</p><p id="CDR0000062890__331">Individuals with ATA-level A mutations have a lower, albeit still elevated, lifetime risk of MTC. MTC associated with these mutations tends to follow a more indolent course and have a later age at onset, although there are several reports of individuals with ATA-level A mutations who developed MTC before age 20 years.[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_127">127</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_131">131</a>] Although PHEO and PHPT are not commonly associated with level A mutations, they have been described.[<a class="bk_pop" href="#CDR0000062890_rl_5_131">131</a>]</p><div id="CDR0000062890__749" class="table"><h3><span class="title">Table 4. Genotype-Phenotype Correlations and American Thyroid Association (ATA) Risk Levels<sup>a,b</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65830.8/table/CDR0000062890__749/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062890__749_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Mutation</th><th colspan="1" rowspan="1" style="vertical-align:top;">ATA Risk Level</th><th colspan="1" rowspan="1" style="vertical-align:top;">Medullary Thyroid Cancer</th><th colspan="1" rowspan="1" style="vertical-align:top;">PHPT</th><th colspan="1" rowspan="1" style="vertical-align:top;">PHEO</th><th colspan="1" rowspan="1" style="vertical-align:top;">References</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">R321G<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_132">132</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">A510V</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_133">133</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">E511K<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_133">133</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">531/9 <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460130/" class="def">base pair</a> duplication</td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_134">134</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">532 duplication<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_135">135</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">C515S<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_136">136</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">C531R<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_133">133</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">G533C</td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">R</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_137">137</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_142">142</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">R600Q<sup>c</sup>
|
|
</td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_143">143</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">K603E<sup>c</sup>
|
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_144">144</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Y606C<sup>c</sup>
|
|
</td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_145">145</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_146">146</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">C609F/R/G/S/Y</td><td colspan="1" rowspan="1" style="vertical-align:top;">B</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">R/MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_35">35</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_120">120</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_126">126</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_147">147</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_151">151</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">C611R/G/F/S/W/Y</td><td colspan="1" rowspan="1" style="vertical-align:top;">B</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">R/MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_120">120</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_126">126</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">C618R/G/F/S/Y</td><td colspan="1" rowspan="1" style="vertical-align:top;">B</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_120">120</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_126">126</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_152">152</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_155">155</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">C620R/G/F/S/W/Y</td><td colspan="1" rowspan="1" style="vertical-align:top;">B</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_120">120</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_126">126</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_148">148</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_154">154</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">C630R/F/S/Y</td><td colspan="1" rowspan="1" style="vertical-align:top;">B</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">R</td><td colspan="1" rowspan="1" style="vertical-align:top;">R</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_114">114</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_156">156</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">D631Y</td><td colspan="1" rowspan="1" style="vertical-align:top;">B</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">R</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_157">157</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_159">159</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">633/9 base pair duplication</td><td colspan="1" rowspan="1" style="vertical-align:top;">B</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_160">160</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">C634R</td><td colspan="1" rowspan="1" style="vertical-align:top;">C</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_120">120</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_161">161</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_162">162</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">C634G/F/S/W/Y</td><td colspan="1" rowspan="1" style="vertical-align:top;">C</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_120">120</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_154">154</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_161">161</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_163">163</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">C634Y/Y791F</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">R</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_164">164</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">634/12 base pair duplication</td><td colspan="1" rowspan="1" style="vertical-align:top;">B</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_165">165</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">635/insertion ELCR;T636P</td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_145">145</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">S649L</td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">R</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_35">35</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_166">166</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_168">168</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">K666E/N<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_133">133</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_145">145</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_169">169</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">S686N<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_154">154</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">E768D</td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">R</td><td colspan="1" rowspan="1" style="vertical-align:top;">R</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_114">114</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_157">157</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_170">170</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">R770Q<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_171">171</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N777S<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_172">172</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">L790F</td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">R</td><td colspan="1" rowspan="1" style="vertical-align:top;">R/MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_157">157</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_173">173</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_174">174</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Y791F</td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_157">157</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_173">173</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_175">175</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">V804L</td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">R</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_173">173</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_176">176</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">V804M</td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">R</td><td colspan="1" rowspan="1" style="vertical-align:top;">R</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_173">173</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_176">176</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_178">178</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">V804M+V778I<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">B</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_179">179</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">V804M+E805K<sup>d</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">D</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_112">112</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">V804M+Y806K<sup>d</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">D</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_113">113</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_115">115</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">V804M+S904C<sup>c,d</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">D</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_116">116</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">G819K<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_35">35</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">R833C<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_180">180</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">R844Q<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_35">35</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_157">157</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">L881V<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_171">171</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">A883F<sup>d</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">D</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_109">109</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_110">110</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_181">181</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">R886W<sup>c</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_182">182</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">S891A</td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">R</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_35">35</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_183">183</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_186">186</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">R912P</td><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;">MI</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_35">35</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_187">187</a>]</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M918T<sup>d</sup></td><td colspan="1" rowspan="1" style="vertical-align:top;">D</td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">MA</td><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000062890_rl_5_56">56</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_154">154</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_188">188</a>]</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">PHEO = pheochromocytoma; PHPT = primary hyperparathyroidism.</p></div></dd><dt></dt><dd><div><p class="no_margin">MA = majority (>50%);
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MI = minority (10%–50%);
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R = rare (<10%).
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</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Refer to <a class="figpopup" href="/books/NBK65830.8/table/CDR0000062890__748/?report=objectonly" target="object" rid-figpopup="figCDR0000062890748" rid-ob="figobCDR0000062890748">Table 5</a> for more information about the ATA risk levels.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>b</sup>Adapted from Kloos et al.[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>]</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>c</sup>Associated with multiple endocrine neoplasia type 2 mutations.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>d</sup>Associated with mutations based on limited families/case reports and may represent <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000556493/" class="def">variants of unknown significance</a>. </p></div></dd></dl></div></div></div><p id="CDR0000062890__332">In addition to the mutations categorized in <a class="figpopup" href="/books/NBK65830.8/table/CDR0000062890__749/?report=objectonly" target="object" rid-figpopup="figCDR0000062890749" rid-ob="figobCDR0000062890749">Table 4</a>, a number of rare or novel <i>RET</i> mutations have been described. Some of these represent mutations that lead to an FMTC or MEN2 phenotype. Others may represent low penetrance <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339337/" class="def">alleles</a> or modifying alleles that confer only a modest risk of developing MTC. Still others may be benign <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000044805/" class="def">polymorphisms</a> of no clinical significance. Research is ongoing into the role of neutral <i>RET</i> sequence variants in modifying the clinical presentation of patients with MEN2A. The presence of certain <i>RET</i> polymorphisms is being analyzed for its impact on the likelihood for development of PHEO, hyperparathyroidism, and metastatic involvement with MTC.[<a class="bk_pop" href="#CDR0000062890_rl_5_189">189</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_191">191</a>] A variety of approaches, including <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000712689/" class="def">segregation analyses</a>, in silico analyses, association studies, and functional assays, can be employed to determine the functional and clinical significance of a given genetic variant. A publicly available <i>RET</i> mutation online database <a href="http://www.arup.utah.edu/database/MEN2/MEN2_welcome.php" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">repository</a> was recently developed and includes a complete list of mutations and their associated pathogenicity, phenotype, and other associated clinical information and literature references.[<a class="bk_pop" href="#CDR0000062890_rl_5_192">192</a>]</p></div><div id="CDR0000062890__1023"><h3>Surveillance</h3><div id="CDR0000062890__121"><h4>Screening of at-risk individuals for PHEO</h4><p id="CDR0000062890__84">The presence of a functioning PHEO should be excluded by
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appropriate biochemical screening before thyroidectomy in any patient with MEN2A or MEN2B. However, childhood PHEOs are rare in MEN2.[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>] The ATA has recommended that annual screening for PHEO be considered after age 8 years in patients with <i>RET</i> mutations in codons 630 and 634 and in patients with <i>RET</i> mutations associated with MEN2B.[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>] In carriers of other MEN2A <i>RET</i> mutations, ATA recommends that annual screening begin by age 20 years. Patients with <i>RET</i> mutations associated only with FMTC should have periodic screening for PHEO beginning at age 20 years.[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>] MRI or other imaging tests should be ordered only if the biochemical results are abnormal.[<a class="bk_pop" href="#CDR0000062890_rl_5_30">30</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_193">193</a>] Studies of individuals with sporadic or hereditary PHEO (including, but not limited to, individuals with MEN2) have suggested that measurement of catecholamine metabolites, specifically plasma-free metanephrines and/or urinary fractionated metanephrines, provides a higher diagnostic sensitivity than urinary catecholamines because of the episodic nature of catecholamine excretion.[<a class="bk_pop" href="#CDR0000062890_rl_5_37">37</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_43">43</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_194">194</a>] Several reviews provide a succinct summary of the biochemical diagnosis, localization, and management of PHEO.[<a class="bk_pop" href="#CDR0000062890_rl_5_43">43</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_195">195</a>] In addition to surgery, there are other clinical situations in which patients with catecholamine excess face special risk. An example is the healthy at-risk female patient who becomes pregnant. Pregnancy, labor, or delivery may precipitate a hypertensive crisis in persons who carry an unrecognized PHEO. Pregnant patients who are found to have catecholamine excess require appropriate pharmacotherapy before delivery. </p><p id="CDR0000062890__130"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000526280/" class="def">Level of evidence: 5</a></p></div><div id="CDR0000062890__122"><h4>Screening of at-risk individuals for hyperparathyroidism</h4><p id="CDR0000062890__90">MEN2-related hyperparathyroidism is generally associated with mild, often asymptomatic hypercalcemia early in the natural history of the disease, which, if left untreated, may become symptomatic.[<a class="bk_pop" href="#CDR0000062890_rl_5_64">64</a>] Childhood hyperparathyroidism is rare in MEN2. Three studies found the median age at diagnosis was about 38 years.[<a class="bk_pop" href="#CDR0000062890_rl_5_64">64</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_196">196</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_197">197</a>] The ATA provides recommendations for annual screening for hyperparathyroidism.[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>] Annual screening should begin at age 8 years in carriers of mutations in codons 630 and 634 and at age 20 years for carriers of other MEN2A <i>RET</i> mutations. Patients with mutations associated only with FMTC should have periodic testing after age 20 years. Testing should include albumin-corrected calcium or ionized serum calcium with or without intact parathyroid hormone (PTH) measurement.</p><p id="CDR0000062890__131"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000526280/" class="def">Level of evidence: 5</a></p></div><div id="CDR0000062890__123"><h4>Screening of at-risk individuals in kindreds without an identifiable <i>RET</i> mutation</h4><p id="CDR0000062890__96">Risk-reducing thyroidectomy is not routinely offered to at-risk
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individuals unless MEN2A is confirmed. The screening
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protocol for MTC in patients with MEN2A is annual calcitonin stimulation test; however, caution
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must be used in interpreting test results because CCH that
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is not a precursor to MTC occurs in about 5% of the population.[<a class="bk_pop" href="#CDR0000062890_rl_5_13">13</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_14">14</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_198">198</a>] In addition, there is significant risk of false-negative test results in patients younger than 15 years.[<a class="bk_pop" href="#CDR0000062890_rl_5_14">14</a>] Screening
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for PHEO and parathyroid disease is the same as described <a href="#CDR0000062890__121">above</a>.
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</p><p id="CDR0000062890__97">For patients at risk of FMTC, annual screening for MTC is the same as for patients with <a href="#CDR0000062890__96">MEN2A</a>.
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</p><p id="CDR0000062890__132"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000526280/" class="def">Level of evidence: 5</a></p></div></div><div id="CDR0000062890__72"><h3>Interventions</h3><div id="CDR0000062890__120"><h4>Risk-reducing thyroidectomy</h4><p id="CDR0000062890__74">Risk-reducing thyroidectomy and parathyroidectomy with reimplantation of one or more parathyroid glands into the neck or nondominant forearm is a
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preventive option for all subtypes of MEN2. To implement this
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management strategy, biochemical screening to identify CCH and/or genetic testing
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to identify persons who carry causative <i>RET</i> mutations is needed to identify
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candidates for risk-reducing surgery (see below). The optimal timing of
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surgery, however, is controversial.[<a class="bk_pop" href="#CDR0000062890_rl_5_3">3</a>] Current recommendations are based on
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clinical experience and vary for different MEN2 subtypes, as noted in <a class="figpopup" href="/books/NBK65830.8/table/CDR0000062890__748/?report=objectonly" target="object" rid-figpopup="figCDR0000062890748" rid-ob="figobCDR0000062890748">Table 5</a>.</p><p id="CDR0000062890__750">In contrast, a prospective analysis of 84 carriers of the <i>RET</i> gene mutation found that basal and pentagastrin-stimulated calcitonin levels could be used to determine the timing of total thyroidectomy.[<a class="bk_pop" href="#CDR0000062890_rl_5_104">104</a>] When the basal or stimulated calcitonin was greater than 10 pg/mL, total thyroidectomy and central neck dissection were strongly recommended. In this series, a basal calcitonin level lower than 60 pg/mL was always associated with an intrathyroidal MTC; none of the 56 patients who went to surgery had metastatic involvement. These findings suggest that surgery can be safely delayed in gene carriers of a <i>RET</i> mutation until basal or stimulated calcitonin is above 10 pg/mL, while still maintaining the ability to achieve a disease-free state (i.e., an undetectable basal and stimulated calcitonin 6–12 months after surgery). The benefits of this approach are particularly noteworthy in the younger population of gene carriers, as a delay in surgery until the patient is older may reduce the risk of surgical complications. While this approach is promising, pentagastrin is currently not available in the United States for stimulation testing. Although calcium may be used as a substitute for pentagastrin, it has not been widely validated.</p><p id="CDR0000062890__971">One series of 503 at-risk individuals with ATA level A or B mutations (i.e. codons 533, 609, 611, 618, 620, 791, and 804) reported cumulative penetrance rates, median time to MTC, and predictive value of preoperative calcitonin.[<a class="bk_pop" href="#CDR0000062890_rl_5_105">105</a>] The risk of developing MTC by age 50 years ranged from 18% to 95%, depending on the codon, with codon 620 having the highest penetrance. Most patients with MTC had node-negative disease, confirming the more indolent disease course that has been previously reported with these mutations. Although an elevated preoperative calcitonin level strongly predicted presence of MTC, relatively high false-negative rates (low normal calcitonin levels with MTC) were noted for many of the codons. This information is useful when counseling mutation carriers regarding surgical decisions.</p><p id="CDR0000062890__952">Another study has confirmed that calcitonin levels could be a useful approach to determine the timing of thyroidectomy.[<a class="bk_pop" href="#CDR0000062890_rl_5_199">199</a>] This study utilized preoperative basal calcitonin levels and ultrasound findings to determine timing of prophylactic thyroidectomy in 24 <i>RET</i> mutation carriers, many of whom carried mutations in the highest risk level and had delayed surgery until after age 20 years. All 17 individuals who underwent surgery had elevated preoperative calcitonin levels on the fully-automated chemiluminescence immunoassay. Fifteen of 17 individuals had MTC, but only two had lymph node involvement and/or local tissue invasion, and 16 of 17 were disease free at 22 months. Two patients had CCH. Of note, only 6 of 15 individuals with MTC had elevated calcitonin levels using the radioimmunoassay. The study is limited by a small population of patients with low disease burden but suggests that some calcitonin assays may be more sensitive than others.</p><div id="CDR0000062890__748" class="table"><h3><span class="title">Table 5. American Thyroid Association Medullary Thyroid Cancer Risk Stratification and Management Guidelines<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65830.8/table/CDR0000062890__748/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062890__748_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Risk Level</th><th colspan="1" rowspan="1" style="vertical-align:top;">Mutated Codon(s)</th><th colspan="1" rowspan="1" style="vertical-align:top;">Age of <i>RET</i> Testing</th><th colspan="1" rowspan="1" style="vertical-align:top;">Timing of Prophylactic Thyroidectomy</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">D</td><td colspan="1" rowspan="1" style="vertical-align:top;">883, 918, and <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000766214/" class="def">compound heterozygotes</a>
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V804M+E805K, V804M+Y806C, and V804M+S904C
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">ASAP and within the first y of life</td><td colspan="1" rowspan="1" style="vertical-align:top;">ASAP and within the first y of life.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">C</td><td colspan="1" rowspan="1" style="vertical-align:top;">634</td><td colspan="1" rowspan="1" style="vertical-align:top;"><3–5 y</td><td colspan="1" rowspan="1" style="vertical-align:top;">Before age 5 y.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">B</td><td colspan="1" rowspan="1" style="vertical-align:top;">609b, 611, 618, 620, 630<sup>b</sup>, and compound heterozygote V804M+V778I </td><td colspan="1" rowspan="1" style="vertical-align:top;"><3–5 y</td><td colspan="1" rowspan="1" style="vertical-align:top;">Consider surgery before age 5 y. May delay surgery after age 5 y if criteria are met.<sup>c</sup></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">A</td><td colspan="1" rowspan="1" style="vertical-align:top;">768, 790, 791, 804, 891</td><td colspan="1" rowspan="1" style="vertical-align:top;"><3–5 y</td><td colspan="1" rowspan="1" style="vertical-align:top;">May delay surgery after age 5 y if criteria are met.<sup>c</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Adapted from Kloos et al.[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>]</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>b</sup>These mutations had not been reported at the time of the 7<sup>th</sup> International Workshop.[<a class="bk_pop" href="#CDR0000062890_rl_5_24">24</a>]</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>c</sup>Criteria include a normal annual basal and/or stimulated serum count, normal annual neck ultrasound, less aggressive medullary thyroid cancer family history, and family preference.</p></div></dd></dl></div></div></div><p id="CDR0000062890__75">In a study of biochemical screening in a large family with MEN2A performed before
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mutation analysis became available, 22 family members without evidence of clinical
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disease had elevated calcitonin and underwent thyroidectomy. During a mean
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follow-up period of 11 years, all remained free of clinical disease, and 3 out
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of 22 had transient elevation of postoperative calcitonin levels.[<a class="bk_pop" href="#CDR0000062890_rl_5_10">10</a>]
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The use of biochemical screening is limited, however, by the lack of data on age-specific calcitonin levels in children younger than 3 years; caution should be used when interpreting these values in this age group.[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>]</p><p id="CDR0000062890__715">A study of 93 patients with MEN2 from a Dutch tumor registry documented the importance of early prophylactic thyroidectomy.[<a class="bk_pop" href="#CDR0000062890_rl_5_200">200</a>] This group of patients represented all known Dutch patients with hereditary MTC; most cases (67%) were codon 634 mutations; only 6% were MEN2B cases. Patients in this series were screened with either biochemical testing (pre-<i>RET</i> era) or <i>RET</i> mutation analysis. In both groups, patients underwent surgery at a later age than recommended by current guidelines (see <a class="figpopup" href="/books/NBK65830.8/table/CDR0000062890__748/?report=objectonly" target="object" rid-figpopup="figCDR0000062890748" rid-ob="figobCDR0000062890748">Table 5</a>), but the percentage from the pre-<i>RET</i> era was significantly higher (96% vs. 69%, <i>P</i> = .004). Older age at prophylactic thyroidectomy was significantly associated with a higher risk of postoperative persistent/recurrent disease. Although there is concern that young age at total thyroidectomy is associated with higher risk of surgical complications, this study found no such evidence.</p><p id="CDR0000062890__76">Two additional case series provide further data supporting early risk-reducing thyroidectomy
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following testing for <i>RET</i> mutations.[<a class="bk_pop" href="#CDR0000062890_rl_5_201">201</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_202">202</a>] Cases reported in both series
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could reflect selection biases: one study reported 71 patients from a national
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registry who had been treated with thyroidectomy but did not specify how these
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patients were selected, whereas the other study reported 21 patients seen at a
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referral center.[<a class="bk_pop" href="#CDR0000062890_rl_5_201">201</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_202">202</a>] In both studies, a series of children from families with MEN2
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or FMTC who were found to have <i>RET</i> mutations were screened for CCH and treated with risk-reducing thyroidectomy. These studies
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documented MTC in 93% of patients with MEN2 and 77% of patients with FMTC. The larger study found
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a correlation between age and larger tumor size, nodal metastases,
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postoperative recurrence of disease, and mean basal calcitonin levels.
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Surgical complications were rare.[<a class="bk_pop" href="#CDR0000062890_rl_5_201">201</a>] No studies have compared the outcome of
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thyroidectomy based on mutation testing with thyroidectomy based on
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biochemical screening.</p><p id="CDR0000062890__163">In one large series, 260 MEN2A patients aged 0 to 20 years were identified as having undergone either an early total thyroidectomy (ages 1–5 years, n = 42) or late thyroidectomy (ages 6–20 years, n = 218).[<a class="bk_pop" href="#CDR0000062890_rl_5_203">203</a>] There was a significantly lower rate of invasive or metastatic MTC among those who underwent surgery at an early age (57%) than among those who underwent surgery at a late age (76%). Follow-up information was available on only 28% of the cohort, as a result of the limitations of study design, with a median follow-up of only 2 years for this nonsystematically selected subgroup. Persistent or recurrent disease was reported among 0 of 9 early-surgery patients, versus 21 of 65 late-surgery patients. Both findings are consistent with the hypothesis that patients undergoing surgery before age 6 years have a more favorable outcome, but the nature of the data prevents this from being a definitive conclusion. Finally, evidence suggested that individuals carrying codon 634 mutations were much more likely to present with invasive or metastatic MTC and to develop persistent or recurrent disease than were those harboring mutations in codons 804, 618, or 620.</p><p id="CDR0000062890__245">A study of young, clinically asymptomatic individuals with MEN2A sought to determine if early thyroidectomy could prevent or cure MTC.[<a class="bk_pop" href="#CDR0000062890_rl_5_204">204</a>] This study included 50 consecutively identified <i>RET</i> mutation carriers who underwent thyroidectomy at 19 years or younger. Preoperative screening for CCH included basal and stimulated calcitonin levels and postoperative follow-up consisted of annual physical exam and intermittent basal and stimulated calcitonin measurements. All 50 individuals had at least 5 years of follow-up. Although MTC was identified in 33 of 50 patients at the time of surgery, in 44 of 50 (88%) there was no evidence of persistent or recurrent disease at a mean of 7 years follow-up. Six patients had basal or stimulated calcitonin abnormalities thought to represent residual MTC. None of the 22 patients who underwent surgery before age 8 years had any evidence of MTC. The data suggested that there was a lower incidence of persistent or recurrent disease in patients who had thyroidectomy earlier in life (defined as younger than 8 years) and who had no evidence of lymph node metastases.</p><p id="CDR0000062890__77">Normal preoperative basal calcitonin does not exclude the possibility of the patient having MTC. In one study of 80 <i>RET</i> mutation carriers, 14 carriers had normal calcitonin tests and eight of these patients had small foci of MTC discovered at thyroidectomy.[<a class="bk_pop" href="#CDR0000062890_rl_5_14">14</a>] Another study confirmed these findings,[<a class="bk_pop" href="#CDR0000062890_rl_5_77">77</a>] as 14 children had total thyroidectomy based on positive genetic testing for MEN2; MTC was present in 11 and only four had elevated stimulated calcitonin levels before surgery. Although basal calcitonin levels may not be able to identify all patients with MTC preoperatively, this test has utility as a predictor of postoperative remission, lymph node metastases, and distant metastases.[<a class="bk_pop" href="#CDR0000062890_rl_5_205">205</a>] In one study of 224 patients from a single institution, preoperative basal calcitonin levels greater than 500 pg/mL predicted failure to achieve biochemical remission.[<a class="bk_pop" href="#CDR0000062890_rl_5_205">205</a>] The authors of this study found that nodal metastases started appearing at basal calcitonin levels of 40 pg/mL (normal, <10 pg/mL). In node-positive patients, distant metastases emerged at basal calcitonin levels of 150 pg/mL to 400 pg/mL. Using current sensitive calcitonin assays, a study of 308 <i>RET </i> carriers found that a normal basal preoperative calcitonin excluded the presence of lymph node metastases (100% negative predictive value).[<a class="bk_pop" href="#CDR0000062890_rl_5_206">206</a>] Therefore, the preoperative basal calcitonin level is a useful prognostic indicator and may help guide the surgical approach.</p><p id="CDR0000062890__717">While thyroidectomy before biochemical evidence of disease (normal preoperative calcitonin) may reduce the risk of recurrent disease, continued monitoring for residual or recurrent MTC is still recommended.[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_207">207</a>] One study found that 10% of patients with MEN2A undergoing thyroidectomy developed recurrent disease, based on an initially undetectable basal and stimulated calcitonin levels (<2 pg/mL) that became positive 5 to 10 years after surgery.[<a class="bk_pop" href="#CDR0000062890_rl_5_204">204</a>] Only 2% of patients had residual disease after prophylactic surgery as assessed by a persistently elevated basal or stimulated calcitonin.[<a class="bk_pop" href="#CDR0000062890_rl_5_204">204</a>]</p><p id="CDR0000062890__78">Questions remain concerning the natural history of MEN2. As more information
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is acquired, recommendations regarding the optimal age for thyroidectomy and
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the potential role for genetics and biochemical screening may change. For
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example, a case report documents MTC before age 5 years in two siblings with MEN2A.[<a class="bk_pop" href="#CDR0000062890_rl_5_208">208</a>]
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Conversely, another case report documents onset of cancer in midlife or later
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in some families with FMTC and in elderly relatives who carry the FMTC
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genotype but have not developed cancer.[<a class="bk_pop" href="#CDR0000062890_rl_5_209">209</a>] The possibility that certain mutations (e.g., Cys634) might convey a significantly worse prognosis, if confirmed, may permit tailoring intervention based on knowing the specific <i>RET</i> mutation.[<a class="bk_pop" href="#CDR0000062890_rl_5_203">203</a>] These clinical observations
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suggest that the natural history of the MEN2 syndromes is variable and could be
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subject to modifying effects related to specific <i>RET</i> mutations, other genes,
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behavioral factors, or environmental exposures.
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</p><p id="CDR0000062890__129"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531821/" class="def">Level of evidence: 5</a></p></div><div id="CDR0000062890__124"><h4>Treatment for those with MTC</h4><p id="CDR0000062890__99">Standard treatment for adults with MTC is surgical removal of the entire thyroid gland, including the posterior capsule, and
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central lymph node dissection. Children with MEN2B having prophylactic thyroidectomy within the first year of life may not require central neck dissection unless there is radiological evidence of nodal disease.[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>] Likewise, children with MEN2A or FMTC having prophylactic thyroidectomy before age 3 to 5 years should not have a central neck dissection in the absence of radiological evidence of metastatic lymph node involvement. The ATA also recommends that MEN2A and FMTC patients older than 5 years or asymptomatic MEN2B patients older than 1 year have a preoperative basal calcitonin test and neck ultrasound. A basal calcitonin level over 40 pg/mL or thyroid nodules greater than or equal to 5 mm requires further evaluation, as the patient may have more extensive disease requiring nodal dissection. If an MEN2B patient older than 1 year has nodules smaller than 5 mm or basal calcitonin lower than 40 pg/mL, then total thyroidectomy may be sufficient therapy, but the ATA task force favors prophylactic central neck dissection without lateral compartment dissection in the absence of radiographic evidence of metastatic involvement (<a href="http://www.uspreventiveservicestaskforce.org/uspstf/grades.htm" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">level C recommendation</a>).[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>] See Table 6 for complete details.</p><div id="CDR0000062890__723" class="table"><h3><span class="title">Table 6. American Thyroid Association Management Guidelines for MEN2A/FMTC and MEN2B<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65830.8/table/CDR0000062890__723/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062890__723_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Syndrome </th><th colspan="1" rowspan="1" style="vertical-align:top;">Age (y)</th><th colspan="1" rowspan="1" style="vertical-align:top;">Nodal Disease</th><th colspan="1" rowspan="1" style="vertical-align:top;">Basal Calcitonin (pg/mL)<sup>b</sup></th><th colspan="1" rowspan="1" style="vertical-align:top;">Nodule ≥ 5mm </th><th colspan="1" rowspan="1" style="vertical-align:top;">Lymph Node Dissection </th><th colspan="1" rowspan="1" style="vertical-align:top;">Strength of Recommendation<sup>c</sup></th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">MEN2A/FMTC</td><td colspan="1" rowspan="1" style="vertical-align:top;"><3–5 </td><td colspan="1" rowspan="1" style="vertical-align:top;">No</td><td colspan="1" rowspan="1" style="vertical-align:top;"><40 </td><td colspan="1" rowspan="1" style="vertical-align:top;">No </td><td colspan="1" rowspan="1" style="vertical-align:top;">No </td><td colspan="1" rowspan="1" style="vertical-align:top;">E</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">MEN2A/FMTC</td><td colspan="1" rowspan="1" style="vertical-align:top;"><3–5 </td><td colspan="1" rowspan="1" style="vertical-align:top;">Yes</td><td colspan="1" rowspan="1" style="vertical-align:top;">>40 </td><td colspan="1" rowspan="1" style="vertical-align:top;">Yes</td><td colspan="1" rowspan="1" style="vertical-align:top;">Yes</td><td colspan="1" rowspan="1" style="vertical-align:top;">B</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">MEN2A/FMTC</td><td colspan="1" rowspan="1" style="vertical-align:top;">>5 </td><td colspan="1" rowspan="1" style="vertical-align:top;">No</td><td colspan="1" rowspan="1" style="vertical-align:top;"><40 </td><td colspan="1" rowspan="1" style="vertical-align:top;">No </td><td colspan="1" rowspan="1" style="vertical-align:top;">No</td><td colspan="1" rowspan="1" style="vertical-align:top;">E</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">MEN2A/FMTC</td><td colspan="1" rowspan="1" style="vertical-align:top;">>5 </td><td colspan="1" rowspan="1" style="vertical-align:top;">Yes</td><td colspan="1" rowspan="1" style="vertical-align:top;">>40 </td><td colspan="1" rowspan="1" style="vertical-align:top;">Yes</td><td colspan="1" rowspan="1" style="vertical-align:top;">Yes</td><td colspan="1" rowspan="1" style="vertical-align:top;">B</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">MEN2B</td><td colspan="1" rowspan="1" style="vertical-align:top;"><1 </td><td colspan="1" rowspan="1" style="vertical-align:top;">No</td><td colspan="1" rowspan="1" style="vertical-align:top;"><40 </td><td colspan="1" rowspan="1" style="vertical-align:top;">No </td><td colspan="1" rowspan="1" style="vertical-align:top;">No</td><td colspan="1" rowspan="1" style="vertical-align:top;">E</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">MEN2B</td><td colspan="1" rowspan="1" style="vertical-align:top;"><1 </td><td colspan="1" rowspan="1" style="vertical-align:top;">Yes</td><td colspan="1" rowspan="1" style="vertical-align:top;">>40 </td><td colspan="1" rowspan="1" style="vertical-align:top;">Yes</td><td colspan="1" rowspan="1" style="vertical-align:top;">Yes</td><td colspan="1" rowspan="1" style="vertical-align:top;">B</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">MEN2B</td><td colspan="1" rowspan="1" style="vertical-align:top;"><1 </td><td colspan="1" rowspan="1" style="vertical-align:top;">No</td><td colspan="1" rowspan="1" style="vertical-align:top;"><40 </td><td colspan="1" rowspan="1" style="vertical-align:top;">No </td><td colspan="1" rowspan="1" style="vertical-align:top;">Yes</td><td colspan="1" rowspan="1" style="vertical-align:top;">C</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">FMTC = familial medullary thyroid carcinoma; MEN2 = multiple endocrine neoplasia type 2.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Adapted from Kloos et al.[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>]</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>b</sup>Basal calcitonin values are applicable in patients older than 6 months.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>c</sup>Based on grading definitions established by the <a href="http://www.uspreventiveservicestaskforce.org/uspstf/grades.htm" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">U.S. Preventive Services Task Force</a>.</p></div></dd></dl></div></div></div><p id="CDR0000062890__719">The ATA recommends lymph node dissection for patients meeting any one of the following criteria:[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>]</p><ul id="CDR0000062890__724"><li class="half_rhythm"><div>Radiographic evidence of nodal disease.</div></li><li class="half_rhythm"><div>Basal calcitonin level greater than 40 pg/mL.</div></li><li class="half_rhythm"><div>A thyroid nodule 5 mm or larger.</div></li></ul><p id="CDR0000062890__720">Patients who have had total thyroidectomy will require lifelong thyroid hormone replacement therapy. The dosing of medication is age-dependent and treatment should be initiated based on ideal body weight. For healthy adults 60 years and younger with no cardiac disease, a reasonable starting dose is 1.6 to 1.8 µg/kg given once daily.[<a class="bk_pop" href="#CDR0000062890_rl_5_210">210</a>] Older patients may require 20% to 30% less thyroid hormone.[<a class="bk_pop" href="#CDR0000062890_rl_5_211">211</a>] Children clear T4 more rapidly than adults and consequently require relatively higher replacement by body weight. Depending on the age of the child, replacement should be between 2 to 6 µg/kg.[<a class="bk_pop" href="#CDR0000062890_rl_5_212">212</a>] It is important to note, however, that patients should be given replacement, rather than suppressive therapy. Since C-cell tumors are not thyroid-stimulating hormone (TSH)-dependent for growth, the T4 therapy for MTC patients therefore should be adjusted to maintain a TSH within the normal reference range. Thyroglobulin measurement may also be useful for adjusting and maintaining TSH levels within a normal reference range to prevent additional regrowth of remnant thyroid tissue.[<a class="bk_pop" href="#CDR0000062890_rl_5_213">213</a>] Further investigation is needed to better interpret how this information should guide management.</p><p id="CDR0000062890__718">There is no difference in survival between familial and sporadic forms of MTC when adjusted for clinicopathologic factors. Chemotherapy and radiation are not effective against
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this type of cancer,[<a class="bk_pop" href="#CDR0000062890_rl_5_3">3</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_214">214</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_215">215</a>] although clinical trials (phases I–III) of various targeted molecular therapies are ongoing at selected centers. Some of these compounds have shown partial responses in a small percentage of patients, but most studies have demonstrated disease stability as the most favorable response.[<a class="bk_pop" href="#CDR0000062890_rl_5_216">216</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_219">219</a>] The use of vandetanib and cabozantinib is approved by the U.S. Food and Drug Administration for adult patients with progressive metastatic MTC who are ineligible for surgery. A phase III study found that progression-free survival was longer in adults who received vandetanib than in those who received placebo.[<a class="bk_pop" href="#CDR0000062890_rl_5_220">220</a>] A phase I/II study of children with MEN2B found an objective partial response rate of 47% with vandetanib.[<a class="bk_pop" href="#CDR0000062890_rl_5_221">221</a>] A double-blind, phase III trial that compared cabozantinib with placebo in 330 patients with progressive MTC showed an improvement in median progression-free survival across all subgroups.[<a class="bk_pop" href="#CDR0000062890_rl_5_222">222</a>] To date, neither cabozantinib nor vandetanib has demonstrated improved overall survival.[<a class="bk_pop" href="#CDR0000062890_rl_5_220">220</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_222">222</a>] Future studies will likely focus on the development of new targeted therapies and the use of combination therapy in MTC. (Refer to <a href="http://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI's List of Clinical Trials</a> for more information about these trials. Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000062913/">Thyroid Cancer Treatment</a> for more information about the treatment of thyroid cancer.)
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</p><p id="CDR0000062890__133"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531846/" class="def">Level of evidence: 5</a></p></div><div id="CDR0000062890__135"><h4>Treatment for those with MEN2-related PHEO</h4><p id="CDR0000062890__144">PHEO may be either unilateral or bilateral in patients with MEN2. Laparoscopic adrenalectomy is the recommended approach by some authorities for the treatment of unilateral PHEO.[<a class="bk_pop" href="#CDR0000062890_rl_5_24">24</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>] The risks, benefits, and potential of life-threatening adrenal insufficiency should be considered at the time of the initial operative planning. If disease appears unilateral, the contralateral gland may develop metachronous disease in 17% to 72% of patients.[<a class="bk_pop" href="#CDR0000062890_rl_5_223">223</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_224">224</a>]
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In one series, 23 patients with a unilateral PHEO and a macroscopically normal contralateral adrenal gland were treated initially with unilateral adrenalectomy.[<a class="bk_pop" href="#CDR0000062890_rl_5_225">225</a>] A PHEO developed within the retained gland in 12 (52%) of these patients, occurring a mean of 11.9 years after initial surgery. During follow-up after unilateral adrenalectomy, no patient experienced a hypertensive crisis or other problems attributable to an undiagnosed PHEO. In contrast, 10 of 43 patients (23%) treated with bilateral adrenalectomy experienced at least one episode of acute adrenal insufficiency; one of these patients died. Unilateral adrenalectomy appears to represent a reasonable management strategy for unilateral PHEO in patients with MEN2.[<a class="bk_pop" href="#CDR0000062890_rl_5_226">226</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_228">228</a>] Many suggest strongly considering a cortical-sparing technique, even at the initial operation for seemingly unilateral disease.[<a class="bk_pop" href="#CDR0000062890_rl_5_229">229</a>] (Refer to the <a href="#CDR0000062890__855">Interventions</a> section in the <a href="#CDR0000062890__850">Familial PHEO and Paraganglioma Syndrome</a> section of this summary for more information.) Because of the risk of contralateral gland disease, periodic surveillance (serum or urinary catecholamine measurements) for the of development of disease in the contralateral adrenal gland is recommended. </p><p id="CDR0000062890__1041">Regarding operative approach, several studies examined the value of a posterior retroperitoneoscopic adrenalectomy and found it to be safe and effective, with very low mortality and a low rate of minor complications, and conversion to open or laparoscopic lateral surgery required in only 1.7% of cases.[<a class="bk_pop" href="#CDR0000062890_rl_5_230">230</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_231">231</a>] This approach appears to be feasible and preferred, but extensive experience is needed.[<a class="bk_pop" href="#CDR0000062890_rl_5_223">223</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_232">232</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_235">235</a>]</p><p id="CDR0000062890__137"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531845/" class="def">Level of evidence: 4</a></p></div><div id="CDR0000062890__139"><h4>Treatment for those with hyperparathyroidism</h4><p id="CDR0000062890__140">Most patients with MEN2-related parathyroid disease are either asymptomatic or diagnosed incidentally at the time of thyroidectomy. Typically, the hypercalcemia (when present) is mild, although it may be associated with increased urinary excretion of calcium and nephrolithiasis. As a consequence, the indications for surgical intervention are generally similar to those recommended for patients with sporadic, primary hyperparathyroidism.[<a class="bk_pop" href="#CDR0000062890_rl_5_24">24</a>] In general, fewer than four of the parathyroid glands are involved at the time of detected abnormalities in calcium metabolism. </p><p id="CDR0000062890__141">Cure of hyperparathyroidism was achieved surgically in 89% of one large series of patients;[<a class="bk_pop" href="#CDR0000062890_rl_5_64">64</a>] however, 22% of resected patients in this study developed postoperative hypoparathyroidism. Five patients (9%) had recurrent hyperparathyroidism. This series employed various surgical techniques, including total parathyroidectomy with autotransplantation to the nondominant forearm, subtotal parathyroidectomy, and resection only of glands that were macroscopically enlarged. Postoperative hypoparathyroidism developed in 4 of 11 patients (36%), 6 of 12 patients (50%), and 3 of 29 patients (10%), respectively. These data indicate that excision of only those parathyroid glands that are enlarged appears to be sufficient in most cases. </p><p id="CDR0000062890__142">Some investigators have suggested using the MEN2 subtype to decide where to place the parathyroid glands that are identified at the time of thyroid surgery. For patients with MEN2B in whom the risk of parathyroid disease is quite low, the parathyroid glands may be left in the neck. For patients with MEN2A and FMTC, it is suggested that the glands be implanted in the nondominant forearm to minimize the need for further surgery on the neck after risk-reducing thyroidectomy and a central lymph node dissection.[<a class="bk_pop" href="#CDR0000062890_rl_5_236">236</a>]</p><p id="CDR0000062890__721">All patients who have undergone parathyroid surgery with autotransplantation of parathyroid tissue should be monitored for hypoparathyroidism.[<a class="bk_pop" href="#CDR0000062890_rl_5_26">26</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_237">237</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_238">238</a>]</p><p id="CDR0000062890__722">Medical therapy of hyperparathyroidism has gained popularity with the advent of calcimimetics, agents that sensitize the calcium-sensing receptors on the parathyroid glands to circulating calcium levels and thereby reduce circulating PTH levels. In a randomized, double-blind, placebo-controlled trial, cinacalcet hydrochloride was shown to induce sustained reduction in circulating calcium and PTH levels in patients with primary hyperparathyroidism.[<a class="bk_pop" href="#CDR0000062890_rl_5_239">239</a>] In patients who are high-risk surgical candidates, those with recurrent hyperparathyroidism, or those in whom life expectancy is limited, medical therapy may be a viable alternative to a surgical approach.</p><p id="CDR0000062890__725"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531846/" class="def">Level of evidence: 5</a></p></div></div><div id="CDR0000062890__100"><h3>Genetic Counseling</h3><div id="CDR0000062890__125"><h4>Mode of inheritance</h4><p id="CDR0000062890__102">All of the MEN2 subtypes are inherited in an <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339338/" class="def">autosomal dominant</a> manner. For the
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child of someone with MEN2, the risk of inheriting the MEN2 mutation is 50%.
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Some individuals with MEN2, however, carry a <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460142/" class="def">de novo gene mutation</a>; that is, they
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carry a new mutation that was not present in previous generations of their
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family and thus do not have an affected parent. The proportion of individuals
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with MEN2 who have an affected parent varies by subtype.
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</p><p id="CDR0000062890__103">MEN2A: About 95% of affected individuals have an affected parent. It is
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appropriate to evaluate the parents of an individual with MEN2A for
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manifestations of the disorder. In the 5% of cases that are not familial,
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either de novo gene mutations or incomplete penetrance of the mutant allele is
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possible.[<a class="bk_pop" href="#CDR0000062890_rl_5_240">240</a>]
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</p><p id="CDR0000062890__104">FMTC: Multiple family members are affected; therefore, all affected individuals
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inherited the mutant gene from a parent.
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</p><p id="CDR0000062890__105">MEN2B: About 50% of affected individuals have de novo <i>RET</i> gene mutations, and 50%
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have inherited the mutation from a parent.[<a class="bk_pop" href="#CDR0000062890_rl_5_241">241</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_242">242</a>] The majority of de novo
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mutations are paternal in origin, but cases of maternal origin have been
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reported.[<a class="bk_pop" href="#CDR0000062890_rl_5_243">243</a>]
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</p><p id="CDR0000062890__106">Siblings of a proband: The risk to siblings depends on the genetic status of the
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parent, which can be clarified by pedigree analysis and/or DNA-based testing.
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In situations of apparent de novo gene mutations, germline <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460197/" class="def">mosaicism</a> in an
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apparently <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460224/" class="def">unaffected</a> parent must be considered, even though such an
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occurrence has not yet been reported.
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</p></div><div id="CDR0000062890__1003"><h4>Attitudes toward preimplantation genetic diagnosis</h4><p id="CDR0000062890__1004">One study explored the attitudes of individuals with MEN1 and MEN2 toward preimplantation genetic diagnosis.[<a class="bk_pop" href="#CDR0000062890_rl_5_244">244</a>] Ninety-one clinic-based patients from a single U.S. institution who had MEN1 and an <i>MEN1</i> mutation or MEN2 and a <i>RET</i> mutation were surveyed. The study found that 30% (10 of 33) of those with MEN1 and 37% (21 of 57) of those with MEN2 were aware of PGD; 82% (27 of 33) of those with MEN1 and 61% (34 of 56) of those with MEN2 thought PGD should be offered; and 61% (19 of 31) of those with MEN1 and 43% (23 of 54) of those with MEN2 would consider PGD. </p></div><div id="CDR0000062890__126"><h4>Psychosocial issues</h4><p id="CDR0000062890__108">The psychosocial impact of genetic testing for mutations in <i>RET</i> has not been extensively studied.
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Published studies have had limitations such as small sample size and heterogeneous populations; thus, the clinical relevance of these findings should be interpreted with caution. Identification as the carrier of a <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000556486/" class="def">deleterious mutation</a> may affect self-esteem, family relationships, and quality of life.[<a class="bk_pop" href="#CDR0000062890_rl_5_245">245</a>] In addition, misconceptions about genetic disease may result in familial blame and guilt.[<a class="bk_pop" href="#CDR0000062890_rl_5_246">246</a>,<a class="bk_pop" href="#CDR0000062890_rl_5_247">247</a>] Several review articles outline both the medical and psychological issues,
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especially those related to the testing of children.[<a class="bk_pop" href="#CDR0000062890_rl_5_248">248</a>-<a class="bk_pop" href="#CDR0000062890_rl_5_251">251</a>] The medical value
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of early screening and risk-reducing treatment are contrasted with the loss of
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decision-making autonomy for the individual. Lack of agreement between parents
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about the value and timing of genetic testing and surgery may spur the
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development of emotional problems within the family.
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</p><p id="CDR0000062890__215">One study examined levels of psychological distress in the interval between submitting a blood sample and receiving genetic test results. Those individuals who experienced the highest level of distress were younger than 25 years, single, and had a history of responding to distressful situations with anxiety.[<a class="bk_pop" href="#CDR0000062890_rl_5_252">252</a>] Mutation-positive parents whose children received negative test results did not seem to be reassured, questioned the reliability of the DNA test, and were eager to continue screening of their noncarrier children.[<a class="bk_pop" href="#CDR0000062890_rl_5_253">253</a>]</p><p id="CDR0000062890__173">A small qualitative study (N = 21) evaluated how patients with MEN2A and family members conceptualized participation in lifelong high-risk surveillance.[<a class="bk_pop" href="#CDR0000062890_rl_5_254">254</a>] Ongoing surveillance was viewed as a reminder of a health threat. Acceptance and incorporation of lifelong surveillance into routine health care was essential for coping with the implications of this condition. Concern about genetic predisposition to cancer was peripheral to concerns about surveillance. Supportive interventions, such as Internet discussion forums, can serve as an ongoing means of addressing informational and support needs of patients with MTC undergoing lifelong surveillance.[<a class="bk_pop" href="#CDR0000062890_rl_5_255">255</a>]</p></div></div><div id="CDR0000062890_rl_5"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062890_rl_5_1">Kaserer K, Scheuba C, Neuhold N, et al.: Sporadic versus familial medullary thyroid microcarcinoma: a histopathologic study of 50 consecutive patients. Am J Surg Pathol 25 (10): 1245-51, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11688458" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11688458</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_2">Robbins J, Merino MJ, Boice JD Jr, et al.: Thyroid cancer: a lethal endocrine neoplasm. Ann Intern Med 115 (2): 133-47, 1991. [<a href="https://pubmed.ncbi.nlm.nih.gov/2058861" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2058861</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_3">Moley JF, Debenedetti MK, Dilley WG, et al.: Surgical management of patients with persistent or recurrent medullary thyroid cancer. J Intern Med 243 (6): 521-6, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9681853" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9681853</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_4">Machens A, Lorenz K, Dralle H: Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities. J Intern Med 266 (1): 114-25, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19522830" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19522830</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_5">DeLellis RA, Lloyd RV, Heitz PU, et al., eds.: Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press, 2004. World Health Organization classification of tumours, vol. 8.</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_6">Eng C: Seminars in medicine of the Beth Israel Hospital, Boston. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease. N Engl J Med 335 (13): 943-51, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8782503" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8782503</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_7">Conte-Devolx B, Schuffenecker I, Niccoli P, et al.: Multiple endocrine neoplasia type 2: management of patients and subjects at risk. French Study Group on Calcitonin-Secreting Tumors (GETC). Horm Res 47 (4-6): 221-6, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9167955" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9167955</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_8">Ponder BA: Multiple endocrine neoplasia type 2. In: Vogelstein B, Kinzler KW, eds.: The Genetic Basis of Human Cancer. 2nd ed. New York, NY: McGraw-Hill, 2002, pp 501-513.</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_9">Schuffenecker I, Virally-Monod M, Brohet R, et al.: Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D'etude des Tumeurs à Calcitonine. J Clin Endocrinol Metab 83 (2): 487-91, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9467562" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9467562</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_10">Gagel RF, Tashjian AH Jr, Cummings T, et al.: The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med 318 (8): 478-84, 1988. [<a href="https://pubmed.ncbi.nlm.nih.gov/2893259" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2893259</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_11">Guyétant S, Rousselet MC, Durigon M, et al.: Sex-related C cell hyperplasia in the normal human thyroid: a quantitative autopsy study. J Clin Endocrinol Metab 82 (1): 42-7, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/8989230" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8989230</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_12">LiVolsi VA: C cell hyperplasia/neoplasia. J Clin Endocrinol Metab 82 (1): 39-41, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/8989229" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8989229</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_13">Landsvater RM, Rombouts AG, te Meerman GJ, et al.: The clinical implications of a positive calcitonin test for C-cell hyperplasia in genetically unaffected members of an MEN2A kindred. Am J Hum Genet 52 (2): 335-42, 1993. [<a href="/pmc/articles/PMC1682203/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1682203</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8094268" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8094268</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_14">Lips CJ, Landsvater RM, Höppener JW, et al.: Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 331 (13): 828-35, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7915822" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7915822</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_15">Elisei R, Bottici V, Luchetti F, et al.: Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders. J Clin Endocrinol Metab 89 (1): 163-8, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/14715844" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14715844</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_16">Kudo T, Miyauchi A, Ito Y, et al.: Serum calcitonin levels with calcium loading tests before and after total thyroidectomy in patients with thyroid diseases other than medullary thyroid carcinoma. Endocr J 58 (3): 217-21, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21358115" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21358115</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_17">Incidence: Thyroid Cancer. Bethesda, Md: National Cancer Institute, SEER, 2004. <a href="http://seer.cancer.gov/" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed October 26, 2015.</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_18">Gharib H, McConahey WM, Tiegs RD, et al.: Medullary thyroid carcinoma: clinicopathologic features and long-term follow-up of 65 patients treated during 1946 through 1970. Mayo Clin Proc 67 (10): 934-40, 1992. [<a href="https://pubmed.ncbi.nlm.nih.gov/1434853" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1434853</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_19">Decker RA, Peacock ML, Borst MJ, et al.: Progress in genetic screening of multiple endocrine neoplasia type 2A: is calcitonin testing obsolete? Surgery 118 (2): 257-63; discussion 263-4, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7638742" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7638742</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_20">Kitamura Y, Goodfellow PJ, Shimizu K, et al.: Novel germline RET proto-oncogene mutations associated with medullary thyroid carcinoma (MTC): mutation analysis in Japanese patients with MTC. Oncogene 14 (25): 3103-6, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9223675" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9223675</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_21">Eng C, Mulligan LM, Smith DP, et al.: Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf) 43 (1): 123-7, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7641404" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7641404</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_22">Wohllk N, Cote GJ, Bugalho MM, et al.: Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 81 (10): 3740-5, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8855832" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8855832</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_23">Lips CJ: Clinical management of the multiple endocrine neoplasia syndromes: results of a computerized opinion poll at the Sixth International Workshop on Multiple Endocrine Neoplasia and von Hippel-Lindau disease. J Intern Med 243 (6): 589-94, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9681863" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9681863</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_24">Brandi ML, Gagel RF, Angeli A, et al.: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86 (12): 5658-71, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11739416" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11739416</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_25">National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version 2.2015. Fort Washington, Pa: National Comprehensive Cancer Network, 2015. <a href="http://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online with free subscription.</a> Last accessed October 14, 2015.</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_26">Kloos RT, Eng C, Evans DB, et al.: Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19 (6): 565-612, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19469690" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19469690</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_27">American Cancer Society: Cancer Facts and Figures 2016. Atlanta, Ga: American Cancer Society, 2016. <a href="http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online.</a> Last accessed July 11, 2016.</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_28">Hundahl SA, Fleming ID, Fremgen AM, et al.: A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see comments] Cancer 83 (12): 2638-48, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9874472" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9874472</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_29">Bhattacharyya N: A population-based analysis of survival factors in differentiated and medullary thyroid carcinoma. Otolaryngol Head Neck Surg 128 (1): 115-23, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12574769" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12574769</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_30">Modigliani E, Vasen HM, Raue K, et al.: Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group. J Intern Med 238 (4): 363-7, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7595173" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7595173</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_31">Roman S, Lin R, Sosa JA: Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer 107 (9): 2134-42, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17019736" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17019736</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_32">Bergholm U, Bergström R, Ekbom A: Long-term follow-up of patients with medullary carcinoma of the thyroid. Cancer 79 (1): 132-8, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/8988737" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8988737</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_33">Kebebew E, Ituarte PH, Siperstein AE, et al.: Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 88 (5): 1139-48, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10699905" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10699905</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_34">Elisei R, Romei C, Cosci B, et al.: RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab 92 (12): 4725-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17895320" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17895320</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_35">Paszko Z, Sromek M, Czetwertynska M, et al.: The occurrence and the type of germline mutations in the RET gene in patients with medullary thyroid carcinoma and their unaffected kindred's from Central Poland. Cancer Invest 25 (8): 742-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/18058472" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18058472</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_36">Pelizzo MR, Boschin IM, Bernante P, et al.: Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients. Eur J Surg Oncol 33 (4): 493-7, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17125960" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17125960</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_37">Lenders JW, Pacak K, Walther MM, et al.: Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 287 (11): 1427-34, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11903030" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11903030</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_38">Gerlo EA, Sevens C: Urinary and plasma catecholamines and urinary catecholamine metabolites in pheochromocytoma: diagnostic value in 19 cases. Clin Chem 40 (2): 250-6, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7906208" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7906208</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_39">Guller U, Turek J, Eubanks S, et al.: Detecting pheochromocytoma: defining the most sensitive test. Ann Surg 243 (1): 102-7, 2006. [<a href="/pmc/articles/PMC1449983/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1449983</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16371743" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16371743</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_40">Raber W, Raffesberg W, Bischof M, et al.: Diagnostic efficacy of unconjugated plasma metanephrines for the detection of pheochromocytoma. Arch Intern Med 160 (19): 2957-63, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11041903" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11041903</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_41">Sawka AM, Jaeschke R, Singh RJ, et al.: A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 88 (2): 553-8, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12574179" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12574179</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_42">Unger N, Pitt C, Schmidt IL, et al.: Diagnostic value of various biochemical parameters for the diagnosis of pheochromocytoma in patients with adrenal mass. Eur J Endocrinol 154 (3): 409-17, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16498054" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16498054</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_43">Pacak K, Eisenhofer G, Ahlman H, et al.: Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab 3 (2): 92-102, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17237836" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17237836</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_44">van der Harst E, de Herder WW, Bruining HA, et al.: [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas. J Clin Endocrinol Metab 86 (2): 685-93, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11158032" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11158032</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_45">Pacak K, Linehan WM, Eisenhofer G, et al.: Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 134 (4): 315-29, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11182843" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11182843</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_46">Kaelin WG Jr: Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2 (9): 673-82, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12209156" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12209156</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_47">Maher ER, Eng C: The pressure rises: update on the genetics of phaeochromocytoma. Hum Mol Genet 11 (20): 2347-54, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12351569" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12351569</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_48">Neumann HP, Bausch B, McWhinney SR, et al.: Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346 (19): 1459-66, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12000816" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12000816</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_49">Amar L, Bertherat J, Baudin E, et al.: Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23 (34): 8812-8, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16314641" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16314641</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_50">Gimenez-Roqueplo AP, Lehnert H, Mannelli M, et al.: Phaeochromocytoma, new genes and screening strategies. Clin Endocrinol (Oxf) 65 (6): 699-705, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17121518" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17121518</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_51">Fraser WD: Hyperparathyroidism. Lancet 374 (9684): 145-58, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19595349" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19595349</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_52">Tonelli F, Marcucci T, Giudici F, et al.: Surgical approach in hereditary hyperparathyroidism. Endocr J 56 (7): 827-41, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19797826" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19797826</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_53">Villablanca A, Calender A, Forsberg L, et al.: Germline and de novo mutations in the HRPT2 tumour suppressor gene in familial isolated hyperparathyroidism (FIHP). J Med Genet 41 (3): e32, 2004. [<a href="/pmc/articles/PMC1735713/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1735713</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14985403" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14985403</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_54">Marx SJ, Simonds WF, Agarwal SK, et al.: Hyperparathyroidism in hereditary syndromes: special expressions and special managements. J Bone Miner Res 17 (Suppl 2): N37-43, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12412776" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12412776</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_55">Sipple JH: The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 31 (1): 163-166, 1961.</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_56">Eng C, Clayton D, Schuffenecker I, et al.: The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276 (19): 1575-9, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8918855" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8918855</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_57">Sanso GE, Domene HM, Garcia R, et al.: Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers. Cancer 94 (2): 323-30, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11900218" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11900218</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_58">Yip L, Cote GJ, Shapiro SE, et al.: Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg 138 (4): 409-16; discussion 416, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12686527" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12686527</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_59">Raue F, Frank-Raue K, Grauer A: Multiple endocrine neoplasia type 2. Clinical features and screening. Endocrinol Metab Clin North Am 23 (1): 137-56, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7913021" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7913021</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_60">Perren A, Komminoth P: Familial pheochromocytomas and paragangliomas: stories from the sign-out room. Endocr Pathol 17 (4): 337-44, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17525482" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17525482</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_61">Webb TA, Sheps SG, Carney JA: Differences between sporadic pheochromocytoma and pheochromocytoma in multiple endocrime neoplasia, type 2. Am J Surg Pathol 4 (2): 121-6, 1980. [<a href="https://pubmed.ncbi.nlm.nih.gov/6103678" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6103678</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_62">Lips KJ, Van der Sluys Veer J, Struyvenberg A, et al.: Bilateral occurrence of pheochromocytoma in patients with the multiple endocrine neoplasia syndrome type 2A (Sipple's syndrome). Am J Med 70 (5): 1051-60, 1981. [<a href="https://pubmed.ncbi.nlm.nih.gov/7234871" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7234871</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_63">Neumann HP, Berger DP, Sigmund G, et al.: Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med 329 (21): 1531-8, 1993. [<a href="https://pubmed.ncbi.nlm.nih.gov/8105382" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8105382</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_64">Kraimps JL, Denizot A, Carnaille B, et al.: Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: retrospective French multicentric study. Groupe d'Etude des Tumeurs á Calcitonine (GETC, French Calcitonin Tumors Study Group), French Association of Endocrine Surgeons. World J Surg 20 (7): 808-12; discussion 812-3, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8678955" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8678955</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_65">Benson L, Ljunghall S, Akerström G, et al.: Hyperparathyroidism presenting as the first lesion in multiple endocrine neoplasia type 1. Am J Med 82 (4): 731-7, 1987. [<a href="https://pubmed.ncbi.nlm.nih.gov/2882676" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2882676</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_66">Trump D, Farren B, Wooding C, et al.: Clinical studies of multiple endocrine neoplasia type 1 (MEN1) QJM 89 (9): 653-69, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8917740" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8917740</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_67">Vasen HF, Lamers CB, Lips CJ: Screening for the multiple endocrine neoplasia syndrome type I. A study of 11 kindreds in The Netherlands. Arch Intern Med 149 (12): 2717-22, 1989. [<a href="https://pubmed.ncbi.nlm.nih.gov/2574567" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2574567</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_68">Bugalho MJ, Limbert E, Sobrinho LG, et al.: A kindred with multiple endocrine neoplasia type 2A associated with pruritic skin lesions. Cancer 70 (11): 2664-7, 1992. [<a href="https://pubmed.ncbi.nlm.nih.gov/1358428" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1358428</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_69">Robinson MF, Furst EJ, Nunziata V, et al.: Characterization of the clinical features of five families with hereditary primary cutaneous lichen amyloidosis and multiple endocrine neoplasia type 2. Henry Ford Hosp Med J 40 (3-4): 249-52, 1992. [<a href="https://pubmed.ncbi.nlm.nih.gov/1362415" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1362415</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_70">Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25394175" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25394175</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_71">Brauckhoff M, Machens A, Hess S, et al.: Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2B: An exploratory analysis. Surgery 144 (6): 1044-50; discussion 1050-3, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/19041016" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19041016</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_72">Kouvaraki MA, Shapiro SE, Perrier ND, et al.: RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid 15 (6): 531-44, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16029119" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16029119</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_73">Pacini F, Castagna MG, Cipri C, et al.: Medullary thyroid carcinoma. Clin Oncol (R Coll Radiol) 22 (6): 475-85, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20627492" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20627492</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_74">Morrison PJ, Nevin NC: Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann-Froboese syndrome). J Med Genet 33 (9): 779-82, 1996. [<a href="/pmc/articles/PMC1050735/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1050735</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8880581" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8880581</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_75">Gorlin RJ, Sedano HO, Vickers RA, et al.: Multiple mucosal neuromas, pheochromocytoma and medullary carcinoma of the thyroid--a syndrome. Cancer 22 (2): 293-9 passim, 1968. [<a href="https://pubmed.ncbi.nlm.nih.gov/5660196" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5660196</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_76">Gorlin RJ, Vickers RA: Multiple mucosal neuromas, pheochromocytoma, medullary carcinoma of the thyroid and marfanoid body build with muscle wasting: reexamination of a syndrome of neural crest malmigration. Birth Defects Orig Artic Ser 7 (6): 69-72, 1971. [<a href="https://pubmed.ncbi.nlm.nih.gov/4950920" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 4950920</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_77">Skinner MA, DeBenedetti MK, Moley JF, et al.: Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg 31 (1): 177-81; discussion 181-2, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8632274" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8632274</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_78">O'Riordain DS, O'Brien T, Weaver AL, et al.: Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B. Surgery 116 (6): 1017-23, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7985081" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7985081</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_79">Vasen HF, van der Feltz M, Raue F, et al.: The natural course of multiple endocrine neoplasia type IIb. A study of 18 cases. Arch Intern Med 152 (6): 1250-2, 1992. [<a href="https://pubmed.ncbi.nlm.nih.gov/1350898" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1350898</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_80">Romeo G, Ceccherini I, Celli J, et al.: Association of multiple endocrine neoplasia type 2 and Hirschsprung disease. J Intern Med 243 (6): 515-20, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9681852" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9681852</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_81">Decker RA, Peacock ML, Watson P: Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Hum Mol Genet 7 (1): 129-34, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9384613" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9384613</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_82">Carrasquillo MM, McCallion AS, Puffenberger EG, et al.: Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease. Nat Genet 32 (2): 237-44, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12355085" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12355085</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_83">Mulligan LM, Eng C, Attié T, et al.: Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Hum Mol Genet 3 (12): 2163-7, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7881414" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7881414</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_84">Emison ES, McCallion AS, Kashuk CS, et al.: A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature 434 (7035): 857-63, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15829955" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15829955</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_85">Gardner E, Papi L, Easton DF, et al.: Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11.2. Hum Mol Genet 2 (3): 241-6, 1993. [<a href="https://pubmed.ncbi.nlm.nih.gov/8098977" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8098977</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_86">Mole SE, Mulligan LM, Healey CS, et al.: Localisation of the gene for multiple endocrine neoplasia type 2A to a 480 kb region in chromosome band 10q11.2. Hum Mol Genet 2 (3): 247-52, 1993. [<a href="https://pubmed.ncbi.nlm.nih.gov/8098978" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8098978</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_87">Takahashi M, Ritz J, Cooper GM: Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 42 (2): 581-8, 1985. [<a href="https://pubmed.ncbi.nlm.nih.gov/2992805" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2992805</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_88">Kwok JB, Gardner E, Warner JP, et al.: Structural analysis of the human ret proto-oncogene using exon trapping. Oncogene 8 (9): 2575-82, 1993. [<a href="https://pubmed.ncbi.nlm.nih.gov/8361767" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8361767</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_89">Myers SM, Eng C, Ponder BA, et al.: Characterization of RET proto-oncogene 3' splicing variants and polyadenylation sites: a novel C-terminus for RET. Oncogene 11 (10): 2039-45, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7478523" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7478523</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_90">Airaksinen MS, Saarma M: The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 3 (5): 383-94, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11988777" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11988777</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_91">Takaya K, Yoshimasa T, Arai H, et al.: Expression of the RET proto-oncogene in normal human tissues, pheochromocytomas, and other tumors of neural crest origin. J Mol Med 74 (10): 617-21, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8912182" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8912182</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_92">Kurokawa K, Kawai K, Hashimoto M, et al.: Cell signalling and gene expression mediated by RET tyrosine kinase. J Intern Med 253 (6): 627-33, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12755958" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12755958</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_93">Manié S, Santoro M, Fusco A, et al.: The RET receptor: function in development and dysfunction in congenital malformation. Trends Genet 17 (10): 580-9, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11585664" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11585664</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_94">Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20065170" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20065170</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_95">Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Am J Hum Genet 57 (5): 1233-41, 1995. [<a href="/pmc/articles/PMC1801355/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1801355</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/7485175" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7485175</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_96">Cooper DS, Doherty GM, Haugen BR, et al.: Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19 (11): 1167-214, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19860577" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19860577</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_97">Sarika HL, Papathoma A, Garofalaki M, et al.: Genetic screening of patients with medullary thyroid cancer in a referral center in Greece during the past two decades. Eur J Endocrinol 172 (4): 501-9, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25624014" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25624014</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_98">Ceccherini I, Hofstra RM, Luo Y, et al.: DNA polymorphisms and conditions for SSCP analysis of the 20 exons of the ret proto-oncogene. Oncogene 9 (10): 3025-9, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/8084609" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8084609</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_99">Xue F, Yu H, Maurer LH, et al.: Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests. Hum Mol Genet 3 (4): 635-8, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7915165" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7915165</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_100">McMahon R, Mulligan LM, Healey CS, et al.: Direct, non-radioactive detection of mutations in multiple endocrine neoplasia type 2A families. Hum Mol Genet 3 (4): 643-6, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7915166" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7915166</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_101">Kambouris M, Jackson CE, Feldman GL: Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B and familial medullary thyroid cancer [FMTC] by multiplex PCR and heteroduplex analyses of RET proto-oncogene mutations. Hum Mutat 8 (1): 64-70, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8807338" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8807338</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_102">Machens A, Niccoli-Sire P, Hoegel J, et al.: Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 349 (16): 1517-25, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/14561794" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14561794</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_103">Valdés N, Navarro E, Mesa J, et al.: RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation. Eur J Endocrinol 172 (3): 301-7, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25515555" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25515555</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_104">Elisei R, Romei C, Renzini G, et al.: The timing of total thyroidectomy in RET gene mutation carriers could be personalized and safely planned on the basis of serum calcitonin: 18 years experience at one single center. J Clin Endocrinol Metab 97 (2): 426-35, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22162466" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22162466</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_105">Rich TA, Feng L, Busaidy N, et al.: Prevalence by age and predictors of medullary thyroid cancer in patients with lower risk germline RET proto-oncogene mutations. Thyroid 24 (7): 1096-106, 2014. [<a href="/pmc/articles/PMC4080849/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4080849</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24617864" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24617864</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_106">Eng C, Smith DP, Mulligan LM, et al.: Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet 3 (2): 237-41, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7911697" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7911697</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_107">Hofstra RM, Landsvater RM, Ceccherini I, et al.: A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 367 (6461): 375-6, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7906866" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7906866</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_108">Carlson KM, Dou S, Chi D, et al.: Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A 91 (4): 1579-83, 1994. [<a href="/pmc/articles/PMC43203/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC43203</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/7906417" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7906417</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_109">Gimm O, Marsh DJ, Andrew SD, et al.: Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab 82 (11): 3902-4, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9360560" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9360560</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_110">Smith DP, Houghton C, Ponder BA: Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene 15 (10): 1213-7, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9294615" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9294615</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_111">Eng C, Mulligan LM, Healey CS, et al.: Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res 56 (9): 2167-70, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8616867" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8616867</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_112">Cranston AN, Carniti C, Oakhill K, et al.: RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B. Cancer Res 66 (20): 10179-87, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17047083" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17047083</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_113">Miyauchi A, Futami H, Hai N, et al.: Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. Jpn J Cancer Res 90 (1): 1-5, 1999. [<a href="/pmc/articles/PMC5925979/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5925979</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/10076558" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10076558</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_114">Kameyama K, Okinaga H, Takami H: RET oncogene mutations in 75 cases of familial medullary thyroid carcinoma in Japan. Biomed Pharmacother 58 (6-7): 345-7, 2004 Jul-Aug. [<a href="https://pubmed.ncbi.nlm.nih.gov/15271413" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15271413</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_115">Iwashita T, Murakami H, Kurokawa K, et al.: A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations. Biochem Biophys Res Commun 268 (3): 804-8, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10679286" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10679286</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_116">Menko FH, van der Luijt RB, de Valk IA, et al.: Atypical MEN type 2B associated with two germline RET mutations on the same allele not involving codon 918. J Clin Endocrinol Metab 87 (1): 393-7, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11788682" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11788682</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_117">Mulligan LM, Eng C, Healey CS, et al.: Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 6 (1): 70-4, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7907913" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7907913</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_118">Seri M, Celli I, Betsos N, et al.: A Cys634Gly substitution of the RET proto-oncogene in a family with recurrence of multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis. Clin Genet 51 (2): 86-90, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9111993" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9111993</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_119">Rothberg AE, Raymond VM, Gruber SB, et al.: Familial medullary thyroid carcinoma associated with cutaneous lichen amyloidosis. Thyroid 19 (6): 651-5, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19445625" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19445625</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_120">Quayle FJ, Fialkowski EA, Benveniste R, et al.: Pheochromocytoma penetrance varies by RET mutation in MEN 2A. Surgery 142 (6): 800-5; discussion 805.e1, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/18063059" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18063059</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_121">Bolino A, Schuffenecker I, Luo Y, et al.: RET mutations in exons 13 and 14 of FMTC patients. Oncogene 10 (12): 2415-9, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7784092" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7784092</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_122">Boccia LM, Green JS, Joyce C, et al.: Mutation of RET codon 768 is associated with the FMTC phenotype. Clin Genet 51 (2): 81-5, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9111992" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9111992</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_123">Lesueur F, Cebrian A, Cranston A, et al.: Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients. J Clin Endocrinol Metab 90 (6): 3454-7, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15741265" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15741265</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_124">Shannon KE, Gimm O, Hinze R: Germline V804M mutation in the RET protooncogene in 2 apparently sporadic cases of MTC presenting in the 7th decade of life. The Journal of Endocrine Genetics 1 (1): 39-46, 1999.</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_125">Raue F, Frank-Raue K: Genotype-phenotype relationship in multiple endocrine neoplasia type 2. Implications for clinical management. Hormones (Athens) 8 (1): 23-8, 2009 Jan-Mar. [<a href="https://pubmed.ncbi.nlm.nih.gov/19269918" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19269918</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_126">Frank-Raue K, Rybicki LA, Erlic Z, et al.: Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat 32 (1): 51-8, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/20979234" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20979234</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_127">Mulligan LM, Marsh DJ, Robinson BG, et al.: Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med 238 (4): 343-6, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7595170" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7595170</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_128">Moers AM, Landsvater RM, Schaap C, et al.: Familial medullary thyroid carcinoma: not a distinct entity? Genotype-phenotype correlation in a large family. Am J Med 101 (6): 635-41, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/9003111" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9003111</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_129">Niccoli-Sire P, Murat A, Rohmer V, et al.: Familial medullary thyroid carcinoma with noncysteine ret mutations: phenotype-genotype relationship in a large series of patients. J Clin Endocrinol Metab 86 (8): 3746-53, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11502806" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11502806</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_130">Machens A, Ukkat J, Brauckhoff M, et al.: Advances in the management of hereditary medullary thyroid cancer. J Intern Med 257 (1): 50-9, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15606376" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15606376</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_131">Mukherjee S, Zakalik D: RET codon 804 mutations in multiple endocrine neoplasia 2: genotype-phenotype correlations and implications in clinical management. Clin Genet 79 (1): 1-16, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/20497437" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20497437</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_132">Dvorakova S, Vaclavikova E, Duskova J, et al.: Exon 5 of the RET proto-oncogene: a newly detected risk exon for familial medullary thyroid carcinoma, a novel germ-line mutation Gly321Arg. J Endocrinol Invest 28 (10): 905-9, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16419493" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16419493</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_133">Muzza M, Cordella D, Bombled J, et al.: Four novel RET germline variants in exons 8 and 11 display an oncogenic potential in vitro. Eur J Endocrinol 162 (4): 771-7, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20103606" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20103606</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_134">Pigny P, Bauters C, Wemeau JL, et al.: A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma. J Clin Endocrinol Metab 84 (5): 1700-4, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10323403" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10323403</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_135">Niccoli-Sire P, Murat A, Rohmer V, et al.: When should thyroidectomy be performed in familial medullary thyroid carcinoma gene carriers with non-cysteine RET mutations? Surgery 134 (6): 1029-36; discussion 1036-7, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/14668737" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14668737</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_136">Fazioli F, Piccinini G, Appolloni G, et al.: A new germline point mutation in Ret exon 8 (cys515ser) in a family with medullary thyroid carcinoma. Thyroid 18 (7): 775-82, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18631007" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18631007</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_137">Da Silva AM, Maciel RM, Da Silva MR, et al.: A novel germ-line point mutation in RET exon 8 (Gly(533)Cys) in a large kindred with familial medullary thyroid carcinoma. J Clin Endocrinol Metab 88 (11): 5438-43, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/14602786" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14602786</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_138">Bethanis S, Koutsodontis G, Palouka T, et al.: A newly detected mutation of the RET protooncogene in exon 8 as a cause of multiple endocrine neoplasia type 2A. Hormones (Athens) 6 (2): 152-6, 2007 Apr-Jun. [<a href="https://pubmed.ncbi.nlm.nih.gov/17704047" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17704047</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_139">Kaldrymides P, Mytakidis N, Anagnostopoulos T, et al.: A rare RET gene exon 8 mutation is found in two Greek kindreds with familial medullary thyroid carcinoma: implications for screening. Clin Endocrinol (Oxf) 64 (5): 561-6, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16649977" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16649977</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_140">Peppa M, Boutati E, Kamakari S, et al.: Multiple endocrine neoplasia type 2A in two families with the familial medullary thyroid carcinoma associated G533C mutation of the RET proto-oncogene. Eur J Endocrinol 159 (6): 767-71, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18805915" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18805915</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_141">Oliveira MN, Hemerly JP, Bastos AU, et al.: The RET p.G533C mutation confers predisposition to multiple endocrine neoplasia type 2A in a Brazilian kindred and is able to induce a malignant phenotype in vitro and in vivo. Thyroid 21 (9): 975-85, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21834681" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21834681</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_142">Signorini PS, França MI, Camacho CP, et al.: A ten-year clinical update of a large RET p.Gly533Cys kindred with medullary thyroid carcinoma emphasizes the need for an individualized assessment of affected relatives. Clin Endocrinol (Oxf) 80 (2): 235-45, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/23745650" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23745650</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_143">Sáez ME, Ruiz A, Cebrián A, et al.: A new germline mutation, R600Q, within the coding region of RET proto-oncogene: a rare polymorphism or a MEN 2 causing mutation? Hum Mutat 15 (1): 122, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10612852" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10612852</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_144">Rey JM, Brouillet JP, Fonteneau-Allaire J, et al.: Novel germline RET mutation segregating with papillary thyroid carcinomas. Genes Chromosomes Cancer 32 (4): 390-1, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11746981" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11746981</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_145">Ahmed SA, Snow-Bailey K, Highsmith WE, et al.: Nine novel germline gene variants in the RET proto-oncogene identified in twelve unrelated cases. J Mol Diagn 7 (2): 283-8, 2005. [<a href="/pmc/articles/PMC1867532/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1867532</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15858153" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15858153</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_146">Ercolino T, Lombardi A, Becherini L, et al.: The Y606C RET mutation causes a receptor gain of function. Clin Endocrinol (Oxf) 69 (2): 253-8, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18248647" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18248647</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_147">Igaz P, Patócs A, Rácz K, et al.: Occurrence of pheochromocytoma in a MEN2A family with codon 609 mutation of the RET proto-oncogene. J Clin Endocrinol Metab 87 (6): 2994, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12050290" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12050290</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_148">Fialkowski EA, DeBenedetti MK, Moley JF, et al.: RET proto-oncogene testing in infants presenting with Hirschsprung disease identifies 2 new multiple endocrine neoplasia 2A kindreds. J Pediatr Surg 43 (1): 188-90, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18206480" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18206480</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_149">Mian C, Barollo S, Zambonin L, et al.: Characterization of the largest kindred with MEN2A due to a Cys609Ser RET mutation. Fam Cancer 8 (4): 379-82, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19475497" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19475497</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_150">Kinlaw WB, Scott SM, Maue RA, et al.: Multiple endocrine neoplasia 2A due to a unique C609S RET mutation presents with pheochromocytoma and reduced penetrance of medullary thyroid carcinoma. Clin Endocrinol (Oxf) 63 (6): 676-82, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16343103" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16343103</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_151">Calva D, O'Dorisio TM, Sue O'Dorisio M, et al.: When is prophylactic thyroidectomy indicated for patients with the RET codon 609 mutation? Ann Surg Oncol 16 (8): 2237-44, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19472011" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19472011</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_152">Jung J, Uchino S, Lee Y, et al.: A Korean family of familial medullary thyroid cancer with Cys618Ser RET germline mutation. J Korean Med Sci 25 (2): 226-9, 2010. [<a href="/pmc/articles/PMC2811288/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2811288</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20119574" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20119574</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_153">Qi XP, Ying RB, Ma JM, et al.: Case report: a p.C618S RET proto-oncogene germline mutation in a large Chinese pedigree with familial medullary thyroid carcinoma. Fam Cancer 11 (1): 131-6, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22068382" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22068382</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_154">Hedayati M, Zarif Yeganeh M, Sheikhol Eslami S, et al.: Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma. J Thyroid Res 2011: 264248, 2011. [<a href="/pmc/articles/PMC3134203/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3134203</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21765987" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21765987</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_155">Neocleous V, Skordis N, Portides G, et al.: RET proto-oncogene mutations are restricted to codon 618 in Cypriot families with multiple endocrine neoplasia 2. J Endocrinol Invest 34 (10): 764-9, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21422799" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21422799</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_156">Chu CS, Lee KT, Lee ST, et al.: Effects of atorvastatin on ventricular late potentials and repolarization dispersion in patients with hypercholesterolemia. Kaohsiung J Med Sci 23 (5): 217-24, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17525003" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17525003</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_157">Berndt I, Reuter M, Saller B, et al.: A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab 83 (3): 770-4, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9506724" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9506724</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_158">Elston MS, Meyer-Rochow GY, Holdaway I, et al.: Patients with RET D631Y mutations most commonly present with pheochromocytoma and not medullary thyroid carcinoma. Horm Metab Res 44 (5): 339-42, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22274720" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22274720</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_159">Asai N, Iwashita T, Murakami H, et al.: Mechanism of Ret activation by a mutation at aspartic acid 631 identified in sporadic pheochromocytoma. Biochem Biophys Res Commun 255 (3): 587-90, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10049754" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10049754</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_160">Höppner W, Dralle H, Brabant G: Duplication of 9 base pairs in the critical cysteine-rich domain of the RET proto-oncogene causes multiple endocrine neoplasia type 2A. Hum Mutat Suppl (1): S128-30, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9452064" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9452064</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_161">Puñales MK, Graf H, Gross JL, et al.: RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab 88 (6): 2644-9, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12788868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12788868</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_162">Zhou YL, Zhu SX, Li JJ, et al.: [The clinical patterns and RET proto-oncogene in fifteen multiple endocrine neoplasia type 2A pedigrees]. Zhonghua Nei Ke Za Zhi 46 (6): 466-70, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17663821" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17663821</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_163">Lemos MC, Carrilho F, Rodrigues FJ, et al.: Early onset of medullary thyroid carcinoma in a kindred with multiple endocrine neoplasia type iia associated with cutaneous lichen amyloidosis. Endocr Pract 8 (1): 19-22, 2002 Jan-Feb. [<a href="https://pubmed.ncbi.nlm.nih.gov/11939755" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11939755</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_164">Toledo RA, Wagner SM, Coutinho FL, et al.: High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene. J Clin Endocrinol Metab 95 (3): 1318-27, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20080836" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20080836</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_165">Höppner W, Ritter MM: A duplication of 12 bp in the critical cysteine rich domain of the RET proto-oncogene results in a distinct phenotype of multiple endocrine neoplasia type 2A. Hum Mol Genet 6 (4): 587-90, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9097963" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9097963</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_166">Wiench M, Wygoda Z, Gubala E, et al.: Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients. J Clin Oncol 19 (5): 1374-80, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11230481" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11230481</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_167">Colombo-Benkmann M, Li Z, Riemann B, et al.: Characterization of the RET protooncogene transmembrane domain mutation S649L associated with nonaggressive medullary thyroid carcinoma. Eur J Endocrinol 158 (6): 811-6, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18322301" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18322301</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_168">Vierhapper H, Bieglmayer C, Heinze G, et al.: Frequency of RET proto-oncogene mutations in patients with normal and with moderately elevated pentagastrin-stimulated serum concentrations of calcitonin. Thyroid 14 (8): 580-3, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15320968" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15320968</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_169">Borrello MG, Aiello A, Peissel B, et al.: Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism. Endocr Relat Cancer 18 (4): 519-27, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21690267" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21690267</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_170">Dabir T, Hunter SJ, Russell CF, et al.: The RET mutation E768D confers a late-onset familial medullary thyroid carcinoma -- only phenotype with incomplete penetrance: implications for screening and management of carrier status. Fam Cancer 5 (2): 201-4, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16736292" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16736292</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_171">Frank-Raue K, Döhring J, Scheumann G, et al.: New mutations in the RET protooncogene-L881V - associated with medullary thyroid carcinoma and -R770Q - in a patient with mixed medullar/follicular thyroid tumour. Exp Clin Endocrinol Diabetes 118 (8): 550-3, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20013610" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20013610</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_172">D'Aloiso L, Carlomagno F, Bisceglia M, et al.: Clinical case seminar: in vivo and in vitro characterization of a novel germline RET mutation associated with low-penetrant nonaggressive familial medullary thyroid carcinoma. J Clin Endocrinol Metab 91 (3): 754-9, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16384843" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16384843</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_173">Frank-Raue K, Machens A, Scheuba C, et al.: Difference in development of medullary thyroid carcinoma among carriers of RET mutations in codons 790 and 791. Clin Endocrinol (Oxf) 69 (2): 259-63, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18248648" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18248648</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_174">Bihan H, Baudin E, Meas T, et al.: Role of prophylactic thyroidectomy in RET 790 familial medullary thyroid carcinoma. Head Neck 34 (4): 493-8, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/21688339" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21688339</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_175">Vestergaard P, Vestergaard EM, Brockstedt H, et al.: Codon Y791F mutations in a large kindred: is prophylactic thyroidectomy always indicated? World J Surg 31 (5): 996-1001; discussion 1002-4, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17483988" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17483988</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_176">Learoyd DL, Gosnell J, Elston MS, et al.: Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations. Clin Endocrinol (Oxf) 63 (6): 636-41, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16343097" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16343097</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_177">Lal G, Nowell AG, Liao J, et al.: Determinants of survival in patients with calciphylaxis: a multivariate analysis. Surgery 146 (6): 1028-34, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19958929" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19958929</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_178">Shifrin AL, Ogilvie JB, Stang MT, et al.: Single nucleotide polymorphisms act as modifiers and correlate with the development of medullary and simultaneous medullary/papillary thyroid carcinomas in 2 large, non-related families with the RET V804M proto-oncogene mutation. Surgery 148 (6): 1274-80; discussion 1280-1, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/21134561" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21134561</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_179">Kasprzak L, Nolet S, Gaboury L, et al.: Familial medullary thyroid carcinoma and prominent corneal nerves associated with the germline V804M and V778I mutations on the same allele of RET. J Med Genet 38 (11): 784-7, 2001. [<a href="/pmc/articles/PMC1734769/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1734769</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11732489" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11732489</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_180">Cranston A, Carniti C, Martin S, et al.: A novel activating mutation in the RET tyrosine kinase domain mediates neoplastic transformation. Mol Endocrinol 20 (7): 1633-43, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16469774" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16469774</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_181">Jasim S, Ying AK, Waguespack SG, et al.: Multiple endocrine neoplasia type 2B with a RET proto-oncogene A883F mutation displays a more indolent form of medullary thyroid carcinoma compared with a RET M918T mutation. Thyroid 21 (2): 189-92, 2011. [<a href="/pmc/articles/PMC3025175/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3025175</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21186952" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21186952</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_182">Prazeres HJ, Rodrigues F, Figueiredo P, et al.: Occurrence of the Cys611Tyr mutation and a novel Arg886Trp substitution in the RET proto-oncogene in multiple endocrine neoplasia type 2 families and sporadic medullary thyroid carcinoma cases originating from the central region of Portugal. Clin Endocrinol (Oxf) 64 (6): 659-66, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16712668" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16712668</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_183">Schulte KM, Machens A, Fugazzola L, et al.: The clinical spectrum of multiple endocrine neoplasia type 2a caused by the rare intracellular RET mutation S891A. J Clin Endocrinol Metab 95 (9): E92-7, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20554711" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20554711</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_184">Hofstra RM, Fattoruso O, Quadro L, et al.: A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab 82 (12): 4176-8, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9398735" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9398735</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_185">Dang GT, Cote GJ, Schultz PN, et al.: A codon 891 exon 15 RET proto-oncogene mutation in familial medullary thyroid carcinoma: a detection strategy. Mol Cell Probes 13 (1): 77-9, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10024437" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10024437</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_186">Jimenez C, Habra MA, Huang SC, et al.: Pheochromocytoma and medullary thyroid carcinoma: a new genotype-phenotype correlation of the RET protooncogene 891 germline mutation. J Clin Endocrinol Metab 89 (8): 4142-5, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15292360" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15292360</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_187">Jimenez C, Dang GT, Schultz PN, et al.: A novel point mutation of the RET protooncogene involving the second intracellular tyrosine kinase domain in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab 89 (7): 3521-6, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15240641" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15240641</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_188">Zenaty D, Aigrain Y, Peuchmaur M, et al.: Medullary thyroid carcinoma identified within the first year of life in children with hereditary multiple endocrine neoplasia type 2A (codon 634) and 2B. Eur J Endocrinol 160 (5): 807-13, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19240193" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19240193</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_189">Siqueira DR, Ceolin L, Ferreira CV, et al.: Role of RET genetic variants in MEN2-associated pheochromocytoma. Eur J Endocrinol 170 (6): 821-8, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24616415" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24616415</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_190">Ceolin L, Siqueira DR, Romitti M, et al.: Molecular basis of medullary thyroid carcinoma: the role of RET polymorphisms. Int J Mol Sci 13 (1): 221-39, 2012. [<a href="/pmc/articles/PMC3269683/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3269683</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22312249" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22312249</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_191">Robledo M, Gil L, Pollán M, et al.: Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A. Cancer Res 63 (8): 1814-7, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12702567" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12702567</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_192">Margraf RL, Crockett DK, Krautscheid PM, et al.: Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Hum Mutat 30 (4): 548-56, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19177457" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19177457</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_193">Wells SA Jr, Donis-Keller H: Current perspectives on the diagnosis and management of patients with multiple endocrine neoplasia type 2 syndromes. Endocrinol Metab Clin North Am 23 (1): 215-28, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7913027" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7913027</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_194">Gardet V, Gatta B, Simonnet G, et al.: Lessons from an unpleasant surprise: a biochemical strategy for the diagnosis of pheochromocytoma. J Hypertens 19 (6): 1029-35, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11403350" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11403350</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_195">Pacak K, Ilias I, Adams KT, et al.: Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour. J Intern Med 257 (1): 60-8, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15606377" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15606377</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_196">Raue F, Kraimps JL, Dralle H, et al.: Primary hyperparathyroidism in multiple endocrine neoplasia type 2A. J Intern Med 238 (4): 369-73, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7595174" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7595174</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_197">Milos IN, Frank-Raue K, Wohllk N, et al.: Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation. Endocr Relat Cancer 15 (4): 1035-41, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18794325" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18794325</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_198">Marsh DJ, McDowall D, Hyland VJ, et al.: The identification of false positive responses to the pentagastrin stimulation test in RET mutation negative members of MEN 2A families. Clin Endocrinol (Oxf) 44 (2): 213-20, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8849577" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8849577</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_199">Qi XP, Zhao JQ, Du ZF, et al.: Prophylactic thyroidectomy for MEN 2-related medullary thyroid carcinoma based on predictive testing for RET proto-oncogene mutation and basal serum calcitonin in China. Eur J Surg Oncol 39 (9): 1007-12, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23849459" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23849459</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_200">Schreinemakers JM, Vriens MR, Valk GD, et al.: Factors predicting outcome of total thyroidectomy in young patients with multiple endocrine neoplasia type 2: a nationwide long-term follow-up study. World J Surg 34 (4): 852-60, 2010. [<a href="/pmc/articles/PMC2832884/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2832884</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20063095" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20063095</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_201">Niccoli-Sire P, Murat A, Baudin E, et al.: Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC). Eur J Endocrinol 141 (5): 468-74, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10576762" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10576762</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_202">Wells SA Jr, Skinner MA: Prophylactic thyroidectomy, based on direct genetic testing, in patients at risk for the multiple endocrine neoplasia type 2 syndromes. Exp Clin Endocrinol Diabetes 106 (1): 29-34, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9516056" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9516056</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_203">Szinnai G, Meier C, Komminoth P, et al.: Review of multiple endocrine neoplasia type 2A in children: therapeutic results of early thyroidectomy and prognostic value of codon analysis. Pediatrics 111 (2): E132-9, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12563086" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12563086</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_204">Skinner MA, Moley JA, Dilley WG, et al.: Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 353 (11): 1105-13, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16162881" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16162881</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_205">Machens A, Schneyer U, Holzhausen HJ, et al.: Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab 90 (4): 2029-34, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15634717" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15634717</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_206">Machens A, Lorenz K, Dralle H: Individualization of lymph node dissection in RET (rearranged during transfection) carriers at risk for medullary thyroid cancer: value of pretherapeutic calcitonin levels. Ann Surg 250 (2): 305-10, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19638924" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19638924</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_207">Franc S, Niccoli-Sire P, Cohen R, et al.: Complete surgical lymph node resection does not prevent authentic recurrences of medullary thyroid carcinoma. Clin Endocrinol (Oxf) 55 (3): 403-9, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11589685" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11589685</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_208">van Heurn LW, Schaap C, Sie G, et al.: Predictive DNA testing for multiple endocrine neoplasia 2: a therapeutic challenge of prophylactic thyroidectomy in very young children. J Pediatr Surg 34 (4): 568-71, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10235324" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10235324</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_209">Hansen HS, Torring H, Godballe C, et al.: Is thyroidectomy necessary in RET mutations carriers of the familial medullary thyroid carcinoma syndrome? Cancer 89 (4): 863-7, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10951350" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10951350</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_210">Mandel SJ, Brent GA, Larsen PR: Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 119 (6): 492-502, 1993. [<a href="https://pubmed.ncbi.nlm.nih.gov/8357116" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8357116</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_211">Sawin CT, Geller A, Hershman JM, et al.: The aging thyroid. The use of thyroid hormone in older persons. JAMA 261 (18): 2653-5, 1989. [<a href="https://pubmed.ncbi.nlm.nih.gov/2709545" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2709545</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_212">Baloch Z, Carayon P, Conte-Devolx B, et al.: Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 13 (1): 3-126, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12625976" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12625976</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_213">Seib CD, Harari A, Conte FA, et al.: Utility of serum thyroglobulin measurements after prophylactic thyroidectomy in patients with hereditary medullary thyroid cancer. Surgery 156 (2): 394-8, 2014. [<a href="/pmc/articles/PMC4099273/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4099273</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24882762" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24882762</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_214">Samaan NA, Schultz PN, Hickey RC: Medullary thyroid carcinoma: prognosis of familial versus nonfamilial disease and the role of radiotherapy. Horm Metab Res Suppl 21: 21-5, 1989. [<a href="https://pubmed.ncbi.nlm.nih.gov/2807151" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2807151</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_215">Scherübl H, Raue F, Ziegler R: Combination chemotherapy of advanced medullary and differentiated thyroid cancer. Phase II study. J Cancer Res Clin Oncol 116 (1): 21-3, 1990. [<a href="https://pubmed.ncbi.nlm.nih.gov/2312602" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2312602</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_216">Cohen EE, Rosen LS, Vokes EE, et al.: Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 26 (29): 4708-13, 2008. [<a href="/pmc/articles/PMC4859206/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4859206</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18541897" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18541897</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_217">Lam ET, Ringel MD, Kloos RT, et al.: Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol 28 (14): 2323-30, 2010. [<a href="/pmc/articles/PMC2881718/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2881718</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20368568" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20368568</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_218">Carr LL, Mankoff DA, Goulart BH, et al.: Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res 16 (21): 5260-8, 2010. [<a href="/pmc/articles/PMC3063514/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3063514</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20847059" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20847059</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_219">Kurzrock R, Sherman SI, Ball DW, et al.: Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 29 (19): 2660-6, 2011. [<a href="/pmc/articles/PMC3646303/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3646303</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21606412" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21606412</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_220">Wells SA Jr, Robinson BG, Gagel RF, et al.: Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 30 (2): 134-41, 2012. [<a href="/pmc/articles/PMC3675689/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3675689</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22025146" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22025146</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_221">Fox E, Widemann BC, Chuk MK, et al.: Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma. Clin Cancer Res 19 (15): 4239-48, 2013. [<a href="/pmc/articles/PMC4274128/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4274128</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23766359" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23766359</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_222">Elisei R, Schlumberger MJ, Müller SP, et al.: Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 31 (29): 3639-46, 2013. [<a href="/pmc/articles/PMC4164813/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4164813</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24002501" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24002501</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_223">Castinetti F, Qi XP, Walz MK, et al.: Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study. Lancet Oncol 15 (6): 648-55, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24745698" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24745698</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_224">Thosani S, Ayala-Ramirez M, Palmer L, et al.: The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 98 (11): E1813-9, 2013. [<a href="/pmc/articles/PMC5399523/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5399523</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24030942" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24030942</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_225">Lairmore TC, Ball DW, Baylin SB, et al.: Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Ann Surg 217 (6): 595-601; discussion 601-3, 1993. [<a href="/pmc/articles/PMC1242859/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1242859</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8099474" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8099474</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_226">Okamoto T, Obara T, Ito Y, et al.: Bilateral adrenalectomy with autotransplantation of adrenocortical tissue or unilateral adrenalectomy: treatment options for pheochromocytomas in multiple endocrine neoplasia type 2A. Endocr J 43 (2): 169-75, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8793332" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8793332</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_227">Inabnet WB, Caragliano P, Pertsemlidis D: Pheochromocytoma: inherited associations, bilaterality, and cortex preservation. Surgery 128 (6): 1007-11;discussion 1011-2, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11114636" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11114636</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_228">Scholten A, Valk GD, Ulfman D, et al.: Unilateral subtotal adrenalectomy for pheochromocytoma in multiple endocrine neoplasia type 2 patients: a feasible surgical strategy. Ann Surg 254 (6): 1022-7, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/22107743" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22107743</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_229">Grubbs EG, Rich TA, Ng C, et al.: Long-term outcomes of surgical treatment for hereditary pheochromocytoma. J Am Coll Surg 216 (2): 280-9, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23317575" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23317575</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_230">Walz MK, Alesina PF, Wenger FA, et al.: Posterior retroperitoneoscopic adrenalectomy--results of 560 procedures in 520 patients. Surgery 140 (6): 943-8; discussion 948-50, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17188142" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17188142</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_231">Walz MK, Alesina PF, Wenger FA, et al.: Laparoscopic and retroperitoneoscopic treatment of pheochromocytomas and retroperitoneal paragangliomas: results of 161 tumors in 126 patients. World J Surg 30 (5): 899-908, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16617419" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16617419</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_232">Perrier ND, Kennamer DL, Bao R, et al.: Posterior retroperitoneoscopic adrenalectomy: preferred technique for removal of benign tumors and isolated metastases. Ann Surg 248 (4): 666-74, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18936580" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18936580</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_233">Behrman SW, Bahr MH, Dickson PV, et al.: The microbiology of secondary and postoperative pancreatic infections: implications for antimicrobial management. Arch Surg 146 (5): 613-9, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21576614" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21576614</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_234">Evans DB, Perrier ND: On "Posterior retroperitoneoscopic adrenalectomy--results of 560 procedures in 520 patients". Surgery 140 (6): 951-2, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17188143" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17188143</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_235">Dickson PV, Jimenez C, Chisholm GB, et al.: Posterior retroperitoneoscopic adrenalectomy: a contemporary American experience. J Am Coll Surg 212 (4): 659-65; discussion 665-7, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21463807" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21463807</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_236">Norton JA, Brennan MF, Wells SA Jr: Surgical Management of Hyperparathyroidism. In: Bilezikian JP, Marcus R, Levine MA: The Parathyroids: Basic and Clinical Concepts. New York: Raven Press, 1994, pp 531-551.</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_237">Khan MI, Waguespack SG, Hu MI: Medical management of postsurgical hypoparathyroidism. Endocr Pract 17 (Suppl 1): 18-25, 2011 Mar-Apr. [<a href="https://pubmed.ncbi.nlm.nih.gov/21134871" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21134871</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_238">Stålberg P, Carling T: Familial parathyroid tumors: diagnosis and management. World J Surg 33 (11): 2234-43, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19184636" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19184636</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_239">Peacock M, Bilezikian JP, Klassen PS, et al.: Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 90 (1): 135-41, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15522938" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15522938</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_240">Schuffenecker I, Ginet N, Goldgar D, et al.: Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d'Etude des Tumeurs a Calcitonine. Am J Hum Genet 60 (1): 233-7, 1997. [<a href="/pmc/articles/PMC1712555/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1712555</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8981969" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8981969</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_241">Norum RA, Lafreniere RG, O'Neal LW, et al.: Linkage of the multiple endocrine neoplasia type 2B gene (MEN2B) to chromosome 10 markers linked to MEN2A. Genomics 8 (2): 313-7, 1990. [<a href="https://pubmed.ncbi.nlm.nih.gov/1979053" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1979053</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_242">Carlson KM, Bracamontes J, Jackson CE, et al.: Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet 55 (6): 1076-82, 1994. [<a href="/pmc/articles/PMC1918453/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1918453</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/7977365" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7977365</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_243">Kitamura Y, Scavarda N, Wells SA Jr, et al.: Two maternally derived missense mutations in the tyrosine kinase domain of the RET protooncogene in a patient with de novo MEN 2B. Hum Mol Genet 4 (10): 1987-8, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/8595427" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8595427</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_244">Rich TA, Liu M, Etzel CJ, et al.: Comparison of attitudes regarding preimplantation genetic diagnosis among patients with hereditary cancer syndromes. Fam Cancer 13 (2): 291-9, 2014. [<a href="/pmc/articles/PMC4159051/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4159051</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24072553" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24072553</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_245">Freyer G, Ligneau B, Schlumberger M, et al.: Quality of life in patients at risk of medullary thyroid carcinoma and followed by a comprehensive medical network: trends for future evaluations. Ann Oncol 12 (10): 1461-5, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11762820" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11762820</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_246">Freyer G, Dazord A, Schlumberger M, et al.: Psychosocial impact of genetic testing in familial medullary-thyroid carcinoma: a multicentric pilot-evaluation. Ann Oncol 10 (1): 87-95, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10076727" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10076727</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_247">Grosfeld FJ, Lips CJ, Ten Kroode HF, et al.: Psychosocial consequences of DNA analysis for MEN type 2. Oncology (Huntingt) 10 (2): 141-6; discussion 146, 152, 157, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8838257" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8838257</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_248">Johnston LB, Chew SL, Trainer PJ, et al.: Screening children at risk of developing inherited endocrine neoplasia syndromes. Clin Endocrinol (Oxf) 52 (2): 127-36, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10671936" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10671936</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_249">MacDonald DJ, Lessick M: Hereditary cancers in children and ethical and psychosocial implications. J Pediatr Nurs 15 (4): 217-25, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10969494" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10969494</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_250">Grosfeld FJ, Lips CJ, Beemer FA, et al.: Psychological risks of genetically testing children for a hereditary cancer syndrome. Patient Educ Couns 32 (1-2): 63-7, 1997 Sep-Oct. [<a href="https://pubmed.ncbi.nlm.nih.gov/9355573" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9355573</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_251">Giarelli E: Multiple endocrine neoplasia type 2a (MEN2a): a call for psycho-social research. Psychooncology 11 (1): 59-73, 2002 Jan-Feb. [<a href="https://pubmed.ncbi.nlm.nih.gov/11835593" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11835593</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_252">Grosfeld FJ, Lips CJ, Beemer FA, et al.: Distress in MEN 2 family members and partners prior to DNA test disclosure. Multiple endocrine neoplasia type 2. Am J Med Genet 91 (1): 1-7, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10751081" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10751081</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_253">Grosfeld FJ, Beemer FA, Lips CJ, et al.: Parents' responses to disclosure of genetic test results of their children. Am J Med Genet 94 (4): 316-23, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11038446" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11038446</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_254">Giarelli E: Bringing threat to the fore: participating in lifelong surveillance for genetic risk of cancer. Oncol Nurs Forum 30 (6): 945-55, 2003 Nov-Dec. [<a href="https://pubmed.ncbi.nlm.nih.gov/14603352" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14603352</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_5_255">Schultz PN: Providing information to patients with a rare cancer: using Internet discussion forums to address the needs of patients with medullary thyroid carcinoma. Clin J Oncol Nurs 6 (4): 219-22, 2002 Jul-Aug. [<a href="https://pubmed.ncbi.nlm.nih.gov/12087618" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12087618</span></a>]</div></li></ol></div></div><div id="CDR0000062890__850"><h2 id="_CDR0000062890__850_">Familial Pheochromocytoma and Paraganglioma Syndrome</h2><div id="CDR0000062890__851"><h3>Introduction</h3><p id="CDR0000062890__870">Paragangliomas (PGLs) and pheochromocytomas (PHEOs) are rare tumors arising from chromaffin cells, which have the ability to synthesize, store, and secrete catecholamines and neuropeptides. Individuals may present with secondary hypertension. In 2004, the World Health Organization characterized adrenal gland tumors as PHEOs.[<a class="bk_pop" href="#CDR0000062890_rl_850_1">1</a>] The term paraganglioma is reserved for non-adrenal (or extra-adrenal) neoplasms and may arise in various sites from the paraganglia along the parasympathetic nerves or the sympathetic trunk. PGLs may be found in the head and neck region, abdomen, or pelvis. Only those arising from sympathetic neural chains have secretory capacity. PGLs found in the skull base or head and neck region typically arise in the glomus cells, near the carotid body, along the vagal nerve or jugular fosse, and are usually from parasympathetic paraganglia and therefore rarely secrete catecholamines.[<a class="bk_pop" href="#CDR0000062890_rl_850_2">2</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_3">3</a>] The most recognizable tumors are found at the carotid body. PGLs below the neck are most commonly located in the upper mediastinum or the urinary bladder.[<a class="bk_pop" href="#CDR0000062890_rl_850_3">3</a>] The reported incidence of these tumors in the general population is variable because they may be asymptomatic but ranges from 1 in 30,000 to 1 in 100,000 individuals.[<a class="bk_pop" href="#CDR0000062890_rl_850_3">3</a>] One autopsy study found a much greater incidence of 1 in 2,000 individuals, suggesting a high frequency of occult tumors.[<a class="bk_pop" href="#CDR0000062890_rl_850_4">4</a>] PGLs have an equal sex distribution and can occur at any age but have the highest incidence between the ages of 40 and 50 years.[<a class="bk_pop" href="#CDR0000062890_rl_850_5">5</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_6">6</a>]</p></div><div id="CDR0000062890__852"><h3>Clinical Description</h3><p id="CDR0000062890__871">PGLs and PHEOs may occur sporadically, as a manifestation of a hereditary syndrome, or as the sole tumor in one of several hereditary PGL/PHEO syndromes. </p><p id="CDR0000062890__872">PGLs and PHEOs are typically slow-growing tumors, and some may be present for many years before coming to clinical attention. Conversely, a minority of these tumors may be malignant and present with a more aggressive clinical course. PGL and PHEO malignancy is defined by the presence of metastases at sites distant from the primary tumor in nonchromaffin tissue. Common sites of metastases include bone, liver, and lungs.[<a class="bk_pop" href="#CDR0000062890_rl_850_1">1</a>] </p><p id="CDR0000062890__1042">There are no reliable molecular, immunohistochemical, or genetic predictors to distinguish benign and malignant tumors,[<a class="bk_pop" href="#CDR0000062890_rl_850_7">7</a>] although some studies have shown a higher malignancy rate in <i>SDHB</i>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460132/" class="def">carriers</a> [<a class="bk_pop" href="#CDR0000062890_rl_850_8">8</a>] and in individuals with larger tumors.[<a class="bk_pop" href="#CDR0000062890_rl_850_9">9</a>] Some experts view local invasion into surrounding tissue as an additional marker of malignancy.[<a class="bk_pop" href="#CDR0000062890_rl_850_10">10</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_11">11</a>] Others have disagreed with this classification because locally invasive tumors tend to follow a more indolent course than tumors with distant metastatic involvement.[<a class="bk_pop" href="#CDR0000062890_rl_850_12">12</a>] Consequently, estimation of the rate of malignancy in PGLs is difficult; rates ranging from 5% to 20% have been reported.[<a class="bk_pop" href="#CDR0000062890_rl_850_13">13</a>-<a class="bk_pop" href="#CDR0000062890_rl_850_15">15</a>] </p></div><div id="CDR0000062890__877"><h3>Clinical Diagnosis of PGL and PHEO</h3><p id="CDR0000062890__874">A PGL may cause a variety of symptoms depending on the location of the tumor and whether the tumor has secretory capacity. PGLs of the head and neck are rarely associated with elevated catecholamines. Secretory PGLs and PHEOs may cause hypertension, headache, tachycardia, sweating, and flushing. Typically, nonsecretory tumors are painless, coming to attention only when growth of the lesion into surrounding structures causes a mass effect. Patients with a head or neck PGL may present with an enlarging lateral neck mass, hoarseness, Horner syndrome, pulsatile tinnitus, dizziness, facial droop, or blurred vision.[<a class="bk_pop" href="#CDR0000062890_rl_850_1">1</a>]</p><p id="CDR0000062890__1043">Patients with clinically apparent catecholamine excess generally undergo biochemical testing to evaluate the secretory capacity of the tumor(s).[<a class="bk_pop" href="#CDR0000062890_rl_850_16">16</a>] This evaluation is best performed by measuring urine and/or plasma fractionated metanephrines (normetanephrine and metanephrine), which yields a higher <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000322883/" class="def">sensitivity</a> and <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000322884/" class="def">specificity</a> than directly measuring catecholamines (norepinephrine, dopamine, and epinephrine).[<a class="bk_pop" href="#CDR0000062890_rl_850_17">17</a>-<a class="bk_pop" href="#CDR0000062890_rl_850_19">19</a>] For patients whose plasma metanephrines levels are measured, blood is collected after an intravenous catheter has been inserted and the patient has been in a supine position for 15 to 20 minutes.[<a class="bk_pop" href="#CDR0000062890_rl_850_20">20</a>] Additionally, the patient should not have food or caffeinated beverages, smoke cigarettes, or engage in strenuous physical activity in the 8 to 12 hours before the blood draw.[<a class="bk_pop" href="#CDR0000062890_rl_850_20">20</a>]</p><p id="CDR0000062890__875">Imaging of PGLs is the mainstay of diagnosis; the initial evaluation includes computed tomography (CT) of the neck and chest. Magnetic resonance imaging (MRI) also has utility for the head and neck. PGLs typically appear homogeneous with intense enhancement after administration of intravenous contrast. MRI may also be used to distinguish the tumor from adjacent vascular and skeletal structures. On T2-weighted images, a tumor that is larger than 2 cm is likely to display a classic "salt and pepper" appearance, a reflection of scattered areas of signal void mingled with areas of high signal intensity from increased vascularity.[<a class="bk_pop" href="#CDR0000062890_rl_850_21">21</a>] </p><p id="CDR0000062890__876">Nuclear imaging, particularly somatostatin receptor scintigraphy in combination with anatomic imaging, may be useful for localization and determination of the extent of disease (multifocality vs. distant metastatic deposits).[<a class="bk_pop" href="#CDR0000062890_rl_850_22">22</a>] <sup>123</sup>I-metaiodobenzylguanidine (MIBG) plus positron emission tomography–computed tomography (PET-CT) is very specific for PGLs. Functional imaging for PGLs and/or PHEOs with 18F-dihydroxyphenylalanine (18F-DOPA), 18F-fluorodopamine, or PET-CT may be particularly helpful in localizing head and neck tumors. Data suggest that the selection of PET tracer utilized for tumor localization should be centered on the patient’s genetic status, based on the metabolic activity of the various tumors.[<a class="bk_pop" href="#CDR0000062890_rl_850_8">8</a>] It has been suggested that patients with <i>SDHx</i> and <i>VHL</i>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000046063/" class="def">mutations</a> are more likely to have higher 18F-fluorodeoxyglucose activity, which is related to gene activation in response to hypoxia.[<a class="bk_pop" href="#CDR0000062890_rl_850_8">8</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_23">23</a>] Some <i>SDHB</i> tumors only weakly concentrate 18F-DOPA, and patients with <i>SDHx</i> mutations may have false-negative results with such scans. Tumors with <i>VHL</i> mutations may likewise be missed with metaiodobenzylguanidine scans.[<a class="bk_pop" href="#CDR0000062890_rl_850_8">8</a>] </p><p id="CDR0000062890__1050">Imaging of PHEOs usually consists of a dedicated CT of the adrenal gland. When biochemical screening in an individual who has or is at risk of multiple endocrine neoplasia type 2 (MEN2) suggests PHEO, localization studies, such as MRI or CT, can be performed.[<a class="bk_pop" href="#CDR0000062890_rl_850_24">24</a>] Confirmation of the diagnosis can be made using <sup>131</sup>I-MIBG scintigraphy or PET imaging.[<a class="bk_pop" href="#CDR0000062890_rl_850_24">24</a>-<a class="bk_pop" href="#CDR0000062890_rl_850_27">27</a>]</p></div><div id="CDR0000062890__853"><h3>Genetics, Inheritance, and Genetic Testing</h3><p id="CDR0000062890__1044">A significant proportion of individuals presenting with apparently sporadic PHEO or PGL are carriers of <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460154/" class="def">germline</a> genetic mutations. Up to 33% of patients with apparently sporadic PHEO, and up to 40% of patients with apparently sporadic PGLs, actually have a recognizable germline mutation in one of the known PGL/PHEO <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460209/" class="def">susceptibility genes</a>.[<a class="bk_pop" href="#CDR0000062890_rl_850_14">14</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_28">28</a>-<a class="bk_pop" href="#CDR0000062890_rl_850_32">32</a>] One study found that in individuals with a single tumor and a negative <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000302456/" class="def">family history</a>, the likelihood of an inherited mutation was 11.6%,[<a class="bk_pop" href="#CDR0000062890_rl_850_14">14</a>] whereas other groups detected mutations in 41% of such patients.[<a class="bk_pop" href="#CDR0000062890_rl_850_32">32</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_33">33</a>] All patients with PHEO or PGL, even those with apparently sporadic tumors, may be considered for genetic testing because of the high frequency of genetic mutations associated with these conditions.[<a class="bk_pop" href="#CDR0000062890_rl_850_34">34</a>]</p><p id="CDR0000062890__919">PGLs and PHEOs can be seen as part of several well-described tumor susceptibility syndromes including <a href="/books/n/pdqcis/CDR0000574548/#CDR0000574548__29">von Hippel-Lindau</a> (VHL), MEN2, neurofibromatosis type 1, Carney-Stratakis syndrome, and familial paraganglioma (FPGL) syndrome. FPGL is most commonly caused by mutations in one of the following four genes: <i>SDHA</i>, <i>SDHB</i>, <i>SDHC</i>, and <i>SDHD</i> (collectively referred to as <i>SDHx</i>). The SDHx proteins form part of the succinate dehydrogenase (SDH) complex, which is located on the inner mitochondrial membrane and plays a critical role in cellular energy metabolism.[<a class="bk_pop" href="#CDR0000062890_rl_850_35">35</a>] Mutations in <i>SDHB</i> are most common, followed by <i>SDHD</i> and rarely <i>SDHC</i> and <i>SDHA</i>. More recently, mutations in the <i>SDHAF2</i> (also called <i>SDH5</i>), <i>TMEM127</i>, and <i>MAX</i> genes have been described in FPGL/PHEO,[<a class="bk_pop" href="#CDR0000062890_rl_850_36">36</a>-<a class="bk_pop" href="#CDR0000062890_rl_850_39">39</a>] but these mutations are rare. The mechanism of tumor formation has remained elusive. One study suggests that <i>SDHx</i>-associated tumors display a hypermethylator <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460203/" class="def">phenotype</a> that is associated with downregulation of important genes involved in the differentiation of neuroendocrine tissues.[<a class="bk_pop" href="#CDR0000062890_rl_850_40">40</a>]</p><p id="CDR0000062890__920">The inheritance pattern of FPGL depends on the gene involved. While most families show traditional <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339338/" class="def">autosomal dominant</a> inheritance, those with mutations in <i>SDHAF2</i> and <i>SDHD</i> show almost exclusive paternal transmission of the phenotype. In other words, while the mutation can be passed down from mother or father, tumors will develop only if the mutation is inherited from the father.[<a class="bk_pop" href="#CDR0000062890_rl_850_41">41</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_42">42</a>] In cases of FPGL not caused by <i>SDHD</i> or <i>SDHAF2</i> mutations, <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460150/" class="def">first-degree relatives</a> (FDRs) of an <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460124/" class="def">affected</a> individual have a 50% chance of carrying the mutation and are at increased risk of developing PGLs. Because the family history can appear negative in families with lower <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339344/" class="def">penetrance</a> mutations, it is important to offer genetic testing to all <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460224/" class="def">unaffected</a> FDRs once the mutation in the family has been identified. </p><p id="CDR0000062890__921">Genetic testing for hereditary PHEO and PGL syndromes is largely based on published algorithms,[<a class="bk_pop" href="#CDR0000062890_rl_850_34">34</a>] whereby testing is performed stepwise based on factors such as tumor type and location, age at diagnosis, family history, and presence of malignancy.[<a class="bk_pop" href="#CDR0000062890_rl_850_14">14</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_43">43</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_44">44</a>] This approach has allowed for cost-effective, targeted testing based on clinical features. Within the last several years, however, <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000763024/" class="def">next-generation sequencing</a> (NGS) technology has led to a dramatic decrease in the cost of genetic testing, and testing for mutations in 10 to 30 genes for the same cost of testing two or three genesis now possible. These tests may be more appropriate for individuals and families who have an atypical presentation or overlapping clinical features. If the cost associated with multigene testing panels continues to decrease, the testing algorithms may soon be obsolete for PGL and PHEO. A recent series analyzed 85 PGL and PHEO samples using an NGS panel test for the ten known PGL susceptibility genes and showed a sensitivity of 98.7%.[<a class="bk_pop" href="#CDR0000062890_rl_850_45">45</a>]</p></div><div id="CDR0000062890__854"><h3>Genotype-Phenotype Correlations</h3><p id="CDR0000062890__922">In FPGL/PHEO, the type and location of tumors, age at onset, and lifetime penetrance vary depending on the gene that is mutated. While these correlations can help guide genetic testing and screening decisions, caution must be used given the high degree of variability seen in this condition. FPGL/PHEO syndromes are among the rare inherited diseases in which <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339334/" class="def">genomic imprinting</a> occurs. For example, the <i>SDHD</i> mutation is normally not activated when inherited from the mother, and the risk of FPGL/PHEO syndromes is not increased. However, the mutation is turned on when the gene is inherited from the father, and the risk is increased.</p><p id="CDR0000062890__923"><i>SDHD</i> mutations are mainly associated with an increased risk of parasympathetic PGLs. These are more commonly multifocal and located in the head and neck, while tumors in <i>SDHB</i> carriers are more often located in the abdomen.[<a class="bk_pop" href="#CDR0000062890_rl_850_46">46</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_47">47</a>] One series showed a risk of 71% for a head and neck tumor in <i>SDHD</i> carriers, as opposed to a 29% risk in <i>SDHB</i> carriers. The lifetime risk for any PGL in any location in <i>SDHD</i> carriers was estimated to be as high as 77% by age 50 years in one series [<a class="bk_pop" href="#CDR0000062890_rl_850_46">46</a>] and 90% by age 70 years in a second series.[<a class="bk_pop" href="#CDR0000062890_rl_850_47">47</a>] A review of more than 1,700 cases reported in the literature provided similar estimates, suggesting a lifetime penetrance of 86%.[<a class="bk_pop" href="#CDR0000062890_rl_850_48">48</a>] The rate of malignancy in <i>SDHD</i> carriers is lower than 5%.[<a class="bk_pop" href="#CDR0000062890_rl_850_48">48</a>]</p><p id="CDR0000062890__917">Mutations in the <i>SDHB</i> gene are associated with sympathetic PGLs, although PHEO and parasympathetic PGLs also have been described. <i>SDHB</i> PGLs are more commonly located in the abdomen and mediastinum than in the head and neck. A review of 1,700 cases suggested a lifetime penetrance of 77%.[<a class="bk_pop" href="#CDR0000062890_rl_850_48">48</a>] The rate of malignancy is higher with <i>SDHB</i> than with the other <i>SDH</i> genes, with up to one-third of patients having malignant tumors in most series.[<a class="bk_pop" href="#CDR0000062890_rl_850_46">46</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_47">47</a>] Mutations in <i>SDHB</i> have also been associated with several other tumors and malignancies, including gastrointestinal stromal tumors (GISTs), renal cell carcinoma, and papillary thyroid cancer.[<a class="bk_pop" href="#CDR0000062890_rl_850_46">46</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_47">47</a>]</p><p id="CDR0000062890__924"><i>SDHC</i> mutations are rare, accounting for an estimated 0.5% of all PGLs.[<a class="bk_pop" href="#CDR0000062890_rl_850_48">48</a>] In one series of 153 patients with multiple PGLs or a single PGL diagnosed before age 40 years, three (2%) had an <i>SDHC</i> mutation.[<a class="bk_pop" href="#CDR0000062890_rl_850_29">29</a>] Another series of 121 index cases from a head and neck PGL registry showed a mutation rate of 4% (5 of 121).[<a class="bk_pop" href="#CDR0000062890_rl_850_49">49</a>] <i>SDHC</i> mutations most commonly cause head and neck PGLs but have been seen in a small number of patients with abdominal PGLs.[<a class="bk_pop" href="#CDR0000062890_rl_850_14">14</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_50">50</a>] Mutations in <i>SDHB</i>, <i>SDHC</i>, and <i>SDHD</i> can also cause Carney-Stratakis syndrome, which is characterized by the dyad of PGLs and GISTs.[<a class="bk_pop" href="#CDR0000062890_rl_850_51">51</a>]</p><p id="CDR0000062890__925">Mutations in <i>SDHA</i>, <i>SDAHF2</i>, <i>MAX</i>, and <i>TMEM127</i> have been described in a small number of cases. Collectively, they account for less than 2% to 3% of all cases. Although biallelic mutations in <i>SDHA</i> have long been known to cause the <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339339/" class="def">autosomal recessive</a> condition inherited juvenile encephalopathy/Leigh syndrome,[<a class="bk_pop" href="#CDR0000062890_rl_850_52">52</a>] it was not until recently that monoallelic mutations were linked to an increased risk of developing PGL. Only a handful of cases have been described. Tumors can develop in the head and neck, the adrenal glands, or in the abdomen (extra-adrenal).[<a class="bk_pop" href="#CDR0000062890_rl_850_53">53</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_54">54</a>] The <i>SDHAF2</i> gene encodes a protein that is responsible for flavination of SDHA and proper functioning of the SDHA subunit of the SDH complex. To date, mutations in <i>SDHAF2</i> have been described in fewer than 20 cases and only with head and neck PGLs.[<a class="bk_pop" href="#CDR0000062890_rl_850_39">39</a>] The <i>MAX</i> gene was first described as a PHEO susceptibility gene in 2011 through exome sequencing of three unrelated cases.[<a class="bk_pop" href="#CDR0000062890_rl_850_36">36</a>] Three different germline mutations were identified, and a follow-up series of 59 cases by the same group identified an additional five mutations. The MAX protein is part of MYC-MAX-MXD1 network, which plays a key role in the development and progression of neural crest cell tumors.[<a class="bk_pop" href="#CDR0000062890_rl_850_55">55</a>] The <i>TMEM127</i> gene is located on chromosome 2q11.2 and encodes a transmembrane protein known to be a negative regulator of mTOR, which regulates multiple cellular processes. A review of 23 patients with <i>TMEM127</i> mutations showed that 96% (22 of 23) had a PHEO and 9% (2 of 23) had a PGL.[<a class="bk_pop" href="#CDR0000062890_rl_850_48">48</a>]</p></div><div id="CDR0000062890__1024"><h3>Surveillance</h3><p id="CDR0000062890__1030">Patients with an identified germline mutation in one of the <i>SDH</i> genes are at a significantly increased risk of developing PGLs, PHEOs, renal tumors, and GISTs. PHEOs and PGLs typically have a slow growth pattern, but unchecked growth can lead to mass effect and, ultimately, neurologic compromise. Further, although most of these tumors are benign, some may undergo malignant transformation. As such, periodic screening for interval development of a tumor is of critical importance because early detection and removal can minimize risk to the patient. Although limited studies have been performed to delineate the ideal protocol, total-body MRI has been proposed as a reasonable method for screening because of its high sensitivity and minimal radiation exposure.[<a class="bk_pop" href="#CDR0000062890_rl_850_34">34</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_56">56</a>] In one study, 37 <i>SDHx</i> mutation carriers underwent annual biochemical testing and annual or biennial whole-body MRI beginning at age 10 years.[<a class="bk_pop" href="#CDR0000062890_rl_850_57">57</a>] This screening protocol identified six tumors in five patients. The sensitivity of MRI was 87.5%, and the specificity was 94.7%. The sensitivity of biochemical testing was significantly lower at 37.5%, with a specificity similar to MRI at 94.9%.[<a class="bk_pop" href="#CDR0000062890_rl_850_57">57</a>] A more-recent retrospective study of 157 patients evaluated a rapid contrast-enhanced angio-MRI protocol for the detection of head and neck paragangliomas in <i>SDH</i> mutation carriers.[<a class="bk_pop" href="#CDR0000062890_rl_850_58">58</a>] This protocol had a high sensitivity and specificity of 88.7% and 93.7%, respectively.</p><p id="CDR0000062890__1046">Although the optimal imaging protocol for surveillance in <i>SDHx</i> mutation carriers remains unclear, annual biochemical testing and clinical surveillance may be considered. Biochemical testing can be performed by measuring plasma-free metanephrines/catecholamines or 24-hour urinary excretion of fractionated catecholamines (including methoxytyramine, a dopamine metabolite, if available). Clinical surveillance may include physical examination and blood pressure measurement. Clinical surveillance and biochemical testing may begin between ages 5 years and 10 years, or 10 years earlier than the earliest age at diagnosis in the family.[<a class="bk_pop" href="#CDR0000062890_rl_850_59">59</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_60">60</a>]</p></div><div id="CDR0000062890__855"><h3>Interventions</h3><div id="CDR0000062890__931"><h4>Preoperative management</h4><p id="CDR0000062890__933">Medical management is the bridge to surgical resection of PGLs/PHEOs. Preoperative medical therapy is not essential for patients without evidence of catecholamine hypersecretion, although some advocate its use regardless of the results of hormonal testing.[<a class="bk_pop" href="#CDR0000062890_rl_850_20">20</a>] The aim of pharmacologic therapy is to control hypertension for at least 10 to 14 days before surgery.[<a class="bk_pop" href="#CDR0000062890_rl_850_61">61</a>] Management is aimed at preventing catecholamine-induced complications, even in patients who may not present with preoperative hypertension, to avoid intraoperative hypertensive crisis, cardiac arrhythmias, pulmonary edema, and cardiac ischemia. Failure to adequately block the catecholamine excess can dramatically increase the risk of perioperative mortality from hypertensive crisis and lethal arrhythmias and cause hypotensive crisis after tumor removal.[<a class="bk_pop" href="#CDR0000062890_rl_850_62">62</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_63">63</a>]</p><p id="CDR0000062890__934">In the absence of a randomized controlled trial comparing the various regimens, there is no universally recommended approach. The alpha-adrenoreceptor blocker phenoxybenzamine (Dibenzyline) is most frequently used to control blood pressure and expand the blood volume.[<a class="bk_pop" href="#CDR0000062890_rl_850_20">20</a>] Other alpha-blocking drugs have also been used with success, including prazosin, terazosin, or doxazosin; these drugs are more specific alpha-1 adrenergic competitive antagonists and have a shorter half-life than phenoxybenzamine.[<a class="bk_pop" href="#CDR0000062890_rl_850_64">64</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_65">65</a>] The noncompetitive binding of phenoxybenzamine to the alpha receptors, coupled with its longer half-life, may result in a sustained effect of the drug, with some patients experiencing postoperative hypotension.[<a class="bk_pop" href="#CDR0000062890_rl_850_20">20</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_66">66</a>] One study found that patients treated with sustained-release doxazosin had more stable perioperative hemodynamic changes and a shorter time interval to preoperative blood pressure control than did patients who received phenoxybenzamine.[<a class="bk_pop" href="#CDR0000062890_rl_850_66">66</a>]</p><p id="CDR0000062890__935">Once the alpha blockade is initiated, expansion of the blood volume is often necessary, as these patients are typically volume contracted.[<a class="bk_pop" href="#CDR0000062890_rl_850_67">67</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_68">68</a>] In addition to the vasodilatory effects from alpha blockade, volume expansion may be achieved by consuming a high-sodium diet and high fluid intake or a preoperative saline infusion. A clinical manifestation of adequate blockade is the symptom of nasal stuffiness or lightheadedness. </p><p id="CDR0000062890__937">Calcium channel blockers such as nicardipine or nifedipine also have been employed to control the hypertension preoperatively.[<a class="bk_pop" href="#CDR0000062890_rl_850_69">69</a>] A calcium channel blocker may be used in conjunction with alpha and beta blockade for refractory hypertension or used alone as a second-line agent for patients with intolerable side effects from alpha blockade.[<a class="bk_pop" href="#CDR0000062890_rl_850_20">20</a>] </p></div><div id="CDR0000062890__1051"><h4>Surgery</h4><p id="CDR0000062890__1047">Surgical resection is the treatment of choice for PGL and PHEO. Both open resection and laparoscopic approaches are safe, but if feasible, laparoscopic removal is preferred.[<a class="bk_pop" href="#CDR0000062890_rl_850_59">59</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_70">70</a>] Open resection is commonly recommended for large tumors (>6 cm–7 cm) because of the increased risk of technical difficulty within the confined space of laparoscopy. Means of exposure and approach are based on the anatomic location of the tumor. Direct access to the adrenal and para-aortic region can be achieved with the posterior approach. It is direct, safe, and efficient.[<a class="bk_pop" href="#CDR0000062890_rl_850_71">71</a>]
|
|
Adequate exposure of the complete tumor is important for complete removal. Robotic assistance can be utilized in select cases because it offers a three-dimensional, magnified view of the anatomy.[<a class="bk_pop" href="#CDR0000062890_rl_850_72">72</a>] The efficacy and safety of posterior retroperitoneoscopic adrenalectomy is established, but ongoing studies are examining the relevance of this approach in familial syndromes (see <a href="https://clinicaltrials.gov/ct2/show/NCT02618694" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT02618694</a>).</p><p id="CDR0000062890__1048">PGLs are commonly located in the para-aortic retroperitoneal sympathetic chain above the aortic bifurcation, below the takeoff of the inferior mesenteric artery (organ of Zuckerkandl), or near the dome of the bladder.[<a class="bk_pop" href="#CDR0000062890_rl_850_73">73</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_74">74</a>] Malignant PGLs have a dense fibrous capsule that may be adherent to surrounding vascularity, which can make complete resection difficult.[<a class="bk_pop" href="#CDR0000062890_rl_850_74">74</a>] Regional lymph nodes may be involved with malignant tumors, and if suspected preoperatively or noted intraoperatively, a regional lymphadenectomy should be performed.</p><p id="CDR0000062890__1049">Genetic testing is best performed before the initial surgery to inform the risk of recurrent or contralateral disease and to guide the extent of resection (e.g., whether to preserve the cortex) because synchronous or metachronous bilateral disease is quite common in hereditary PHEO. In one retrospective series that spanned nearly 50 years, 15 of the 49 patients (30%) who presented with a unilateral PHEO and underwent unilateral total adrenalectomy developed PHEO in the contralateral gland at a median of 8.2 years (range, 1–20 years) after initial diagnosis.[<a class="bk_pop" href="#CDR0000062890_rl_850_75">75</a>] Of the 15 patients who developed PHEO in the contralateral gland, 8 had MEN2A, 2 had MEN2B, 2 had VHL, and 1 had familial PHEO. The risk of developing a contralateral tumor increased over time, with 25% of patients developing tumors after a median of 6 years and 43% after a median of 32 years. Cortical-sparing surgery is an attractive option because it minimizes the risk of adrenal insufficiency and the need for lifelong steroid supplementation. In large series of patients, cortical-sparing surgery has a 3% to 7% recurrence rate after cortical preservation versus a 2% to 3% recurrence rate after total resection (recurrence in the adrenal bed).[<a class="bk_pop" href="#CDR0000062890_rl_850_75">75</a>,<a class="bk_pop" href="#CDR0000062890_rl_850_76">76</a>] The frequency of steroid dependence in both studies was lower in patients who underwent cortical-sparing techniques than in patients who did not (57% compared to 86%). One of 39 patients (3%) developed adrenal insufficiency after a cortical-sparing procedure; 5 of 25 patients (20%) developed adrenal insufficiency after total adrenalectomy.[<a class="bk_pop" href="#CDR0000062890_rl_850_75">75</a>] These study authors recommend cortical-sparing surgery as a viable option for patients with hereditary PHEO, including patients who initially present with seemingly unilateral disease.</p><p id="CDR0000062890__1025"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531846/" class="def">Level of evidence: 5</a></p></div></div><div id="CDR0000062890_rl_850"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062890_rl_850_1">DeLellis RA, Lloyd RV, Heitz PU, et al., eds.: Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press, 2004. World Health Organization classification of tumours, vol. 8.</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_2">Offergeld C, Brase C, Yaremchuk S, et al.: Head and neck paragangliomas: clinical and molecular genetic classification. Clinics (Sao Paulo) 67 (Suppl 1): 19-28, 2012. [<a href="/pmc/articles/PMC3328838/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3328838</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22584701" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22584701</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_3">Raygada M, Pasini B, Stratakis CA: Hereditary paragangliomas. Adv Otorhinolaryngol 70: 99-106, 2011. [<a href="/pmc/articles/PMC4221053/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4221053</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21358191" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21358191</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_4">McNeil AR, Blok BH, Koelmeyer TD, et al.: Phaeochromocytomas discovered during coronial autopsies in Sydney, Melbourne and Auckland. Aust N Z J Med 30 (6): 648-52, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11198571" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11198571</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_5">O'Riordain DS, Young WF Jr, Grant CS, et al.: Clinical spectrum and outcome of functional extraadrenal paraganglioma. World J Surg 20 (7): 916-21; discussion 922, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8678971" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8678971</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_6">Erickson D, Kudva YC, Ebersold MJ, et al.: Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab 86 (11): 5210-6, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11701678" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11701678</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_7">Jovanovic R, Kostadinova-Kunovska S, Bogoeva B, et al.: Histological features, Ki-67 and Bcl-2 immunohistochemical expression and their correlation with the aggressiveness of pheochromocytomas. Prilozi 33 (2): 23-40, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/23425867" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23425867</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_8">Taïeb D, Neumann H, Rubello D, et al.: Modern nuclear imaging for paragangliomas: beyond SPECT. J Nucl Med 53 (2): 264-74, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22302963" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22302963</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_9">Eisenhofer G, Lenders JW, Siegert G, et al.: Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer 48 (11): 1739-49, 2012. [<a href="/pmc/articles/PMC3372624/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3372624</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22036874" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22036874</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_10">Eisenhofer G, Bornstein SR, Brouwers FM, et al.: Malignant pheochromocytoma: current status and initiatives for future progress. Endocr Relat Cancer 11 (3): 423-36, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15369446" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15369446</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_11">Zarnegar R, Kebebew E, Duh QY, et al.: Malignant pheochromocytoma. Surg Oncol Clin N Am 15 (3): 555-71, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16882497" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16882497</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_12">Medeiros LJ, Wolf BC, Balogh K, et al.: Adrenal pheochromocytoma: a clinicopathologic review of 60 cases. Hum Pathol 16 (6): 580-9, 1985. [<a href="https://pubmed.ncbi.nlm.nih.gov/3997135" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3997135</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_13">Walz MK, Alesina PF, Wenger FA, et al.: Laparoscopic and retroperitoneoscopic treatment of pheochromocytomas and retroperitoneal paragangliomas: results of 161 tumors in 126 patients. World J Surg 30 (5): 899-908, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16617419" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16617419</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_14">Mannelli M, Castellano M, Schiavi F, et al.: Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab 94 (5): 1541-7, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19223516" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19223516</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_15">Lee JH, Barich F, Karnell LH, et al.: National Cancer Data Base report on malignant paragangliomas of the head and neck. Cancer 94 (3): 730-7, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11857306" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11857306</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_16">Grossman A, Pacak K, Sawka A, et al.: Biochemical diagnosis and localization of pheochromocytoma: can we reach a consensus? Ann N Y Acad Sci 1073: 332-47, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17102103" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17102103</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_17">Lenders JW, Pacak K, Walther MM, et al.: Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 287 (11): 1427-34, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11903030" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11903030</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_18">Eisenhofer G, Lenders JW, Linehan WM, et al.: Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. N Engl J Med 340 (24): 1872-9, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10369850" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10369850</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_19">Sawka AM, Jaeschke R, Singh RJ, et al.: A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 88 (2): 553-8, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12574179" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12574179</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_20">Chen H, Sippel RS, O'Dorisio MS, et al.: The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas 39 (6): 775-83, 2010. [<a href="/pmc/articles/PMC3419007/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3419007</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20664475" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20664475</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_21">Olsen WL, Dillon WP, Kelly WM, et al.: MR imaging of paragangliomas. AJR Am J Roentgenol 148 (1): 201-4, 1987. [<a href="https://pubmed.ncbi.nlm.nih.gov/3024473" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3024473</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_22">Gimenez-Roqueplo AP, Dahia PL, Robledo M: An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm Metab Res 44 (5): 328-33, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22328163" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22328163</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_23">Span PN, Rao JU, Oude Ophuis SB, et al.: Overexpression of the natural antisense hypoxia-inducible factor-1alpha transcript is associated with malignant pheochromocytoma/paraganglioma. Endocr Relat Cancer 18 (3): 323-31, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21422080" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21422080</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_24">Pacak K, Eisenhofer G, Ahlman H, et al.: Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab 3 (2): 92-102, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17237836" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17237836</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_25">Lips CJ, Landsvater RM, Höppener JW, et al.: Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 331 (13): 828-35, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/7915822" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7915822</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_26">van der Harst E, de Herder WW, Bruining HA, et al.: [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas. J Clin Endocrinol Metab 86 (2): 685-93, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11158032" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11158032</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_27">Pacak K, Linehan WM, Eisenhofer G, et al.: Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 134 (4): 315-29, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11182843" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11182843</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_28">Jafri M, Whitworth J, Rattenberry E, et al.: Evaluation of SDHB, SDHD and VHL gene susceptibility testing in the assessment of individuals with non-syndromic phaeochromocytoma, paraganglioma and head and neck paraganglioma. Clin Endocrinol (Oxf) 78 (6): 898-906, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23072324" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23072324</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_29">Pęczkowska M, Kowalska A, Sygut J, et al.: Testing new susceptibility genes in the cohort of apparently sporadic phaeochromocytoma/paraganglioma patients with clinical characteristics of hereditary syndromes. Clin Endocrinol (Oxf) 79 (6): 817-23, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23551045" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23551045</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_30">Karasek D, Frysak Z, Pacak K: Genetic testing for pheochromocytoma. Curr Hypertens Rep 12 (6): 456-64, 2010. [<a href="/pmc/articles/PMC3061287/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3061287</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20938758" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20938758</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_31">Neumann HP, Bausch B, McWhinney SR, et al.: Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346 (19): 1459-66, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12000816" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12000816</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_32">Fishbein L, Merrill S, Fraker DL, et al.: Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol 20 (5): 1444-50, 2013. [<a href="/pmc/articles/PMC4291281/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4291281</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23512077" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23512077</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_33">Bacca A, Sellari Franceschini S, Carrara D, et al.: Sporadic or familial head neck paragangliomas enrolled in a single center: clinical presentation and genotype/phenotype correlations. Head Neck 35 (1): 23-7, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/22290790" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22290790</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_34">Lenders JW, Duh QY, Eisenhofer G, et al.: Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 99 (6): 1915-42, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24893135" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24893135</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_35">Hussain I, Husain Q, Baredes S, et al.: Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management. J Neurosurg 120 (2): 321-30, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24236653" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24236653</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_36">Comino-Méndez I, Gracia-Aznárez FJ, Schiavi F, et al.: Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 43 (7): 663-7, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21685915" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21685915</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_37">Neumann HP, Sullivan M, Winter A, et al.: Germline mutations of the TMEM127 gene in patients with paraganglioma of head and neck and extraadrenal abdominal sites. J Clin Endocrinol Metab 96 (8): E1279-82, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21613359" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21613359</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_38">Burnichon N, Lepoutre-Lussey C, Laffaire J, et al.: A novel TMEM127 mutation in a patient with familial bilateral pheochromocytoma. Eur J Endocrinol 164 (1): 141-5, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/20923864" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20923864</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_39">Bayley JP, Kunst HP, Cascon A, et al.: SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol 11 (4): 366-72, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20071235" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20071235</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_40">Letouzé E, Martinelli C, Loriot C, et al.: SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23 (6): 739-52, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23707781" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23707781</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_41">van der Mey AG, Maaswinkel-Mooy PD, Cornelisse CJ, et al.: Genomic imprinting in hereditary glomus tumours: evidence for new genetic theory. Lancet 2 (8675): 1291-4, 1989. [<a href="https://pubmed.ncbi.nlm.nih.gov/2574254" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2574254</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_42">Baysal BE: Mitochondrial complex II and genomic imprinting in inheritance of paraganglioma tumors. Biochim Biophys Acta 1827 (5): 573-7, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23291190" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23291190</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_43">Amar L, Bertherat J, Baudin E, et al.: Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23 (34): 8812-8, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16314641" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16314641</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_44">Neumann HP, Erlic Z, Boedeker CC, et al.: Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res 69 (8): 3650-6, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19351833" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19351833</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_45">Rattenberry E, Vialard L, Yeung A, et al.: A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 98 (7): E1248-56, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23666964" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23666964</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_46">Neumann HP, Pawlu C, Peczkowska M, et al.: Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292 (8): 943-51, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15328326" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15328326</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_47">Ricketts CJ, Forman JR, Rattenberry E, et al.: Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat 31 (1): 41-51, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/19802898" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19802898</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_48">Welander J, Söderkvist P, Gimm O: Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocr Relat Cancer 18 (6): R253-76, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/22041710" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22041710</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_49">Schiavi F, Boedeker CC, Bausch B, et al.: Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA 294 (16): 2057-63, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16249420" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16249420</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_50">Peczkowska M, Cascon A, Prejbisz A, et al.: Extra-adrenal and adrenal pheochromocytomas associated with a germline SDHC mutation. Nat Clin Pract Endocrinol Metab 4 (2): 111-5, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18212813" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18212813</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_51">Pasini B, McWhinney SR, Bei T, et al.: Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 16 (1): 79-88, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/17667967" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17667967</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_52">Horváth R, Abicht A, Holinski-Feder E, et al.: Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA). J Neurol Neurosurg Psychiatry 77 (1): 74-6, 2006. [<a href="/pmc/articles/PMC2117401/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2117401</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16361598" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16361598</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_53">Burnichon N, Brière JJ, Libé R, et al.: SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 19 (15): 3011-20, 2010. [<a href="/pmc/articles/PMC2901140/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2901140</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20484225" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20484225</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_54">Korpershoek E, Favier J, Gaal J, et al.: SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab 96 (9): E1472-6, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21752896" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21752896</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_55">Grandori C, Cowley SM, James LP, et al.: The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu Rev Cell Dev Biol 16: 653-99, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11031250" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11031250</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_56">Schiffman JD: No child left behind in SDHB testing for paragangliomas and pheochromocytomas. J Clin Oncol 29 (31): 4070-2, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21969491" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21969491</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_57">Jasperson KW, Kohlmann W, Gammon A, et al.: Role of rapid sequence whole-body MRI screening in SDH-associated hereditary paraganglioma families. Fam Cancer 13 (2): 257-65, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/23934599" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23934599</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_58">Gravel G, Niccoli P, Rohmer V, et al.: The value of a rapid contrast-enhanced angio-MRI protocol in the detection of head and neck paragangliomas in SDHx mutations carriers: a retrospective study on behalf of the PGL.EVA investigators. Eur Radiol 26 (6): 1696-704, 2016. [<a href="https://pubmed.ncbi.nlm.nih.gov/26427697" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26427697</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_59">Timmers HJ, Gimenez-Roqueplo AP, Mannelli M, et al.: Clinical aspects of SDHx-related pheochromocytoma and paraganglioma. Endocr Relat Cancer 16 (2): 391-400, 2009. [<a href="/pmc/articles/PMC4711350/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4711350</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19190077" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19190077</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_60">Lefebvre M, Foulkes WD: Pheochromocytoma and paraganglioma syndromes: genetics and management update. Curr Oncol 21 (1): e8-e17, 2014. [<a href="/pmc/articles/PMC3921052/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3921052</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24523625" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24523625</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_61">Pacak K: Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab 92 (11): 4069-79, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17989126" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17989126</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_62">GRAHAM JB: Pheochromocytoma and hypertension; an analysis of 207 cases. Int Abstr Surg 92 (2): 105-21, 1951. [<a href="https://pubmed.ncbi.nlm.nih.gov/14823753" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14823753</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_63">Goldstein RE, O'Neill JA Jr, Holcomb GW 3rd, et al.: Clinical experience over 48 years with pheochromocytoma. Ann Surg 229 (6): 755-64; discussion 764-6, 1999. [<a href="/pmc/articles/PMC1420821/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1420821</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/10363888" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10363888</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_64">Miura Y, Yoshinaga K: Doxazosin: a newly developed, selective alpha 1-inhibitor in the management of patients with pheochromocytoma. Am Heart J 116 (6 Pt 2): 1785-9, 1988. [<a href="https://pubmed.ncbi.nlm.nih.gov/2904751" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2904751</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_65">Prys-Roberts C, Farndon JR: Efficacy and safety of doxazosin for perioperative management of patients with pheochromocytoma. World J Surg 26 (8): 1037-42, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12192533" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12192533</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_66">Zhu Y, He HC, Su TW, et al.: Selective α1-adrenoceptor antagonist (controlled release tablets) in preoperative management of pheochromocytoma. Endocrine 38 (2): 254-9, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/21046486" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21046486</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_67">Ross EJ, Prichard BN, Kaufman L, et al.: Preoperative and operative management of patients with phaeochromocytoma. Br Med J 1 (5534): 191-8, 1967. [<a href="/pmc/articles/PMC1840518/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1840518</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/4381157" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 4381157</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_68">Hack HA: The perioperative management of children with phaeochromocytoma. Paediatr Anaesth 10 (5): 463-76, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11012949" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11012949</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_69">Proye C, Thevenin D, Cecat P, et al.: Exclusive use of calcium channel blockers in preoperative and intraoperative control of pheochromocytomas: hemodynamics and free catecholamine assays in ten consecutive patients. Surgery 106 (6): 1149-54, 1989. [<a href="https://pubmed.ncbi.nlm.nih.gov/2588118" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2588118</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_70">Vargas HI, Kavoussi LR, Bartlett DL, et al.: Laparoscopic adrenalectomy: a new standard of care. Urology 49 (5): 673-8, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9145969" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9145969</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_71">Perrier ND, Kennamer DL, Bao R, et al.: Posterior retroperitoneoscopic adrenalectomy: preferred technique for removal of benign tumors and isolated metastases. Ann Surg 248 (4): 666-74, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18936580" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18936580</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_72">Dickson PV, Jimenez C, Chisholm GB, et al.: Posterior retroperitoneoscopic adrenalectomy: a contemporary American experience. J Am Coll Surg 212 (4): 659-65; discussion 665-7, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21463807" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21463807</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_73">Ober WB: Emil Zuckerkandl and his delightful little organ. Pathol Annu 18 Pt 1: 103-19, 1983. [<a href="https://pubmed.ncbi.nlm.nih.gov/6348671" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6348671</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_74">Mundschenk J, Lehnert H: Malignant pheochromocytoma. Exp Clin Endocrinol Diabetes 106 (5): 373-6, 1998. [<a href="https://pubmed.ncbi.nlm.nih.gov/9831301" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9831301</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_75">Grubbs EG, Rich TA, Ng C, et al.: Long-term outcomes of surgical treatment for hereditary pheochromocytoma. J Am Coll Surg 216 (2): 280-9, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23317575" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23317575</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_850_76">Castinetti F, Qi XP, Walz MK, et al.: Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study. Lancet Oncol 15 (6): 648-55, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24745698" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24745698</span></a>]</div></li></ol></div></div><div id="CDR0000062890__972"><h2 id="_CDR0000062890__972_">Carney-Stratakis Syndrome</h2><div id="CDR0000062890__973"><h3>Clinical Description</h3><p id="CDR0000062890__991">Carney-Stratakis syndrome (CSS; also known as Carney-Stratakis dyad) was first described in 2002. Although similarly named, this syndrome is distinctly different from Carney Complex and Carney Triad (see Table 7). CSS is characterized by an <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339338/" class="def">autosomal dominant</a>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000046063/" class="def">mutation</a> in the <i>succinate dehydrogenase</i> (<i>SDH</i>) subunit <i>B</i>, <i>C</i>, or <i>D</i> (<i>SDHx</i>) <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045693/" class="def">genes</a> that demonstrates incomplete <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339344/" class="def">penetrance</a>. <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460124/" class="def">Affected</a> individuals develop multifocal, locally aggressive gastrointestinal stromal tumors (GISTs) and multiple neck, intrathoracic, and intra-abdominal paragangliomas (PGLs) at relatively early ages.[<a class="bk_pop" href="#CDR0000062890_rl_972_1">1</a>-<a class="bk_pop" href="#CDR0000062890_rl_972_3">3</a>] CSS-associated GISTs and PGLs display <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460203/" class="def">phenotypes</a> that differ from their sporadically occurring, more-common counterparts; as a result, it is important to understand the unique features of imaging, treatment, and <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000496506/" class="def">surveillance</a> in patients with CSS.</p><div id="CDR0000062890__1007" class="table"><h3><span class="title">Table 7. Comparison of Carney-Stratakis Syndrome, Carney Triad, and Carney Complex</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65830.8/table/CDR0000062890__1007/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062890__1007_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Syndrome</th><th colspan="1" rowspan="1" style="vertical-align:top;">Inheritance Pattern</th><th colspan="1" rowspan="1" style="vertical-align:top;">Mean Age at Onset (y)</th><th colspan="1" rowspan="1" style="vertical-align:top;">Affected Sex</th><th colspan="1" rowspan="1" style="vertical-align:top;">Associated Lesions</th><th colspan="1" rowspan="1" style="vertical-align:top;">Mutations</th><th colspan="1" rowspan="1" style="vertical-align:top;">Tumor Behavior</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Carney-Stratakis Syndrome [<a class="bk_pop" href="#CDR0000062890_rl_972_1">1</a>,<a class="bk_pop" href="#CDR0000062890_rl_972_3">3</a>,<a class="bk_pop" href="#CDR0000062890_rl_972_4">4</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">AD</td><td colspan="1" rowspan="1" style="vertical-align:top;">23</td><td colspan="1" rowspan="1" style="vertical-align:top;">M, F</td><td colspan="1" rowspan="1" style="vertical-align:top;">Paraganglioma, stomach epithelioid GIST</td><td colspan="1" rowspan="1" style="vertical-align:top;">Germline <i>SDHx</i> mutations; no <i>KIT</i> or <i>PDGFRA</i> mutations</td><td colspan="1" rowspan="1" style="vertical-align:top;">GIST metastasis but protracted course; paraganglioma aggressive</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Carney Triad [<a class="bk_pop" href="#CDR0000062890_rl_972_4">4</a>-<a class="bk_pop" href="#CDR0000062890_rl_972_6">6</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">None</td><td colspan="1" rowspan="1" style="vertical-align:top;"><30</td><td colspan="1" rowspan="1" style="vertical-align:top;">>95% F</td><td colspan="1" rowspan="1" style="vertical-align:top;">Lung chondroma, paraganglioma, stomach epithelioid GIST</td><td colspan="1" rowspan="1" style="vertical-align:top;">No <i>KIT</i>, <i>PDGFRA</i>, or <i>SDHx</i> mutations</td><td colspan="1" rowspan="1" style="vertical-align:top;">GIST metastasis but protracted course</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Carney Complex [<a class="bk_pop" href="#CDR0000062890_rl_972_7">7</a>,<a class="bk_pop" href="#CDR0000062890_rl_972_8">8</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">AD</td><td colspan="1" rowspan="1" style="vertical-align:top;">20</td><td colspan="1" rowspan="1" style="vertical-align:top;">M, F</td><td colspan="1" rowspan="1" style="vertical-align:top;">Lentigines, myxomas, schwannoma, thyroid follicular adenomas or carcinoma, primary pigmented nodular adrenocortical disease, pituitary adenomas</td><td colspan="1" rowspan="1" style="vertical-align:top;">Germline <i>PRKAR1A</i> mutations</td><td colspan="1" rowspan="1" style="vertical-align:top;">N/A</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; GIST = gastrointestinal stromal tumor; F = female; M = male.</p></div></dd></dl></div></div></div></div><div id="CDR0000062890__975"><h3>Genetics, Inheritance, and Genetic Testing</h3><p id="CDR0000062890__994">The tumorigenesis of CSS-associated GISTs appears to involve succinate dehydrogenase deficiency rather than gain-of-function mutations in the <i>KIT</i> or <i>PDGFRA</i> gene, as is seen in the vast majority of GISTs.[<a class="bk_pop" href="#CDR0000062890_rl_972_9">9</a>] SDH deficiency is also a characteristic finding of pediatric-type GISTs; CSS-associated GISTs display clinical findings similar to these tumors, including young age at onset (median age, 19 years), specificity to the stomach, multifocality, and resistance to imatinib.[<a class="bk_pop" href="#CDR0000062890_rl_972_3">3</a>,<a class="bk_pop" href="#CDR0000062890_rl_972_10">10</a>-<a class="bk_pop" href="#CDR0000062890_rl_972_12">12</a>] Furthermore, tumor size and mitotic rate do not accurately predict metastatic potential or survival, as SDH-deficient GISTs frequently metastasize to regional lymph nodes, the peritoneal cavity, and the liver; however, long-term survival is common.[<a class="bk_pop" href="#CDR0000062890_rl_972_6">6</a>,<a class="bk_pop" href="#CDR0000062890_rl_972_13">13</a>] </p><p id="CDR0000062890__1001">Refer to the <a href="#CDR0000062890__853">Genetics, Inheritance, and Genetic Testing</a> section in the <a href="#CDR0000062890__850">Familial PGL</a> section of this summary for more information about genetic testing for the genes involved in CSS.</p></div><div id="CDR0000062890__1002"><h3>Surveillance</h3><p id="CDR0000062890__997">Although the natural history of CSS is poorly understood, experts recommend that ongoing surveillance include the following: close patient follow-up with annual history that focuses on symptoms of anemia and catecholamine excess, physical exam, biochemical analysis with plasma metanephrine level and chromogranin A to detect recurrent PGLs, and radial imaging. Although many PGLs do not secrete catecholamines, chromogranin A has been found to be elevated in PGLs and may be a useful marker for tumor recurrence. The appropriate screening imaging modality is unknown at this time, but 18F-FDG PET/CT is highly sensitive at identifying extra-adrenal PGLs and GISTs. Because of the risks of ionizing radiation exposure from CT, some suggest using MRI for annual surveillance.[<a class="bk_pop" href="#CDR0000062890_rl_972_14">14</a>,<a class="bk_pop" href="#CDR0000062890_rl_972_15">15</a>] </p></div><div id="CDR0000062890__976"><h3>Interventions</h3><p id="CDR0000062890__992">Because multiple primary GISTs and PGLs are common with CSS, preoperative imaging is paramount to accurately identify the extent of disease before surgical planning. Most patients will present having already undergone imaging with computed tomography (CT) or magnetic resonance imaging (MRI). Both methods have excellent sensitivity for identifying PGLs, but additional functional imaging is recommended because of the diffuse nature of these tumors. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/CT is superior to <sup>123</sup>I-metaiodobenzylguanidine at identifying <i>SDHx</i>-associated PGLs and, because of the high metabolic activity of GISTs, has excellent sensitivity in identifying them.[<a class="bk_pop" href="#CDR0000062890_rl_972_14">14</a>,<a class="bk_pop" href="#CDR0000062890_rl_972_16">16</a>] Thus, in patients with <i>SDHx</i> mutations, including those with CSS, 18F-FDG PET/CT is the preferred functional imaging modality to optimally detect and stage all GISTs and PGLs.[<a class="bk_pop" href="#CDR0000062890_rl_972_15">15</a>] Some evidence suggests that 18F-fluoro-L-dihydroxyphenylalanine (18F-FDOPA) PET/CT is superior at identifying the primary PGL, while 18F-FDG PET/CT is superior at identifying metastases. </p><p id="CDR0000062890__993">There are no prospective treatment studies involving patients with CSS; therefore, recommendations are based on limited clinical experience, single case series, and extrapolations from genetically-similar tumors with similar clinical behavior. The mainstay of treatment for CSS-associated GISTs and PGLs is complete surgical resection of the tumor. The timing of the operation correlates with the presentation of the tumor. Surgical resection can be accomplished with laparoscopic or open techniques. For PGLs, vascular reconstruction is uncommon. Although PGLs are commonly present in the paraaortic region, the need for major vascular reconstruction is uncommon. GIST tumors can be resected with wedge resection and primary closure and re-anastomosis. Ensuring negative margins is important, as patients for whom a complete resection is accomplished experience the longest survival.[<a class="bk_pop" href="#CDR0000062890_rl_972_17">17</a>] In the rare setting of synchronous disease, combined resection is appropriate if tolerable by the patient. More commonly, tumors develop metachronously, with GISTs arising first; individual resection occurs at the time of diagnosis of each tumor. </p><p id="CDR0000062890__995">A thorough preoperative endoscopy and complete surgical exploration of the stomach are essential, as multiple separate GISTs are frequently encountered. The high frequency of multifocality and the likelihood of tumor recurrence do not justify a prophylactic total gastrectomy because of its substantial associated morbidity. Furthermore, a total gastrectomy is generally only performed when the current disease burden precludes a lesser resection. To this end, gastric wedge resection with gross negative margins is the surgical goal.[<a class="bk_pop" href="#CDR0000062890_rl_972_18">18</a>] Sampling of any suspicious nodes at the time of resection is commonly performed. Evidence suggests that locally advanced CSS-associated GISTs demonstrate a rather indolent course;[<a class="bk_pop" href="#CDR0000062890_rl_972_19">19</a>] thus, the concern for nodal involvement based on preoperative imaging or abdominal exploration need not deter resection of the primary tumor. While a role for neoadjuvant imatinib in locally advanced adult-type GISTs has been widely described to improve resectability or reduce the burden of resection, it is unlikely to have any effect in locally advanced SDH-deficient GISTs.[<a class="bk_pop" href="#CDR0000062890_rl_972_20">20</a>] Evidence suggests that for these tumors, the second-line targeted agents, including sorafenib, sunitinib, dasatinib, and nilotinib, may be beneficial in the adjuvant setting.[<a class="bk_pop" href="#CDR0000062890_rl_972_21">21</a>,<a class="bk_pop" href="#CDR0000062890_rl_972_22">22</a>] No data support using these agents in the neoadjuvant setting at this time.</p><p id="CDR0000062890__996">Regarding treatment of CSS-associated PGLs, patients are commonly initiated on alpha-blockade preoperatively to minimize perioperative cardiac morbidity and mortality. PGLs typically occur in the para-aortic chain from the urinary bladder and the aortic bifurcation to the superior mediastinum and head and neck. As in the treatment of GISTs, the operative goal is resection of all known disease. Preoperative imaging and intra-operative exploration are essential to achieving this goal. Multiple tumors are common; when disease is present in the bilateral adrenal glands, the surgeon faces the possibility of rendering a patient steroid dependent with a lifelong risk of a fatal Addisonian crisis. In this setting, a surgeon proficient in performing a cortical-sparing adrenalectomy should be consulted.</p><p id="CDR0000062890__1026"><a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000531846/" class="def">Level of evidence: 5</a></p></div><div id="CDR0000062890_rl_972"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062890_rl_972_1">Carney JA, Stratakis CA: Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet 108 (2): 132-9, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11857563" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11857563</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_2">McWhinney SR, Pasini B, Stratakis CA, et al.: Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med 357 (10): 1054-6, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17804857" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17804857</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_3">Pasini B, McWhinney SR, Bei T, et al.: Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 16 (1): 79-88, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/17667967" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17667967</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_4">Gaal J, Stratakis CA, Carney JA, et al.: SDHB immunohistochemistry: a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol 24 (1): 147-51, 2011. [<a href="/pmc/articles/PMC3415983/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3415983</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20890271" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20890271</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_5">Agaimy A, Pelz AF, Corless CL, et al.: Epithelioid gastric stromal tumours of the antrum in young females with the Carney triad: a report of three new cases with mutational analysis and comparative genomic hybridization. Oncol Rep 18 (1): 9-15, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17549339" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17549339</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_6">Zhang L, Smyrk TC, Young WF Jr, et al.: Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. Am J Surg Pathol 34 (1): 53-64, 2010. [<a href="/pmc/articles/PMC3652406/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3652406</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19935059" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19935059</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_7">Boikos SA, Stratakis CA: Carney complex: pathology and molecular genetics. Neuroendocrinology 83 (3-4): 189-99, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17047382" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17047382</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_8">Correa R, Salpea P, Stratakis CA: Carney complex: an update. Eur J Endocrinol 173 (4): M85-97, 2015. [<a href="/pmc/articles/PMC4553126/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4553126</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26130139" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26130139</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_9">Hensen EF, Bayley JP: Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma. Fam Cancer 10 (2): 355-63, 2011. [<a href="/pmc/articles/PMC3100491/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3100491</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21082267" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21082267</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_10">Agaram NP, Laquaglia MP, Ustun B, et al.: Molecular characterization of pediatric gastrointestinal stromal tumors. Clin Cancer Res 14 (10): 3204-15, 2008. [<a href="/pmc/articles/PMC3805121/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3805121</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18483389" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18483389</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_11">Miettinen M, Wang ZF, Sarlomo-Rikala M, et al.: Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol 35 (11): 1712-21, 2011. [<a href="/pmc/articles/PMC3193596/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3193596</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21997692" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21997692</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_12">Sawhney SA, Chapman AD, Carney JA, et al.: Incomplete Carney triad--a review of two cases. QJM 102 (9): 649-53, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19561114" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19561114</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_13">Rege TA, Wagner AJ, Corless CL, et al.: "Pediatric-type" gastrointestinal stromal tumors in adults: distinctive histology predicts genotype and clinical behavior. Am J Surg Pathol 35 (4): 495-504, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21358303" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21358303</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_14">Ayala-Ramirez M, Callender GG, Kupferman ME, et al.: Paraganglioma syndrome type 1 in a patient with Carney-Stratakis syndrome. Nat Rev Endocrinol 6 (2): 110-5, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20098451" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20098451</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_15">Timmers HJ, Kozupa A, Chen CC, et al.: Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma. J Clin Oncol 25 (16): 2262-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17538171" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17538171</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_16">Timmers HJ, Chen CC, Carrasquillo JA, et al.: Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 94 (12): 4757-67, 2009. [<a href="/pmc/articles/PMC2795662/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2795662</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19864450" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19864450</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_17">Abadin SS, Ayala-Ramirez M, Jimenez C, et al.: Impact of surgical resection for subdiaphragmatic paragangliomas. World J Surg 38 (3): 733-41, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24390286" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24390286</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_18">Demetri GD, Benjamin RS, Blanke CD, et al.: NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 (Suppl 2): S1-29; quiz S30, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17624289" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17624289</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_19">Maki RG, Blay JY, Demetri GD, et al.: Key Issues in the Clinical Management of Gastrointestinal Stromal Tumors: An Expert Discussion. Oncologist 20 (7): 823-30, 2015. [<a href="/pmc/articles/PMC4492234/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4492234</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26070915" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26070915</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_20">Ganjoo KN, Villalobos VM, Kamaya A, et al.: A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib. Ann Oncol 25 (1): 236-40, 2014. [<a href="/pmc/articles/PMC4271129/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4271129</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24356634" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24356634</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_21">Gill AJ, Chou A, Vilain R, et al.: Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types. Am J Surg Pathol 34 (5): 636-44, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20305538" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20305538</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062890_rl_972_22">Janeway KA, Albritton KH, Van Den Abbeele AD, et al.: Sunitinib treatment in pediatric patients with advanced GIST following failure of imatinib. Pediatr Blood Cancer 52 (7): 767-71, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19326424" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19326424</span></a>]</div></li></ol></div></div><div id="CDR0000062890__161"><h2 id="_CDR0000062890__161_">Changes to This Summary (06/24/2016)</h2><p id="CDR0000062890__151">The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.</p><p id="CDR0000062890__1069"><b><a href="#CDR0000062890__286">Introduction</a></b></p><p id="CDR0000062890__1070">Revised <a href="#CDR0000062890__899">text</a> to state that in 2004, the World Health Organization characterized pheochromocytomas (PHEOs) as adrenal gland tumors and paragangliomas (PGLs) as extra-adrenal tumors. Also revised text to state that either tumor may occur sporadically, as a manifestation of a hereditary syndrome, or as the sole tumor in familial PGL and PHEO syndrome.</p><p id="CDR0000062890__1076"><b><a href="#CDR0000062890__760">Multiple Endocrine Neoplasia Type 1 (MEN1)</a></b></p><p id="CDR0000062890__1071">Revised <a href="#CDR0000062890__806">text</a> to state that familial MEN1 is defined as at least one MEN1 case plus at least one first-degree relative (FDR) with parathyroid tumors and primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors (NETs), or pituitary tumors; or two FDRs with a germline mutation in <i>MEN1</i>. </p><p id="CDR0000062890__1072">Added <a href="#CDR0000062890__1067">text</a> to state that the initial clinical presentation of symptoms typically occurs between the ages of 20 years and 30 years, although a diagnosis of MEN1 may not be confirmed for many more years; the age-related penetrance of MEN1 is 45% to 73% by age 30 years, 82% by age 50 years, and 96% by age 70 years.</p><p id="CDR0000062890__1077">Revised <a href="#CDR0000062890__791">text</a> to state that duodenopancreatic NETs seen in MEN1 include gastrinomas (cited MacFarlane et al. as reference 19) and nonfunctioning NETs.</p><p id="CDR0000062890__1073">Revised <a href="#CDR0000062890__770">text</a> to state that pituitary tumors can include
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somatotropinomas and corticotropinomas, or they may be
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nonfunctioning.</p><p id="CDR0000062890__1074">Added <a href="#CDR0000062890__799">text</a> to state that <i>MEN1</i> germline mutation yield ranged from
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16% to 38% for apparently sporadic cases of parathyroid, pancreatic islet, or pituitary
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tumors, warranting consideration of genetic testing in
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these individuals because a diagnosis of MEN1 would
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prompt screening for other MEN1-related tumors.</p><p id="CDR0000062890__1075">Added <a class="figpopup" href="/books/NBK65830.8/table/CDR0000062890__857/?report=objectonly" target="object" rid-figpopup="figCDR0000062890857" rid-ob="figobCDR0000062890857">text</a> to Table 2, Practice Guidelines for
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Surveillance of MEN1, to state that the age to initiate
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screening and the screening frequency for pituitary tumors
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may be debatable because the clinical significance of small,
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nonfunctional tumors is unclear (cited de Laat et al. as reference 62); further study may be warranted.</p><p id="CDR0000062890__disclaimerHP_3">This summary is written and maintained by the <a href="http://www.cancer.gov/publications/pdq/editorial-boards/genetics" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Cancer Genetics Editorial Board</a>, which is
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editorially independent of NCI. The summary reflects an independent review of
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the literature and does not represent a policy statement of NCI or NIH. More
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information about summary policies and the role of the PDQ Editorial Boards in
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maintaining the PDQ summaries can be found on the <a href="#CDR0000062890__AboutThis_1">About This PDQ Summary</a> and <a href="http://www.cancer.gov/publications/pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ® - NCI's Comprehensive Cancer Database</a> pages.
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</p></div><div id="CDR0000062890__AboutThis_1"><h2 id="_CDR0000062890__AboutThis_1_">About This PDQ Summary</h2><div id="CDR0000062890__AboutThis_2"><h3>Purpose of This Summary</h3><p id="CDR0000062890__AboutThis_3">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of endocrine and neuroendocrine neoplasias. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.</p></div><div id="CDR0000062890__AboutThis_4"><h3>Reviewers and Updates</h3><p id="CDR0000062890__AboutThis_5">This summary is reviewed regularly and updated as necessary by the <a href="http://www.cancer.gov/publications/pdq/editorial-boards/genetics" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Cancer Genetics Editorial Board</a>, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p><p id="CDR0000062890__AboutThis_22"> Board members review recently published articles each month to determine whether an article should:</p><ul id="CDR0000062890__AboutThis_6"><li class="half_rhythm"><div>be discussed at a meeting,</div></li><li class="half_rhythm"><div>be cited with text, or</div></li><li class="half_rhythm"><div>replace or update an existing article that is already cited.</div></li></ul><p id="CDR0000062890__AboutThis_7">Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.</p><p>The lead reviewers for Genetics of Endocrine and Neuroendocrine Neoplasias are:</p><ul><li class="half_rhythm"><div>Kathleen A. Calzone, PhD, RN, APNG, FAAN (National Cancer Institute)</div></li><li class="half_rhythm"><div>Sarah Nielsen, MS, LCGC (The University of Chicago)</div></li><li class="half_rhythm"><div>Suzanne M. O'Neill, MS, PhD, CGC (Northwestern University)</div></li><li class="half_rhythm"><div>Nancy D. Perrier, MD, FACS (University of Texas, M.D. Anderson Cancer Center)</div></li><li class="half_rhythm"><div>Beth N. Peshkin, MS, CGC (Lombardi Comprehensive Cancer Center at Georgetown University Medical Center)</div></li><li class="half_rhythm"><div>Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)</div></li><li class="half_rhythm"><div>Jennifer Sipos, MD (The Ohio State University)</div></li><li class="half_rhythm"><div>Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)</div></li><li class="half_rhythm"><div>Catharine Wang, PhD, MSc (Boston University School of Public Health)</div></li></ul><p id="CDR0000062890__AboutThis_9">Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's <a href="http://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.</p></div><div id="CDR0000062890__AboutThis_10"><h3>Levels of Evidence</h3><p id="CDR0000062890__AboutThis_11">Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a <a href="/books/n/pdqcis/CDR0000685387/">formal evidence ranking system</a> in developing its level-of-evidence designations.</p></div><div id="CDR0000062890__AboutThis_12"><h3>Permission to Use This Summary</h3><p id="CDR0000062890__AboutThis_13">PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”</p><p id="CDR0000062890__AboutThis_14">The preferred citation for this PDQ summary is:</p><p id="CDR0000062890__AboutThis_15">PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Endocrine and Neuroendocrine Neoplasias. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: <a href="http://www.cancer.gov/types/thyroid/hp/medullary-thyroid-genetics-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www.cancer.gov/types/thyroid/hp/medullary-thyroid-genetics-pdq</a>. Accessed <MM/DD/YYYY>. [PMID: 26389271]</p><p id="CDR0000062890__AboutThis_16">Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in <a href="http://visualsonline.cancer.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Visuals Online</a>, a collection of over 2,000 scientific images.
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</p></div><div id="CDR0000062890__AboutThis_17"><h3>Disclaimer</h3><p id="CDR0000062890__AboutThis_19">The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the <a href="http://www.cancer.gov/about-cancer/managing-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Managing Cancer Care</a> page.</p></div><div id="CDR0000062890__AboutThis_20"><h3>Contact Us</h3><p id="CDR0000062890__AboutThis_21">More information about contacting us or receiving help with the Cancer.gov website can be found on our <a href="http://www.cancer.gov/contact" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Contact Us for Help</a> page. Questions can also be submitted to Cancer.gov through the website’s <a href="http://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>.</p></div></div></div></div>
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Pheochromocytoma and Paraganglioma Syndrome</a></li><li><a href="#CDR0000062890__972" ref="log$=inpage&link_id=inpage">Carney-Stratakis Syndrome</a></li><li><a href="#CDR0000062890__161" ref="log$=inpage&link_id=inpage">Changes to This Summary (06/24/2016)</a></li><li><a href="#CDR0000062890__AboutThis_1" ref="log$=inpage&link_id=inpage">About This PDQ Summary</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=2823694" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a 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Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Multiple Endocrine Neoplasia Type 2 (MEN2) (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Cancer Genetics Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/39591488" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> PALB2: Cancer Risks and Management (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> PALB2: Cancer Risks and Management (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Cancer Genetics Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/38113349" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> RUNX1-Familial Platelet Disorder (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> RUNX1-Familial Platelet Disorder (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Cancer Genetics Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/38113347" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> DDX41-Associated Myeloid Malignancies (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> DDX41-Associated Myeloid Malignancies (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Cancer Genetics Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/38113348" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> CEBPA-Associated Familial Acute Myeloid Leukemia (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> CEBPA-Associated Familial Acute Myeloid Leukemia (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Cancer Genetics Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 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