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<title>X-linked acro-gigantism (X-LAG): a new form of infant-onset pituitary gigantism | NIH Research Festival</title>
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<article><div class="banner banner--gray banner--compact" style="--banner-background-image: url('/sites/default/files/media/image/2021-03/2015.jpg');--banner-background-focus: 50% 50%"><div class="banner__wrapper"><div class="banner__container"><h2 class="banner__heading">NIH Research Festival</h2><div class="banner__content"><p><strong><time datetime="2015-09-16">September 16</time> – <time datetime="2015-09-18">18, 2015</time></strong></p></div></div></div></div></article>
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<div class="section"><div data-drupal-messages-fallback class="hidden"></div></div><main role="main"><div id="main-content" tabindex="-1"></div><div class="section"><div class="content-sidebar"><div class="content-sidebar__main"><div class="content-sidebar__main-content"><div id="block-mainpagecontent-2"><article><h1>X-linked acro-gigantism (X-LAG): a new form of infant-onset pituitary gigantism</h1><div class="schedule"><div class="schedule__label"><div class="schedule__label-text"><time datetime="2015-09-18">Friday, September 18, 2015</time>
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– Poster Session IV
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</div></div><div class="schedule__content"><div class="schedule__item"><div class="schedule__time">12:00 – 1:30 p.m.</div><div class="schedule__description"><p><strong>FAES Terrace</strong></p></div><div class="schedule__description"><p><strong>NICHD</strong></p></div><div class="schedule__description"><p><strong>GEN-41</strong></p></div></div></div></div><p><strong>FARE Award Winner</strong></p><h2>Authors</h2><ul><li>G Trivellin</li><li>AF Daly</li><li>FR Faucz</li><li>B Yuan</li><li>L Rostomyan</li><li>DO Larco</li><li>MH Schernthaner-Reiter</li><li>LF Leal</li><li>C Villa</li><li>A Dimopoulos</li><li>P Chittiboina</li><li>TJ Wu</li><li>CS Choong</li><li>M Quezado</li><li>I Bjelobaba</li><li>SS Stojilkovic</li><li>S Costanzi</li><li>JR Lupski</li><li>A Beckers</li><li>CA Stratakis</li></ul><h2>Abstract</h2><p>Introduction: High growth hormone (GH) secretion is a rare condition that leads to gigantism in childhood and acromegaly in adults. Aim: We studied gigantism and acromegaly for genetic defects. Methods: We performed genome-wide analyses in an international cohort of 46 patients with gigantism and 248 patients with acromegaly. Results: We detected a novel microduplication at chromosome Xq26.3 in 2 unrelated kindreds and 13 sporadic cases with infantile gigantism. All patients had disease onset before 5 years of age and presented with mixed GH/prolactin-secreting tumors and/or hyperplasia. All sporadic cases harbored non-recurrent duplications, whereas familial cases inherited the duplications from their mothers. Breakpoint junctions revealed microhomology, suggesting a replicative mechanism for their formation. Patients shared a common duplicated region of approximately 500 Kb containing 4 protein-coding genes, of which only GPR101, a G-protein coupled receptor (GPCR) that activates cAMP signaling, was consistently overexpressed in patients’ pituitary lesions. We also identified a recurrent GPR101 variant in 11 out of 248 patients with acromegaly, mostly in tumors. When transfected into somatotrope cells the mutation led to increased GH secretion. Low GPR101 expression was seen in non-duplicated GH-secreting tumors and in the normal pituitary. Conclusions: We describe a new genomic disorder characterized by early-onset gigantism and caused by Xq26 microduplications (X-LAG for X-linked acrogigantism). This syndrome is likely caused by overexpression of GPR101, a dosage-sensitive GPCR that activates the cAMP pathway, whose mitogenic effects in pituitary somatotropes are well established. GPR101 may also be mutated in adult patients with acromegaly.</p><p><strong>Scientific Focus Area</strong>: Genetics and Genomics</p><p class="updated"><small>This page was last updated on Friday, March 26, 2021</small></p></article>
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