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</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="7ZXleHf90MLRFnkudLVNAfuN2H4HwQRDoMHqRxIvAnylzOqkQ4yP4n0rALMTprpX">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="7ZXleHf90MLRFnkudLVNAfuN2H4HwQRDoMHqRxIvAnylzOqkQ4yP4n0rALMTprpX">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="7ZXleHf90MLRFnkudLVNAfuN2H4HwQRDoMHqRxIvAnylzOqkQ4yP4n0rALMTprpX">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="7ZXleHf90MLRFnkudLVNAfuN2H4HwQRDoMHqRxIvAnylzOqkQ4yP4n0rALMTprpX">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="7ZXleHf90MLRFnkudLVNAfuN2H4HwQRDoMHqRxIvAnylzOqkQ4yP4n0rALMTprpX">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="35677616">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://dx.doi.org/10.2147/JMDH.S251861"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=7093&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=35677616&amp;db=pubmed&amp;nlmid=101512691"
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Dove Medical Press
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/35677616/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=35677616&amp;db=pubmed&amp;nlmid=101512691"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="35677616"
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Free PMC article
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</div>
</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/35677616/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/35677616/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="35677616" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F35677616%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="7ZXleHf90MLRFnkudLVNAfuN2H4HwQRDoMHqRxIvAnylzOqkQ4yP4n0rALMTprpX"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
id="collections-action-dialog-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="collections_button"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label">
Choose a collection:
</label><select id="collections-action-dialog-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="collections_button"
data-ga-action="select_collection"
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It is very unusual to see evidence of arterial calcification in infants and children, and when detected, genetic disorders of calcium metabolism should be suspected. Generalized arterial calcification of infancy (GACI) is a hereditary disease, which is characterized by severe arterial calcification of medium sized arteries, mostly involving the media with marked intimal proliferation and ectopic mineralization of the extravascular tissues. It is caused by inactivating variants in genes encoding either ENPP1, in a majority of cases (70-75%), or ABCC6, in a minority (9-10%). Despite similar histologic appearances between ENPP1 and ABCC6 deficiencies, including arterial calcification, organ calcification, and cardiovascular calcification, mortality is higher in subjects carrying the ENPP1 versus ABCC6 variants (40% vs 10%, respectively). Overall mortality in individuals with GACI is high (55%) before the age of 6 months, with 24.4% dying in utero or being stillborn. Rare cases show spontaneous regression with age, while others who survive into adulthood often manifest musculoskeletal complications (osteoarthritis and interosseous membrane ossification), enthesis mineralization, and cervical spine fusion. Despite recent advances in the understanding of the genetic mechanisms underlying this disease, there is still no ideal therapy for the resolution of vascular calcification in GACI. Although bisphosphonates with anti-calcification properties have been commonly used for the treatment of CAGI, their benefit is controversial, with favorable results reported at one year and questionable benefit with delayed initiation of treatment. Enzyme replacement therapy with administration of recombinant form of ENPP1 prevents calcification and mortality, improves hypertension and cardiac function, and prevents intimal proliferation and osteomalacia in mouse models of ENPP1 deficiency. Therefore, newer treatments targeting genes are on the horizon. In this article, we review up to date knowledge of the understanding of GACI, its clinical, pathologic, and etiologic understanding and treatment in support of more comprehensive care of GACI patients.
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ATP binding cassette subfamily C member 6; ectonucleotide pyrophosphatase/phosphodiesterase 1; generalized arterial calcification of infancy; vascular calcification.
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<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Dr. Aloke V. Finn received consultant fees/honoraria from Abbott Vascular, Amgen, Biosensors, Boston Scientific, Celonova, Cook Medical, CSI, Lutonix Bard, Sinomed, and Terumo Corporation. Dr. Renu Virmani is a consultant of Abbott Vascular, Boston Scientific, Celonova, OrbusNeich Medical, Terumo Corporation, W. L. Gore, Edwards Lifesciences, Cook Medical, CSI, ReCor Medical, SinoMedical Sciences Technology, Surmodics, Bard BD and a scientific Advisory Board Member of Medtronic and Xeltis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or any other conflict with the subject matter or materials discussed.</p>
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<strong class="figure-label">
<p> Figure 1 </p>
</strong>
<div class="figure-caption-contents"><p> Overview of Rare Monogenic Diseases… </p></div>
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<p> Figure 1 </p>
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<div class="figure-caption-contents"><p> Overview of Rare Monogenic Diseases with Vascular Calcification Due to Mutation of the… </p></div>
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Figure 1
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<div class="figure-caption-contents">Overview of Rare Monogenic Diseases with Vascular Calcification Due to Mutation of the Purine Metabolism Pathway. ATP gains access via ATP transporters into extracellular space, where it is hydrolyzed by ENPP1 into AMP and PPi. AMP is then hydrolyzed by CD73 into adenosine and Pi while PPi is hydrolyzed by TNAP into inorganic phosphate. PiT1/2 (Na<sup>+</sup>-dependent Pi cotransporter) mediates cellular Pi uptake and transport into the cell. PPi is a potent inhibitor of calcification. Adenosine can interact with adenosine receptors and suppress TNAP expression, as well as have various effects based on specific receptors. The specific substrate for ABCC6 has yet to be identified. ENPP1, CD73, and ABCC6 deficiencies drive the molecular pathophysiology of several monogenic diseases associated with arterial calcification (GACI, ACDC, and PXE). Reproduced with permission from Cudrici CD et al.</div>
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<p> Figure 2 </p>
</strong>
<div class="figure-caption-contents"><p> Gross, radiographic, and histologic images… </p></div>
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<p> Figure 2 </p>
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<div class="figure-caption-contents"><p> Gross, radiographic, and histologic images of the heart and coronary artery from a… </p></div>
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Figure 2
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<div class="figure-caption-contents">Gross, radiographic, and histologic images of the heart and coronary artery from a 8-months-old male with GACI. Radiographs of excised coronary arteries (CA) (<b>A</b>) demonstrate focal calcification of all four major branches [left main, left anterior descending (LAD), left circumflex (LCX), and right CA (RCA)] and smaller branches. (<b>B</b>) Mid-left and right ventricular slices of the heart show dilatation of the LV and subendocardial circumferential healed myocardial infarction, along with transmural scarring of the posterolateral wall of LV. (<b>C</b><b>H</b>). Hematoxylin and eosin-stained sections of the major coronary arteries and branch vessels demonstrating moderate to severe luminal narrowing with or without medial calcification (<b>A</b>, <b>B</b>, <b>E</b><b>H</b>) are reproduced with permission from Federici et al.</div>
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<strong class="figure-label">
<p> Figure 3 </p>
</strong>
<div class="figure-caption-contents"><p> Representative histologic sections of the… </p></div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 3 </p>
</strong>
<div class="figure-caption-contents"><p> Representative histologic sections of the right coronary artery, from the same case shown… </p></div>
</div>
<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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Figure 3
</strong>
<div class="figure-caption-contents">Representative histologic sections of the right coronary artery, from the same case shown in Figure 2. Top row: low-power images of RCA stained with Movat Pentachrome (<b>A</b>), hematoxylin and eosin (<b>B</b>), and triple immunofluorescence for SMC and inflammatory markers [macrophage (CD68) and T cells (CD3)], and α-actin (SMA) (<b>C</b>). Early- (<b>D</b><b>F</b>), intermediate- (<b>G</b><b>I</b>), and late-phase (<b>J</b><b>O</b>) lesion morphologies are shown. There is moderate luminal narrowing with SMC-rich neointima. Regions of interest shown at higher magnification are within the colored boxed areas on the low-magnification image (<b>A</b>). Areas highlighted by the red box (<b>D</b><b>F</b>) show early calcification with degradation of the IEL and relative absence of inflammation. The purple-boxed area (<b>G</b><b>I</b>) represents fragmentation and focal thickening of elastic fibers with calcification, along with early inflammation (macrophages, yellow in panel (<b>I</b>) and neoangiogenesis (black arrow). A more advanced late phase (black in panel (<b>A</b>) and yellow boxes in panel (<b>J</b>) shows more prominent calcification (<b>M</b>, alizarin red) and neoangiogenesis (black arrows in panel (<b>J</b>) with inflammatory infiltrate (<b>C</b> and <b>L</b>) consisting mostly of macrophages and T cells together with a loss of adjacent SMCs. These areas were also typically positive for the calcification markers, osteoprotegerin(<b>N</b>) and receptor activator of the nuclear κB (RANK) (<b>O</b>). (<b>A</b><b>O</b>) are reproduced with permission from Federici et al.</div>
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<strong class="figure-label">
<p> Figure 4 </p>
</strong>
<div class="figure-caption-contents"><p> Representative histologic sections of the… </p></div>
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</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 4 </p>
</strong>
<div class="figure-caption-contents"><p> Representative histologic sections of the aorta and major branches with varying degrees of… </p></div>
</div>
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<strong class="figure-label">
Figure 4
</strong>
<div class="figure-caption-contents">Representative histologic sections of the aorta and major branches with varying degrees of IEL fragmentation and calcification. Low-power images of the thoracic aorta (<b>A</b>), abdominal aorta (<b>B</b>), left subclavian artery (<b>C</b>), left common carotid artery (<b>D</b>), celiac artery (<b>E</b>), superior mesenteric artery (<b>F</b>), renal artery (<b>G</b>), and left common iliac artery (<b>H</b>) showing varying degrees of IEL fragmentation and calcificationLeft images are stained with hematoxylin and eosin stain and right images are stained with von Kossa stain. (<b>A</b><b>H</b>) are reproduced with permission from Federici et al.</div>
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<strong class="figure-label">
<p> Figure 5 </p>
</strong>
<div class="figure-caption-contents"><p> Radiography and histologic images of… </p></div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 5 </p>
</strong>
<div class="figure-caption-contents"><p> Radiography and histologic images of the coronary arteries and myocardium from a 20-days-old… </p></div>
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Figure 5
</strong>
<div class="figure-caption-contents">Radiography and histologic images of the coronary arteries and myocardium from a 20-days-old female infant with GACI. Radiograph of the heart shows calcification of the major coronary arteries: RCA (yellow arrows), LAD (red arrows), and LCX (white arrows) (<b>A</b>). Proximal RCA (<b>B</b><b>E</b>), proximal LAD (<b>F</b><b>I</b>), and proximal LCX (<b>J</b><b>M</b>) show moderate to severe luminal narrowing with circumferential calcification of IEL. Images B, C, F, G, J, and K of coronary arteries are stained with hematoxylin and eosin and Movat Pentachrome D, E, H, I, L, and M, stains, respectively. The boxed areas in the left panels, B, D, F, H, J, and L, are shown at high power in the right panels, C, E, G, I, K, and M. Panels C and K show bone metaplasia within calcified areas. Histologic section of the left ventricular wall showing normal histology of the intramyocardial coronary arteries [boxed area in (<b>O</b>); note an absence of calcification and intimal proliferation (<b>P</b> and <b>Q</b>)]. (<b>O</b> and <b>P</b>) are stained by hematoxylin and eosin; (<b>Q</b>) is stained by Movat pentachrome stain.</div>
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</figure>
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itemprop="contentUrl"
aria-describedby="figure-caption-5"
role="button"
data-image-width="800"
data-image-height="922"
data-image-alt="Figure 6"
data-pmc-id="PMC9167688"
data-figure-id="f0006">
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<strong class="figure-label">
<p> Figure 6 </p>
</strong>
<div class="figure-caption-contents"><p> Radiography of the lungs and… </p></div>
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</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 6 </p>
</strong>
<div class="figure-caption-contents"><p> Radiography of the lungs and histology of pulmonary artery and thoracic aorta, from… </p></div>
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<figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 6
</strong>
<div class="figure-caption-contents">Radiography of the lungs and histology of pulmonary artery and thoracic aorta, from the same case as Figure 5. Radiography of right and left lungs demonstrates diffuse calcification of pulmonary arteries (<b>A</b>). (<b>B</b>). Histologic section of the right lung showing diffuse narrowing of multiple branches of the pulmonary arteries (hematoxylin and eosin). The boxed area in panel B is shown at higher magnification, demonstrating severe luminal narrowing from intimal proliferation and circumferential calcification (<b>C</b><b>F</b>). Images (<b>C</b> and <b>D</b>) are stained with hematoxylin and eosin and (<b>E</b> and <b>F</b>) are stained with Movat Pentachrome. A section of the thoracic aorta showing circumferential calcification (<b>G</b> and <b>H</b>). (<b>I</b> and <b>J</b>) are higher-power magnifications from the boxed areas in (<b>G</b> and <b>H</b>), showing diffuse calcification of the media. (<b>K</b> and <b>L</b>) show an area of bone metaplasia within the lesions of calcification. The upper and lower panels are stained with hematoxylin and eosin (<b>G</b>, <b>I</b>, and <b>K</b>) and Movat Pentachrome (<b>H</b>, <b>J</b>, and <b>L</b>).</div>
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