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<meta name="description" content="Familial HLH is inherited in an autosomal recessive manner. (Autosomal dominant inheritance of &lt;i&gt;STXBP2&lt;/i&gt;-fHLH is suggested by rare reports of symptomatic individuals with heterozygous gain-of-function variants. Autosomal dominant inheritance will not be discussed further in this section.) If bot …"><meta name="keywords" content="pmid:20301617, NBK1444, Review, Kejian Zhang, Itziar Astigarraga, Kim E Nichols, PubMed Abstract, NIH, NLM, NCBI, National Institutes of Health, National Center for Biotechnology Information, National Library of Medicine, MEDLINE"><meta name="robots" content="index,nofollow,noarchive"><meta property="og:title" content="Familial Hemophagocytic Lymphohistiocytosis - PubMed"><meta property="og:url" content="https://pubmed.ncbi.nlm.nih.gov/20301617/"><meta property="og:description" content="Familial HLH is inherited in an autosomal recessive manner. (Autosomal dominant inheritance of &lt;i&gt;STXBP2&lt;/i&gt;-fHLH is suggested by rare reports of symptomatic individuals with heterozygous gain-of-function variants. Autosomal dominant inheritance will not be discussed further in this section.) If bot …"><meta property="og:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:image:secure_url" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:type" content="website"><meta property="og:site_name" content="PubMed"><meta name="twitter:domain" content="pubmed.ncbi.nlm.nih.gov"><meta name="twitter:card" content="summary_large_image"><meta name="twitter:title" content="Familial Hemophagocytic Lymphohistiocytosis - PubMed"><meta name="twitter:url" content="https://pubmed.ncbi.nlm.nih.gov/20301617/"><meta name="twitter:description" content="Familial HLH is inherited in an autosomal recessive manner. (Autosomal dominant inheritance of &lt;i&gt;STXBP2&lt;/i&gt;-fHLH is suggested by rare reports of symptomatic individuals with heterozygous gain-of-function variants. Autosomal dominant inheritance will not be discussed further in this section.) If bot …"><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">
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<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="8Kl8g3Alb4tFjk5wxS6WhVEu8NWs3TCrpx5dTT3HLFg9dLbmabJYL3a8GREEWuaL">
<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="8Kl8g3Alb4tFjk5wxS6WhVEu8NWs3TCrpx5dTT3HLFg9dLbmabJYL3a8GREEWuaL">
<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="8Kl8g3Alb4tFjk5wxS6WhVEu8NWs3TCrpx5dTT3HLFg9dLbmabJYL3a8GREEWuaL">
<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="8Kl8g3Alb4tFjk5wxS6WhVEu8NWs3TCrpx5dTT3HLFg9dLbmabJYL3a8GREEWuaL">
<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="8Kl8g3Alb4tFjk5wxS6WhVEu8NWs3TCrpx5dTT3HLFg9dLbmabJYL3a8GREEWuaL">
<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="20301617">
<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
book
dialog-focus"
href="https://www.ncbi.nlm.nih.gov/books/NBK1444"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3057&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=20301617&amp;db=pubmed"
title="See full text options at NCBI Bookshelf"
data-ga-category="full_text"
data-ga-action="NCBI Bookshelf"
data-ga-label="20301617"
><img class="book-icon" src="https://cdn.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene.png" alt="book cover photo"><div class="book-icon-label"><div class="book-icon-label-title">GeneReviews<sup>®</sup> [Internet]</div></div><span class="text">
NCBI Bookshelf
</span></a>
</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="/20301617/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/20301617/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="20301617" 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%2F20301617%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="8Kl8g3Alb4tFjk5wxS6WhVEu8NWs3TCrpx5dTT3HLFg9dLbmabJYL3a8GREEWuaL"><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"
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="collections_button"
data-ga-action="click"
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="collections_button"
data-ga-action="click"
data-ga-label="cancel">
Cancel
</button></div></form></div></div></div></div><button class="more-actions-button more-actions-dialog-trigger"
title="Open dialog with more actions to take"
ref="linksrc=more_actions_btn"></button><div class="display-options" data-format-key="format"
data-default-format-value="abstract"
data-current-format-value="abstract" role="region"><button
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<div class="book-citation">
<div class="citation">In: GeneReviews<sup>®</sup> [Internet]. Seattle (WA): University of Washington, Seattle; 1993.</div>
<div class="chapter-date"><span class="chapter-contribution-date" ><time class="chapter-contribution-date-value" datetime="2006-03-22"
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Affiliations
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><sup class="key">1</sup> Mount Sinai Genomics;, Sema4, New York, New York</li>
<li data-affiliation-id="short-view-affiliation-2"
id="short-view-affiliation-2"
><sup class="key">2</sup> Department of Pediatrics, Hospital Universitario Cruces, Osakidetza, IIS Biocruces Bizkaia, UPV/EHU, Barakaldo, Spain</li>
<li data-affiliation-id="short-view-affiliation-3"
id="short-view-affiliation-3"
><sup class="key">3</sup> Department of Medicine, Karolinska Institutet, Stockholm, Sweden</li>
<li data-affiliation-id="short-view-affiliation-4"
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><sup class="key">4</sup> Department of Pediatric Hematology and Oncology, Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Eppendorf, Hamburg, Germany</li>
<li data-affiliation-id="short-view-affiliation-5"
id="short-view-affiliation-5"
><sup class="key">5</sup> Medical University of Warsaw, Warsaw, Poland</li>
<li data-affiliation-id="short-view-affiliation-6"
id="short-view-affiliation-6"
><sup class="key">6</sup> Cincinnati Children&#x27;s Hospital;, University of Cincinnati, Cincinnati, Ohio</li>
<li data-affiliation-id="short-view-affiliation-7"
id="short-view-affiliation-7"
><sup class="key">7</sup> Meyer Children&#x27;s University Hospital, Florence, Italy</li>
<li data-affiliation-id="short-view-affiliation-8"
id="short-view-affiliation-8"
><sup class="key">8</sup> Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China</li>
<li data-affiliation-id="short-view-affiliation-9"
id="short-view-affiliation-9"
><sup class="key">9</sup> Department of Oncology, St Jude Children&#x27;s Research Hospital, Memphis, Tennessee</li>
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<div class="abstract" id="abstract">
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Excerpt
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<div class="abstract-content selected"
id="eng-abstract">
<p>
<strong class="sub-title">
Clinical characteristics:
</strong>
Familial hemophagocytic lymphohistiocytosis (fHLH), defined as the presence of biallelic pathogenic variants in one of four genes (<i>PRF1</i>, <i>STX11</i>, <i>STXBP2</i>, or <i>UNC13D</i>), is an immune deficiency characterized by the overactivation and excessive proliferation of T lymphocytes and macrophages, leading to infiltration and damage of organs including the bone marrow, liver, spleen, and brain. Familial HLH usually presents as an acute illness with prolonged and high fever, cytopenias, and hepatosplenomegaly. Rash and lymphadenopathy are less common. Individuals with fHLH may also exhibit liver dysfunction and neurologic abnormalities. Although manifestations of fHLH are usually evident within the first months or years of life and may develop in utero, symptomatic presentation can occur throughout childhood and into adulthood. Median survival in untreated infants with fHLH who develop active disease is less than two months after onset of manifestations; progressive manifestations of fHLH, organ dysfunction, invasive infection, and bleeding account for the majority of deaths. However, the use of newer chemoimmunotherapy protocols followed by allogeneic hematopoietic stem cell transplantation (HSCT) has improved survival.
</p>
<p>
<strong class="sub-title">
Diagnosis/testing:
</strong>
The diagnosis of fHLH is established in a proband with suggestive findings by identification of either biallelic pathogenic variants in one of four genes (<i>PRF1</i>, <i>STX11</i>, <i>STXBP2</i>, or <i>UNC13D</i>) or (rarely) a gain-of-function heterozygous variant in <i>STXBP2.</i>
</p>
<p>
<strong class="sub-title">
Management:
</strong>
<i>Targeted therapies:</i> Treatment regimens focus on use of chemoimmunotherapy to treat active disease followed by allogeneic HSCT, the only curative therapy. Etoposide-containing regimens such as HLH-94 and HLH-2004, followed by allogeneic HSCT, are typically used. A regimen that includes anti-interferon-gamma antibody (emapalumab) is FDA approved for the treatment of children and adults with relapsed or refractory HLH or intolerance of conventional therapies.
</p>
<p>
<i>Supportive care:</i> Management should be coordinated by or in consultation with a multidisciplinary team with expertise in fHLH, including specialists in hematology/oncology, bone marrow and stem cell transplantation, immunology, rheumatology, infectious diseases, critical care, neurology, nephrology, pathology, and medical genetics. Supportive care that should accompany treatment with chemoimmunotherapy and allogenic HSCT includes antibiotics or antiviral agents to treat or prevent infections, and antipyretics, intravenous fluids, electrolyte replacement, transfusion of packed red blood cells and platelets, infusions of immunoglobulin, fresh frozen plasma, and/or cryoprecipitate.
</p>
<p>
<i>Surveillance:</i> Individuals responding to treatment and HSCT are technically not at risk for other organ system involvement; thus, surveillance focuses on potential complications of fHLH while fHLH is active, such as bleeding, hypotension, respiratory distress, neurologic complications, malnutrition, infection, liver, or other organ failure.
</p>
<p>
<i>Agents/circumstances to avoid:</i> Live vaccines; exposure to infections; acetaminophen in persons with liver failure; nonsteroidal anti-inflammatory drugs in persons with thrombocytopenia; areas of construction or soil manipulation (which increase the risk for fungal infection in individuals with neutropenia); transfusion of non-irradiated blood products in individuals undergoing chemoimmunotherapy and/or allogeneic HSCT.
</p>
<p>
<i>Evaluation of relatives at risk:</i> It is appropriate to identify before symptoms occur those at-risk sibs who have the family-specific pathogenic variants so that they can be monitored and preemptive HSCT considered (particularly during febrile episodes) for development of manifestations of active disease. Any manifestations of possible active disease should prompt more detailed evaluation and referral to a clinician with expertise in fHLH.
</p>
<p>
<strong class="sub-title">
Genetic counseling:
</strong>
Familial HLH is inherited in an autosomal recessive manner. (Autosomal dominant inheritance of <i>STXBP2</i>-fHLH is suggested by rare reports of symptomatic individuals with heterozygous gain-of-function variants. Autosomal dominant inheritance will not be discussed further in this section.)
</p>
<p>
If both parents are known to be heterozygous for an fHLH-causing pathogenic variant, each sib of an affected individual has a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial fHLH-causing pathogenic variants. Once the fHLH-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
</p>
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Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.
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<div class="book-sections" id="book-sections">
<h2 class="title">
Sections
</h2>
<ul>
<li>
<a href="https://www.ncbi.nlm.nih.gov/books/NBK1444/#hlh.Summary" target="_blank" rel="noopener" ref="linksrc=book_abstract_section_link">
Summary
</a>
</li>
<li>
<a href="https://www.ncbi.nlm.nih.gov/books/NBK1444/#hlh.GeneReview_Scope" target="_blank" rel="noopener" ref="linksrc=book_abstract_section_link">
<italic>GeneReview</italic> Scope
</a>
</li>
<li>
<a href="https://www.ncbi.nlm.nih.gov/books/NBK1444/#hlh.Diagnosis" target="_blank" rel="noopener" ref="linksrc=book_abstract_section_link">
Diagnosis
</a>
</li>
<li>
<a href="https://www.ncbi.nlm.nih.gov/books/NBK1444/#hlh.Clinical_Characteristics" target="_blank" rel="noopener" ref="linksrc=book_abstract_section_link">
Clinical Characteristics
</a>
</li>
<li>
<a href="https://www.ncbi.nlm.nih.gov/books/NBK1444/#hlh.Genetically_Related_Allelic_Disorder" target="_blank" rel="noopener" ref="linksrc=book_abstract_section_link">
Genetically Related (Allelic) Disorders
</a>
</li>
<li>
<a href="https://www.ncbi.nlm.nih.gov/books/NBK1444/#hlh.Differential_Diagnosis" target="_blank" rel="noopener" ref="linksrc=book_abstract_section_link">
Differential Diagnosis
</a>
</li>
<li>
<a href="https://www.ncbi.nlm.nih.gov/books/NBK1444/#hlh.Management" target="_blank" rel="noopener" ref="linksrc=book_abstract_section_link">
Management
</a>
</li>
<li>
<a href="https://www.ncbi.nlm.nih.gov/books/NBK1444/#hlh.Genetic_Counseling" target="_blank" rel="noopener" ref="linksrc=book_abstract_section_link">
Genetic Counseling
</a>
</li>
<li>
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Resources
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Molecular Genetics
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Chapter Notes
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<li>
<a href="https://www.ncbi.nlm.nih.gov/books/NBK1444/#hlh.References" target="_blank" rel="noopener" ref="linksrc=book_abstract_section_link">
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