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- #603903 - SICKLE CELL DISEASE
- OMIM
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<span class="h4">#603903</span>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/603903"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#populationGenetics">Population Genetics</a>
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<div><a href="https://clinicaltrials.gov/search?cond=SICKLE CELL DISEASE" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=125&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Hemoglobin-S-ACT-Sheet.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG ACT Sheet</a></div><div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Hemoglobin-SC-Disease-ACT-Sheet.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG ACT Sheet</a></div><div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Sickle-Cell-Anemia-HBss.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG ACT Sheet</a></div><div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Sickle-Cell-Carrier-ACT-Sheet.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG ACT Sheet</a></div><div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/HB-S-Screening-Algorithm.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG Algorithm</a></div>
</div>
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=232" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
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</a>
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</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0081445" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/603903" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:603903" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 127040003, 417357006<br />
<strong>ICD10CM:</strong> D57, D57.1<br />
<strong>ICD9CM:</strong> 282.6, 282.60<br />
<strong>ORPHA:</strong> 232<br />
<strong>DO:</strong> 0081445<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
603903
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
SICKLE CELL DISEASE
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
SICKLE CELL ANEMIA
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/110?start=-3&limit=10&highlight=110">
11p15.4
</a>
</span>
</td>
<td>
<span class="mim-font">
Sickle cell disease
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603903"> 603903 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
HBB
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/141900"> 141900 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/603903" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/603903" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/603903" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Vascular </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Vasculopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/27550009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">27550009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042373&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042373</a>]</span><br /> -
Microcirculatory occlusion <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4315238&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4315238</a>]</span><br /> -
Pulmonary hypertension <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/70995007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">70995007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I27.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I27.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020542&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020542</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002092" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002092</a>]</span><br /> -
Hyperemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30098003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30098003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020452&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020452</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> RESPIRATORY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Lung </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Acute chest syndrome <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/372146004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">372146004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/517.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">517.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0742343&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0742343</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Abdominal pain <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/21522001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">21522001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R10.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R10.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/789.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0000737&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0000737</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002027</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002027</a>]</span><br />
</span>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Spleen </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Functional asplenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38096003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38096003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0272405&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0272405</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> External Genitalia (Male) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Priapism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/6273006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">6273006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N48.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N48.30</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N48.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N48.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/607.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">607.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0033117&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0033117</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0200023" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0200023</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0200023" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0200023</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Kidneys </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Renal failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/42399005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">42399005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N19" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N19</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/586" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">586</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0035078&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035078</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000083</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000083</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Limbs </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Avascular joint necrosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4315240&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4315240</a>]</span><br /> -
Joint and leg pain <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4315239&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4315239</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pain, secondary to vasoocclusion <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4315242&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4315242</a>]</span><br /> -
Stroke <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230690007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230690007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I63.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I63.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038454&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038454</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEMATOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Sickled erythrocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2237347&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2237347</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030058" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030058</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030058" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030058</a>]</span><br /> -
Anisocytosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165475005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165475005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/57241006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">57241006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R71.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R71.8</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221278&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221278</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011273" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011273</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011273" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011273</a>]</span><br /> -
Poikilocytosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165479004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165479004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R71.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R71.8</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221281&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221281</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004447" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004447</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004447" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004447</a>]</span><br /> -
Sickle cell anemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/127040003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">127040003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/417357006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">417357006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D57.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D57.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D57" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D57</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/282.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">282.6</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/282.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">282.60</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002895&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002895</a>]</span><br /> -
Anemia, chronic <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/191268006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">191268006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/291262006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">291262006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D53.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D53.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0581384&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0581384</a>]</span><br /> -
Hemolysis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/73320003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">73320003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/260882000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">260882000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/404227002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">404227002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2945560&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2945560</a>, <a href="https://bioportal.bioontology.org/search?q=C1548777&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1548777</a>, <a href="https://bioportal.bioontology.org/search?q=C2937287&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2937287</a>, <a href="https://bioportal.bioontology.org/search?q=C1553188&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1553188</a>, <a href="https://bioportal.bioontology.org/search?q=C0019054&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019054</a>]</span><br /> -
Hypoxemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1157018000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1157018000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/389087006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">389087006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R09.02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R09.02</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/799.02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">799.02</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700292&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700292</a>, <a href="https://bioportal.bioontology.org/search?q=C5548348&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5548348</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012418" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012418</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012418" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012418</a>]</span><br /> -
Leukocytosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/414478003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">414478003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111583006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111583006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.82" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.82</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.829</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/288.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.60</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/288.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.6</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023518&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023518</a>, <a href="https://bioportal.bioontology.org/search?q=C0750426&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0750426</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001974" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001974</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001974" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001974</a>]</span><br />
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<div>
<span class="h5 mim-font">
<strong> IMMUNOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Increased susceptibility to bacterial infections <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748958&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748958</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002718</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002718</a>]</span><br /> -
Resistance to falciparum malaria infection <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4315241&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4315241</a>]</span><br />
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<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Persistence of fetal hemoglobin can ameliorate many disease aspects<br /> -
Presence of comorbid alpha-thalassemia may have beneficial effects<br />
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<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the hemoglobin beta gene (HBB, <a href="/entry/141900#0243">141900.0243</a>)<br />
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<p>A number sign (#) is used with this entry because sickle cell disease is the result of mutant beta globin (HBB; <a href="/entry/141900">141900</a>) in which the mutation causes sickling of hemoglobin.</p>
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<p>Sickle cell disease is a multisystem disease associated with episodes of acute illness and progressive organ damage. Hemoglobin polymerization, leading to erythrocyte rigidity and vasoocclusion, is central to the pathophysiology of the disease, but the importance of chronic anemia, hemolysis, and vasculopathy has been established. The most common cause of sickle cell anemia is the HbS variant (<a href="/entry/141900#0243">141900.0243</a>), with hemoglobin SS disease being most prevalent in Africans (review by <a href="#59" class="mim-tip-reference" title="Rees, D. C., Williams, T. N., Gladwin, M. T. &lt;strong&gt;Sickle cell disease.&lt;/strong&gt; Lancet 376: 2018-2031, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21131035/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21131035&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(10)61029-X&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21131035">Rees et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21131035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>See review of infection in sickle cell disease by <a href="#6" class="mim-tip-reference" title="Booth, C., Inusa, B., Obaro, S. K. &lt;strong&gt;Infection in sickle cell disease: a review.&lt;/strong&gt; Int. J. Infect. Dis. 14: e2-e12, 2010. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19497774/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19497774&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ijid.2009.03.010&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19497774">Booth et al. (2010)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19497774" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#55" class="mim-tip-reference" title="Piel, F. B., Steinberg, M. H., Rees, D. C. &lt;strong&gt;Sickle cell disease.&lt;/strong&gt; New Eng. J. Med. 376: 1561-1573, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28423290/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28423290&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMra1510865&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28423290">Piel et al. (2017)</a> reviewed the genetic and nongenetic modifiers of the severity of sickle cell disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28423290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#65" class="mim-tip-reference" title="Scriver, J. B., Waugh, T. R. &lt;strong&gt;Studies on a case of sickle-cell anaemia.&lt;/strong&gt; Canad. Med. Assoc. J. 23: 375-380, 1930.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20317973/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20317973&lt;/a&gt;]" pmid="20317973">Scriver and Waugh (1930)</a> reported detailed studies of a 7-year-old child with sickle cell anemia. Her main complaints were cough, night sweats, vague pains in the legs and joints, occasional abdominal pain, poor appetite, and increasing fatigue. In a series of clever experiments that involved taking venous blood from the arm under different circumstances, the authors showed a correlation between oxygen tension and sickling of the red blood cells in vivo. Increased sickling was observed when oxygen pressure fell below 40 to 45 mm Hg. <a href="#65" class="mim-tip-reference" title="Scriver, J. B., Waugh, T. R. &lt;strong&gt;Studies on a case of sickle-cell anaemia.&lt;/strong&gt; Canad. Med. Assoc. J. 23: 375-380, 1930.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20317973/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20317973&lt;/a&gt;]" pmid="20317973">Scriver and Waugh (1930)</a> concluded that large aggregations of sickle cells seen in sinuses, vessels, and organs of sickle cell patients at autopsy reflected lowered oxygen tension resulting from death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20317973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In many children with sickle cell anemia, functional asplenia develops during the first year of life and septicemia is the leading cause of death in childhood. The risk of septicemia in sickle cell anemia is greatest during the first 3 years of life and is reduced markedly by prophylactic penicillin therapy. Less is known about splenic dysfunction and the risk of overwhelming sepsis in children with sickle cell-hemoglobin C disease (see HbC; <a href="/entry/141900#0038">141900.0038</a>), although functional asplenia has been documented by radionuclide liver-spleen scans in some adult patients (<a href="#4" class="mim-tip-reference" title="Ballas, S. K., Lewis, C. N., Noone, A. M., Krasnow, S. H., Kamarulzaman, E., Burka, E. R. &lt;strong&gt;Clinical, hematological, and biochemical features of Hb SC disease.&lt;/strong&gt; Am. J. Hemat. 13: 37-51, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7137165/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7137165&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajh.2830130106&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7137165">Ballas et al., 1982</a>) and an elevated erythrocyte pit count, a finding that indicates functional asplenia in children with sickle cell anemia, also has been found in some children with SC disease (<a href="#52" class="mim-tip-reference" title="Pearson, H. A., Gallagher, D., Chilcote, R., Sullivan, E., Wilimas, J., Espeland, M., Ritchey, A. K., Cooperative Study of Sickle Cell Disease. &lt;strong&gt;Developmental pattern of splenic dysfunction in sickle cell disorders.&lt;/strong&gt; Pediatrics 76: 392-397, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2412200/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2412200&lt;/a&gt;]" pmid="2412200">Pearson et al., 1985</a>). <a href="#35" class="mim-tip-reference" title="Lane, P. A., Rogers, Z. R., Woods, G. M., Wang, W. C., Wilimas, J. A., Miller, S. T., Khakoo, Y., Buchanan, G. R. &lt;strong&gt;Fatal pneumococcal septicemia in hemoglobin SC disease.&lt;/strong&gt; J. Pediat. 124: 859-862, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8201467/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8201467&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(05)83171-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8201467">Lane et al. (1994)</a> reported 7 fatal cases of pneumococcal septicemia in children with SC disease. The earliest death occurred in a 1-year-old child who had cyanotic congenital heart; the other children were aged 3.5 to 15 years. Only 1 child had received pneumococcal vaccine or prophylactic penicillin therapy. All 7 children had an acute febrile illness and rapid deterioration despite parenterally administered antibiotic therapy and intensive medical support. Erythrocyte pit counts in 2 patients were 40.3 and 41.7%, respectively (normal, less than 3.6%). Autopsy findings in 5 cases included splenic congestion without infarction in 5, splenomegaly in 4, and bilateral adrenal hemorrhage in 3. <a href="#35" class="mim-tip-reference" title="Lane, P. A., Rogers, Z. R., Woods, G. M., Wang, W. C., Wilimas, J. A., Miller, S. T., Khakoo, Y., Buchanan, G. R. &lt;strong&gt;Fatal pneumococcal septicemia in hemoglobin SC disease.&lt;/strong&gt; J. Pediat. 124: 859-862, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8201467/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8201467&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(05)83171-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8201467">Lane et al. (1994)</a> concluded that pneumococcal vaccine should be administered in all children with SC disease. The routine use of prophylactic penicillin therapy in infants and children with SC disease remained controversial. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2412200+7137165+8201467" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Morris, J., Dunn, D., Beckford, M., Grandison, Y., Mason, K., Higgs, D., De Ceulaer, K., Serjeant, B., Serjeant, G. &lt;strong&gt;The haematology of homozygous sickle cell disease after the age of 40 years.&lt;/strong&gt; Brit. J. Haemat. 77: 382-385, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1707292/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1707292&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1365-2141.1991.tb08588.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1707292">Morris et al. (1991)</a> reported hematologic findings in 181 patients, aged 40 to 73 years, with hemoglobin SS disease. The studies showed a downward age-related trend in hemoglobin and platelets and falling reticulocyte count consistent with progressive bone marrow failure which could not be explained by renal impairment. <a href="#32" class="mim-tip-reference" title="Kodish, E., Lantos, J., Stocking, C., Singer, P. A., Siegler, M., Johnson, F. L. &lt;strong&gt;Bone marrow transplantation for sickle cell disease: a study of parents&#x27; decisions.&lt;/strong&gt; New Eng. J. Med. 325: 1349-1353, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1922237/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1922237&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199111073251905&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1922237">Kodish et al. (1991)</a> concluded that despite current rates of mortality and morbidity with bone marrow transplantation, a substantial minority of parents of children with sickle cell disease would consent to bone marrow transplantation for their children. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1707292+1922237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Adams, R. J. &lt;strong&gt;Sickle cell disease and stroke. (Editorial)&lt;/strong&gt; J. Child Neurol. 10: 75-76, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7782612/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7782612&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1177/088307389501000201&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7782612">Adams (1995)</a> reviewed the literature on sickle cell disease and stroke. Previous studies had shown clinically evident cerebral vascular disease in 7 to 8% of cohorts followed during the first 2 weeks of life. However, MRI series demonstrated 11 to 24% of cerebral vascular accidents in patients with sickle cell disease, indicating a large proportion of silent infarctions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7782612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The defect in urine concentrating ability in persons with sickle cell trait is thought to result from intracellular polymerization of Hb S in erythrocytes, leading to microvascular occlusion, in the vasa recta of the renal medulla. Reasoning that the severity of the concentration defect might be related to the percentage of sickle hemoglobin present in erythrocytes, <a href="#23" class="mim-tip-reference" title="Gupta, A. K., Kirchner, K. A., Nicholson, R., Adams, J. G., III, Schechter, A. N., Noguchi, C. T., Steinberg, M. H. &lt;strong&gt;Effects of alpha-thalassemia and sickle polymerization tendency on the urine-concentrating defect of individuals with sickle cell trait.&lt;/strong&gt; J. Clin. Invest. 88: 1963-1968, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1752955/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1752955&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI115521&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1752955">Gupta et al. (1991)</a> studied urine concentrating ability in 3 classes of A/S individuals, those with a normal alpha-globin genotype and those who were either heterozygous or homozygous for the gene-deletion type of alpha-thalassemia. They found a correlation between urine concentrating ability and the percentage of sickle hemoglobin, which was highest in the individuals with normal alpha-globin genotype and lowest in those homozygous for the deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1752955" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#72" class="mim-tip-reference" title="Steinberg, M. H. &lt;strong&gt;Sickle cell anemia in a septuagenarian.&lt;/strong&gt; Brit. J. Haemat. 71: 297-298, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2923816/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2923816&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1365-2141.1989.tb04274.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2923816">Steinberg (1989)</a> described a 73-year-old black man in Mississippi who had hematologically and genotypically typical sickle cell anemia with, however, very mild clinical manifestations. He had had cholecystectomy for asymptomatic cholelithiasis at the age of about 47. He had had partial priapism. In a large study involving 2,590 patients over 5 years of age at entry and followed for an average of 5.6 years, <a href="#41" class="mim-tip-reference" title="Milner, P. F., Kraus, A. P., Sebes, J. I., Sleeper, L. A., Dukes, K. A., Embury, S. H., Bellevue, R., Koshy, M., Moohr, J. W., Smith, J. &lt;strong&gt;Sickle cell disease as a cause of osteonecrosis of the femoral head.&lt;/strong&gt; New Eng. J. Med. 325: 1476-1481, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1944426/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1944426&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199111213252104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1944426">Milner et al. (1991)</a> found an overall prevalence of osteonecrosis of the femoral head of about 10%. Patients with the hemoglobin SS genotype and alpha-thalassemia and those with frequent painful crises were at highest risk. Osteonecrosis was found in patients as young as 5 years old. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1944426+2923816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#71" class="mim-tip-reference" title="Steinberg, M. H., Ballas, S. K., Brunson, C. Y., Bookchin, R. &lt;strong&gt;Sickle cell anemia in septuagenarians. (Letter)&lt;/strong&gt; Blood 86: 3997-4002, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7579371/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7579371&lt;/a&gt;]" pmid="7579371">Steinberg et al. (1995)</a> presented 5 cases of sickle cell anemia in individuals in their 70s. They concluded that 'We do not understand why some patients with sickle cell anemia survive their peers by decades just as we have little insight into why occasional normal individuals live far beyond the average number of years.' Sickle cell patients that express gamma-globin at 10 to 20% of the level of sickle globin in most of their red blood cells have greatly improved clinical prognoses (<a href="#33" class="mim-tip-reference" title="Lan, N., Howrey, R. P., Lee, S.-W., Smith, C. A., Sullenger, B. A. &lt;strong&gt;Ribozyme-mediated repair of sickle beta-globin mRNAs in erythrocyte precursors.&lt;/strong&gt; Science 280: 1593-1596, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9616120/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9616120&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.280.5369.1593&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9616120">Lan et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9616120+7579371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Langdown, J. V., Williamson, D., Knight, C. B., Rubenstein, D., Carrell, R. W. &lt;strong&gt;A new doubly substituted sickling haemoglobin: HbS-Oman.&lt;/strong&gt; Brit. J. Haemat. 71: 443-444, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2930724/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2930724&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1365-2141.1989.tb04304.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2930724">Langdown et al. (1989)</a> described a doubly substituted sickling hemoglobin, called HbS (Oman) (<a href="/entry/141900#0245">141900.0245</a>). The higher expressors of HbS (Oman) had a sickle cell anemia clinical syndrome of moderate intensity, whereas the lower expressors had no clinical syndrome and were comparable to the solitary case first described in Oman. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2930724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#58" class="mim-tip-reference" title="Popp, R. A., Popp, D. M., Shinpock, S. G., Yang, M. Y., Mural, J. G., Aguinaga, M. P., Kopsombut, P., Roa, P. D., Turner, E. A., Rubin, E. M. &lt;strong&gt;A transgenic mouse model of hemoglobin S Antilles disease.&lt;/strong&gt; Blood 89: 4204-4212, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9166865/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9166865&lt;/a&gt;]" pmid="9166865">Popp et al. (1997)</a> stated that the sickle cell anemia syndrome produced by HbS Antilles (<a href="/entry/141900#0244">141900.0244</a>) is a more severe phenotype than that produced by HbS. Humans heterozygous for HbS have RBCs that contain approximately 40% HbS, but do not exhibit clinical symptoms of sickle cell disease. In comparison, humans heterozygous for HbS Antilles have RBCs that contain approximately 40% HbS Antilles, but these individuals exhibit clinical symptoms of sickle cell disease that are similar in severity to those in persons who are homozygous for HbS. This is because Hb S Antilles is less soluble and has a right shift in its oxygen association-dissociation curve, properties that favor deoxygenation and polymerization of Hb S Antilles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9166865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#60" class="mim-tip-reference" title="Rey, K. S., Unger, C. A., Rao, S. P., Miller, S. T. &lt;strong&gt;Sickle cell-hemoglobin E disease: clinical findings and implications.&lt;/strong&gt; J. Pediat. 119: 949-951, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1960615/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1960615&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(05)83053-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1960615">Rey et al. (1991)</a> described sickle cell/hemoglobin E (SE) disease (<a href="/entry/141900#0071">141900.0071</a>) in 3 black American children of Haitian origin. They pointed out that the disorder is probably more benign than SC disease, SC (Arab) disease (<a href="/entry/141900#0202">141900.0202</a>), and SC (Harlem) disease (<a href="/entry/141900#0039">141900.0039</a>), all of which have increased risk of the complications of sickling including pneumococcal sepsis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1960615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#80" class="mim-tip-reference" title="Walker, T. M., Hambleton, I. R., Serjeant, G. R. &lt;strong&gt;Gallstones in sickle cell disease: observations from the Jamaican Cohort Study.&lt;/strong&gt; J. Pediat. 136: 80-85, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10636979/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10636979&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(00)90054-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10636979">Walker et al. (2000)</a> studied the prevalence, incidence, risk factors, clinical associations, and morbidity of gallstones in 311 patients with homozygous sickle cell disease and 167 patients with sickle cell-hemoglobin C disease in a cohort studied from birth. Gallstones developed in 96 patients with hemoglobin SS disease and 18 patients with SC disease; specific symptoms necessitating cholecystectomy occurred in only 7 patients with homozygous SS disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10636979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Adler, B. K., Salzman, D. E., Carabasi, M. H., Vaughan, W. P., Reddy, V. V. B., Prchal, J. T. &lt;strong&gt;Fatal sickle cell crisis after granulocyte colony-stimulating factor administration. (Letter)&lt;/strong&gt; Blood 97: 3313-3314, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11368061/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11368061&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood.v97.10.3313&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11368061">Adler et al. (2001)</a> described a patient with mild HbSC disease who, after administration of granulocyte colony-stimulating factor (GCSF; <a href="/entry/138970">138970</a>) for collection of peripheral stem cells, developed sickle cell crisis and died within 36 hours. The case strongly suggested a role for granulocytes in acute sickle cell complications and a need for caution in the use of GCSF in this disorder. The patient was a 47-year-old African American woman who had learned she had HbSC disease only 6 weeks earlier. She had no history of sickle cell crisis. HbSC disease was diagnosed after a hemoglobinopathy evaluation at the time of HLA typing, done in preparation for her to become a stem cell donor for her sister, who had chronic myeloid leukemia and mild HbSC disease. The patient was the only sib and had a 6 of 6 antigen match. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11368061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#74" class="mim-tip-reference" title="Thomas, P. W., Singhal, A., Hemmings-Kelly, M., Serjeant, G. R. &lt;strong&gt;Height and weight reference curves for homozygous sickle cell disease.&lt;/strong&gt; Arch. Dis. Child. 82: 204-208, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10685921/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10685921&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.82.3.204&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10685921">Thomas et al. (2000)</a> presented growth curves for children aged 0-18 years with homozygous sickle cell disease. These were derived from 315 participants in a longitudinal cohort study in Kingston, Jamaica. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10685921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Ashley-Koch, A., Murphy, C. C., Khoury, M. J., Boyle, C. A. &lt;strong&gt;Contribution of sickle cell disease to the occurrence of developmental disabilities: a population-based study.&lt;/strong&gt; Genet. Med. 3: 181-186, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11388758/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11388758&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00125817-200105000-00006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11388758">Ashley-Koch et al. (2001)</a> performed population-based surveillance of children aged 3 to 10 years from metropolitan Atlanta to determine if stroke-related neurologic damage in children with sickle cell disease is associated with developmental disabilities. Children with sickle cell disease had an increased risk for developmental disabilities of 3.2, with a P value of less than 0.0001, particularly mental retardation (RR = 2.7, P = 0.0005) and cerebral palsy (RR = 10.8, P less than 0.0001). This risk was confined to developmental disabilities associated with stroke (RR = 130, P less than 0.0001; for developmental disabilities without stroke the relative risk was only 1.3 with a P value of 0.23). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11388758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Gladwin, M. T., Sachdev, V., Jison, M. L., Shizukuda, Y., Plehn, J. F., Minter, K., Brown, B., Coles, W. A., Nichols, J. S., Ernst, I., Hunter, L. A., Blackwelder, W. C., Schechter, A. N., Rodgers, G. P., Castro, O., Ognibene, F. P. &lt;strong&gt;Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.&lt;/strong&gt; New Eng. J. Med. 350: 886-895, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14985486/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14985486&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa035477&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14985486">Gladwin et al. (2004)</a> demonstrated that pulmonary hypertension, diagnosed by doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14985486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Priapism, although uncommon in the general population, is one of the most serious complications associated with sickle cell disease. <a href="#47" class="mim-tip-reference" title="Nolan, V. G., Wyszynski, D. F., Farrer, L. A., Steinberg, M. H. &lt;strong&gt;Hemolysis-associated priapism in sickle cell disease.&lt;/strong&gt; Blood 106: 3264-3267, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15985542/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15985542&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2005-04-1594&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15985542">Nolan et al. (2005)</a> assembled 273 patients with sickle cell disease and priapism and 979 control subjects with sickle cell disease and no priapism. Case subjects, compared with controls, had significantly lower hemoglobin levels, higher levels of lactate dehydrogenase, bilirubin, and aspartate aminotransferase, and higher reticulocyte, white blood cell, and platelet counts. The findings suggested an association of priapism with increased hemolysis. Hemolysis decreases the availability of circulating nitric oxide, which plays an important role in erectile function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15985542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Gladwin, M. T. &lt;strong&gt;Unraveling the hemolytic subphenotype of sickle cell disease.&lt;/strong&gt; Blood 106: 2925-2926, 2005."None>Gladwin (2005)</a> discussed the hemolytic subphenotype of sickle cell disease. He pointed out that hemolytic anemia, while silent from a vasoocclusive pain crisis standpoint, leads to sustained nitric oxide depletion, oxidant stress, vasoconstriction, and proliferative vasculopathy in a number of organ systems, ultimately contributing to the development of priapism, cutaneous leg ulceration, pulmonary hypertension, sudden death, and possibly stroke.</p><p>In a Jamaican study, <a href="#68" class="mim-tip-reference" title="Serjeant, G. R., Richards, R., Barbor, P. R. H., Milner, P. F. &lt;strong&gt;Relatively benign sickle cell anaemia in 60 patients aged over 30 in the West Indies.&lt;/strong&gt; Brit. Med. J. 3: 86-91, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4232783/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4232783&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/bmj.3.5610.86&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4232783">Serjeant et al. (1968)</a> described 60 patients with homozygous sickle cell disease who were 30 years of age or older, and <a href="#56" class="mim-tip-reference" title="Platt, O. S., Brambilla, B. J., Rosse, W. F., Milner, P. F., Castro, O., Steinberg, M. H., Klug, P. P. &lt;strong&gt;Mortality in sickle cell disease: life expectancy and risk factors for early death.&lt;/strong&gt; New Eng. J. Med. 330: 1639-1644, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7993409/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7993409&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199406093302303&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7993409">Platt et al. (1994)</a> estimated a median survival of 42 to 48 years. <a href="#67" class="mim-tip-reference" title="Serjeant, G. R., Higgs, D. R., Hambleton, I. R. &lt;strong&gt;Elderly survivors with homozygous sickle cell disease. (Letter)&lt;/strong&gt; New Eng. J. Med. 356: 642-643, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17287491/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17287491&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMc066547&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17287491">Serjeant et al. (2007)</a> stated that the sickle cell clinic at the University of West Indies had treated 102 patients (64.7% women) who survived beyond their 60th birthday. None of the patients received hydroxyurea, and only 2 patients with renal impairment received regular transfusions. The ages of the patients ranged from 60.2 to 85.6 years. Measurement of fetal hemoglobin levels suggested that higher fetal hemoglobin levels probably conferred protection in childhood. The major clinical problems emerging with age were renal impairment and decreased levels of hemoglobin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17287491+7993409+4232783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Malaria Resistance</em></strong></p><p>
<a href="#19" class="mim-tip-reference" title="Friedman, M. J., Trager, W. &lt;strong&gt;The biochemistry of resistance to malaria.&lt;/strong&gt; Sci. Am. 244(3): 154-164, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6163210/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6163210&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/scientificamerican0381-154&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6163210">Friedman and Trager (1981)</a> reviewed the mechanism of resistance of SA cells to falciparum malaria (see <a href="/entry/611162">611162</a>). The cell infected by the falciparum but not by the other malarial parasites develops knobs in its surface which leads to its sticking to the endothelium of small blood vessels such as those in the brain. In such sequestered sites sickling takes place because of the low oxygen concentration. Perforation of the membranes of the parasite as a result of physical injury and perforation of the red cell membrane occur with loss of potassium. In an in vitro test system, death of the parasites can be prevented by high potassium in the medium. The infected red cell is more acidic than the uninfected cell so that the rate of sickling is increased by this factor also. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6163210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Studying transgenic mice expressing the human A-gamma and G-gamma globin chains and challenged with rodent malaria, <a href="#69" class="mim-tip-reference" title="Shear, H. L., Grinberg, L., Gilman, J., Fabry, M. E., Stamatoyannopoulos, G., Goldberg, D. E., Nagel, R. L. &lt;strong&gt;Transgenic mice expressing human fetal globin are protected from malaria by a novel mechanism.&lt;/strong&gt; Blood 92: 2520-2526, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9746793/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9746793&lt;/a&gt;]" pmid="9746793">Shear et al. (1998)</a> found that the mice cleared the infection and survived even if splenectomy had been performed. Light microscopy showed that intraerythrocytic parasites developed slowly in HbF erythrocytes, and electron microscopy showed that hemozoin formation was defective in transgenic mice. Digestion studies of HbF by recombinant plasmepsin II demonstrated that HbF is digested only half as well as hemoglobin A (HBA). <a href="#69" class="mim-tip-reference" title="Shear, H. L., Grinberg, L., Gilman, J., Fabry, M. E., Stamatoyannopoulos, G., Goldberg, D. E., Nagel, R. L. &lt;strong&gt;Transgenic mice expressing human fetal globin are protected from malaria by a novel mechanism.&lt;/strong&gt; Blood 92: 2520-2526, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9746793/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9746793&lt;/a&gt;]" pmid="9746793">Shear et al. (1998)</a> concluded that HbF provides protection from Plasmodium falciparum malaria by the retardation of parasite growth. The mechanism involves resistance to digestion by malarial hemoglobinases based on the data presented and with the well-known properties of HbF as a super stable tetramer. In addition, the resistance of normal neonates for malaria can now be explained a by double mechanism: increased malaria invasion rates, reported in neonatal RBC, will direct parasites to fetal cells, as well as F cells, and less to the approximately 20% of cells that contain HbA, thus amplifying the antimalarial effects of HbF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9746793" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Sickle Trait</em></strong></p><p>
In Denver, <a href="#34" class="mim-tip-reference" title="Lane, P. A., Githens, J. H. &lt;strong&gt;Splenic syndrome at mountain altitudes in sickle cell trait: its occurrence in nonblack persons.&lt;/strong&gt; JAMA 253: 2251-2254, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3974118/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3974118&lt;/a&gt;]" pmid="3974118">Lane and Githens (1985)</a> observed the splenic syndrome (severe left-upper-quadrant abdominal pain) in 6 nonblack men with sickle cell trait who developed symptoms within 48 hours of arrival in Colorado from lower altitudes. The authors discussed the possibility that nonblacks may be at greater risk of trouble because of lack of other genetic make-up that through evolution has come to ameliorate the effects of the sickle gene in Africans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3974118" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Kark, J. A., Posey, D. M., Schumacher, H. R., Ruehle, C. J. &lt;strong&gt;Sickle-cell trait as a risk factor for sudden death in physical training.&lt;/strong&gt; New Eng. J. Med. 317: 781-787, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3627196/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3627196&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198709243171301&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3627196">Kark et al. (1987)</a> studied the frequency of sudden unexplained death among enlisted recruits during basic training in the U.S. Armed Forces from 1977 to 1981. They found that death rates per 100,000 were 32.2 for sudden unexplained deaths, 2.7 for sudden explained deaths, and zero for nonsudden deaths among black recruits with hemoglobin AS, as compared with 1.2, 1.2, and 0.7 among black recruits without hemoglobin S and 0.7, 0.5 and 1.1 among nonblack recruits without hemoglobin S. Among black recruits the relative risk of sudden unexplained death (hemoglobin AS vs nonhemoglobin S) was 27.6, whereas among all recruits this risk was 39.8. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3627196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Acute Chest Syndrome</em></strong></p><p>
The acute chest syndrome is a leading cause of death among patients with sickle cell disease. In a 30-center study, <a href="#79" class="mim-tip-reference" title="Vichinsky, E. P., Neumayr, L. D., Earles, A. N., Williams, R., Lennette, E. T., Dean, D., Nickerson, B., Orringer, E., McKie, V., Bellevue, R., Daeschner, C., Manci, E. A. &lt;strong&gt;Causes and outcomes of the acute chest syndrome in sickle cell disease.&lt;/strong&gt; New Eng. J. Med. 342: 1855-1865, 2000. Note: Erratum: New Eng. J. Med. 343: 824 only, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10861320/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10861320&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM200006223422502&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10861320">Vichinsky et al. (2000)</a> analyzed 671 episodes of the acute chest syndrome in 538 patients with sickle cell disease to determine the cause, outcome, and response to therapy. They found that among patients with sickle cell disease, the acute chest syndrome is commonly precipitated by fat embolism and infection, especially community-acquired pneumonia. Among older patients and those with neurologic symptoms, the syndrome often progressed to respiratory failure. Treatment with transfusions and bronchodilators improved oxygenation, and with aggressive treatment most patients who had respiratory failure recovered. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#57" class="mim-tip-reference" title="Platt, O. S. &lt;strong&gt;The acute chest syndrome of sickle cell disease. (Editorial)&lt;/strong&gt; New Eng. J. Med. 342: 1904-1907, 2000. Note: Erratum: New Eng. J. Med. 343: 591 only, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10861328/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10861328&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM200006223422510&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10861328">Platt (2000)</a> commented on the acute chest syndrome in sickle cell disease. A good working definition of the acute chest syndrome is the presence of a new pulmonary infiltrate, not atelectasis, involving at least one complete lung segment, with chest pain, a temperature of more than 38.5 degrees C, tachypnea, wheezing, or cough in a patient with sickle cell disease. As reported by <a href="#11" class="mim-tip-reference" title="Charache, S., Terrin, M. L., Moore, R. D., Dover, G. J., Barton, F. B., Eckert, S. V., McMahon, R. P., Bonds, D. R., Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. &lt;strong&gt;Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia.&lt;/strong&gt; New Eng. J. Med. 332: 1317-1322, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7715639/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7715639&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199505183322001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7715639">Charache et al. (1995)</a>, there is a 50% reduction in both painful crises and episodes of the acute chest syndrome with long-term treatment with hydroxyurea which results in increased production of fetal hemoglobin and decreased polymerization. The positive effect on the acute chest syndrome probably results from the fact that there are fewer episodes of bone marrow ischemia and embolization. Another explanation may be that the small reduction in white cell count associated with hydroxyurea therapy enhances the effect of increased fetal hemoglobin by dampening the inflammatory response that promotes polymerization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10861328+7715639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>As indicated by <a href="#26" class="mim-tip-reference" title="Hebbel, R. P. &lt;strong&gt;Adhesive interactions of sickle erythrocytes with endothelium.&lt;/strong&gt; J. Clin. Invest. 99: 2561-2564, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9169483/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9169483&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI119442&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9169483">Hebbel (1997)</a>, a factor contributing to the vasoocclusive process in sickle cell disease is abnormal adhesion of sickle cells (even oxygenated ones) to the vascular endothelium. <a href="#31" class="mim-tip-reference" title="Kaul, D. K., Tsai, H. M., Liu, X. D., Nakada, M. T., Nagel, R. L., Coller, B. S. &lt;strong&gt;Monoclonal antibodies to alpha-v-beta-3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor.&lt;/strong&gt; Blood 95: 368-374, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10627437/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10627437&lt;/a&gt;]" pmid="10627437">Kaul et al. (2000)</a> explored experimentally in animals the use of monoclonal antibodies to block adhesion of sickle cells to endothelium. This approach was evaluated by <a href="#27" class="mim-tip-reference" title="Hebbel, R. P. &lt;strong&gt;Blockade of adhesion of sickle cells to endothelium by monoclonal antibodies. (Editorial)&lt;/strong&gt; New Eng. J. Med. 342: 1910-1912, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10861330/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10861330&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM200006223422512&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10861330">Hebbel (2000)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10861330+9169483+10627437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Manci, E. A., Culberson, D. E., Yang, Y.-M., Gardner, T. M., Powell, R., Haynes, J., Jr., Shah, A. K., Mankad, V. N., Investigators of the Cooperative Study of Sickle Cell Disease. &lt;strong&gt;Causes of death in sickle cell disease: an autopsy study.&lt;/strong&gt; Brit. J. Haemat. 123: 359-365, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14531921/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14531921&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1046/j.1365-2141.2003.04594.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14531921">Manci et al. (2003)</a> studied the morphologic evidence of the cause of death in 306 autopsies of sickle cell disease, accrued between 1929 and 1996. The most common cause of death for all sickle variants and for all age groups was infection (33 to 48%). Other causes of death included stroke (9.8%), complications of therapy (7%), splenic sequestration (6.6%), pulmonary emboli/thrombi (4.9%), renal failure (4.1%), pulmonary hypertension (2.9%), hepatic failure (0.8%), massive hemolysis/red cell aplasia (0.4%), and left ventricular failure (0.4%). Death was frequently sudden and unexpected (40.8%) or occurred within 24 hours after presentation (28.4%), and was usually associated with acute events (63.3%). The study showed that the first 24 hours after presentation for medical care is an especially perilous time for patients with sickle cell disease and an acute event. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14531921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="diagnosis" class="mim-anchor"></a>
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<strong>Diagnosis</strong>
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<p><strong><em>Prenatal Diagnosis</em></strong></p><p>
As a preliminary step to preimplantation diagnosis of sickle cell disease in unfertilized eggs or 8-cell embryos of heterozygous parents, <a href="#43" class="mim-tip-reference" title="Monk, M., Kenealy, M.-R., Mohadjerani, S. &lt;strong&gt;Detection of both the normal and mutant alleles in single cells of individuals heterozygous for the sickle cell mutation--prelude to preimplantation diagnosis.&lt;/strong&gt; Prenatal Diag. 13: 45-53, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8446570/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8446570&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/pd.1970130107&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8446570">Monk et al. (1993)</a> established quality control by detection of the mutant and normal alleles of the HBB gene using single buccal cells. Efficient PCR amplification of a 680-bp sequence of the HBB gene spanning the site of the HbS mutation was obtained for 79% of single heterozygous cells. In 71% of cases, both alleles were detected. <a href="#43" class="mim-tip-reference" title="Monk, M., Kenealy, M.-R., Mohadjerani, S. &lt;strong&gt;Detection of both the normal and mutant alleles in single cells of individuals heterozygous for the sickle cell mutation--prelude to preimplantation diagnosis.&lt;/strong&gt; Prenatal Diag. 13: 45-53, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8446570/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8446570&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/pd.1970130107&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8446570">Monk et al. (1993)</a> predicted that with that level of efficiency, a clinical preimplantation diagnosis at the 8-cell embryo stage could be carried out safely and reliably for a couple at risk of transmitting sickle cell disease to their children. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8446570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>As a substitute for obtaining fetal cells for genetic diagnosis by the invasive procedures of amniocentesis, chorionic villus sampling, and fetal blood sampling, <a href="#12" class="mim-tip-reference" title="Cheung, M.-C., Goldberg, J. D., Kan, Y. W. &lt;strong&gt;Prenatal diagnosis of sickle cell anaemia and thalassaemia by analysis of fetal cells in maternal blood.&lt;/strong&gt; Nature Genet. 14: 264-268, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8896554/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8896554&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1196-264&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8896554">Cheung et al. (1996)</a> reported a method for detecting point mutations in single gene disorders by enriching fetal cells from maternal blood by magnetic cell sorting followed by isolation of pure fetal cells by microdissection. In 2 pregnancies at risk for sickle cell anemia and beta-thalassemia, they successfully identified the fetal genotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8896554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#85" class="mim-tip-reference" title="Xu, K., Shi, Z. M., Veeck, L. L., Hughes, M. R., Rosenwaks, Z. &lt;strong&gt;First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia.&lt;/strong&gt; JAMA 281: 1701-1706, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10328069/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10328069&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/jama.281.18.1701&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10328069">Xu et al. (1999)</a> performed preimplantation genetic diagnosis (PGD) for sickle cell anemia on 7 embryos produced by in vitro fertilization for a couple who were both carriers of the sickle cell gene. PGD indicated that 4 were normal and 2 were carriers; diagnosis was not possible in 1. The embryos were transferred to the uterus on the fourth day after oocyte retrieval. A twin pregnancy was confirmed by ultrasonography, and subsequent amniocentesis showed that both fetuses were unaffected and were not carriers of the sickle cell mutation. The patient delivered healthy twins at 39 weeks' gestation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10328069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Clinical Management</strong>
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<p><a href="#86" class="mim-tip-reference" title="Yawn, B. P., Buchanan, G. R., Afenyi-Annan, A. N., Ballas, S. K., Hassell, K. L., James, A. H., Jordan, L., Lanzkron, S. M., Lottenberg, R., Savage, W. J., Tanabe, P. J., Ware, R. E., and 6 others. &lt;strong&gt;Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members.&lt;/strong&gt; JAMA 312: 1033-1048, 2014. Note: Erratum: JAMA 312: 1932 only, 2014. Erratum: JAMA 313: 729 only, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25203083/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25203083&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/jama.2014.10517&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25203083">Yawn et al. (2014)</a> summarized evidence-based recommendations for the management of sickle cell disease based on a review by an expert panel of 34 years of published studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25203083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#75" class="mim-tip-reference" title="Trompeter, S., Roberts, I. &lt;strong&gt;Haemoglobin F modulation in childhood sickle cell disease.&lt;/strong&gt; Brit. J. Haemat. 144: 308-316, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19036119/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19036119&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1365-2141.2008.07482.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19036119">Trompeter and Roberts (2008)</a> provided a review of agents that increase fetal hemoglobin production and of the therapeutic use of such agents, including hydroxycarbamide, decitabine, and butyrate, in children with sickle cell disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19036119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a report on a sickle cell workshop, <a href="#39" class="mim-tip-reference" title="Luzzatto, L., Goodfellow, P. &lt;strong&gt;Sickle cell anemia: a simple disease with no cure.&lt;/strong&gt; Nature 337: 17-18, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2909889/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2909889&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/337017a0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2909889">Luzzatto and Goodfellow (1989)</a> reviewed current treatment of this disease. The lessons learned from sickle cell anemia will be applicable in other genetic diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2909889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Stimulating fetal hemoglobin by increasing gamma-globin synthesis in patients with sickle cell disease would be expected, if the production of sickle hemoglobin is decreased concomitantly, to reduce the formation of intracellular S polymer and improve the acute and chronic hemolytic and vasoocclusive complications of the disease. Azacytidine and hydroxyurea have been shown to increase fetal hemoglobin levels in some patients with sickle cell disease (<a href="#10" class="mim-tip-reference" title="Charache, S., Dover, G., Smith, K., Talbot, C. C., Jr., Moyer, M., Boyer, S. &lt;strong&gt;Treatment of sickle cell anemia with 5-azacytidine results in increased fetal hemoglobin production and is associated with nonrandom hypomethylation of DNA around the gamma-delta-beta-globin gene complex.&lt;/strong&gt; Proc. Nat. Acad. Sci. 80: 4842-4846, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6192443/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6192443&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.80.15.4842&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6192443">Charache et al., 1983</a>; <a href="#14" class="mim-tip-reference" title="Dover, G. J., Humphries, R. K., Moore, J. G., Ley, T. J., Young, N. S., Charache, S., Nienhuis, A. W. &lt;strong&gt;Hydroxyurea induction of hemoglobin F production in sickle cell disease: relationship between cytotoxicity and F cell production.&lt;/strong&gt; Blood 67: 735-738, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2418898/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2418898&lt;/a&gt;]" pmid="2418898">Dover et al., 1986</a>). <a href="#61" class="mim-tip-reference" title="Rodgers, G. P., Dover, G. J., Uyesaka, N., Noguchi, C. T., Schechter, A. N., Nienhuis, A. W. &lt;strong&gt;Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease.&lt;/strong&gt; New Eng. J. Med. 328: 73-80, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7677965/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7677965&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199301143280201&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7677965">Rodgers et al. (1993)</a> found that administration of intravenous recombinant erythropoietin with iron supplementation alternating with hydroxyurea elevated fetal hemoglobin levels more than hydroxyurea alone. The increases reduced intracellular polymerization of hemoglobin S. The program reduced the myelotoxic effects of hydroxyurea and was beneficial in patients who had not been helped by hydroxyurea alone. Not only does fetal hemoglobin inhibit the polymerization of hemoglobin S but it also can function as a substitute for the beta-globin chains that are defective or absent in patients with the beta-thalassemias. Butyrate has also been tried for the stimulation of fetal hemoglobin synthesis (<a href="#53" class="mim-tip-reference" title="Perrine, S. P., Ginder, G. D., Faller, D. V., Dover, G. H., Ikuta, T., Witkowska, H. E., Cai, S., Vichinsky, E. P., Olivieri, N. F. &lt;strong&gt;A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders.&lt;/strong&gt; New Eng. J. Med. 328: 81-86, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7677966/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7677966&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199301143280202&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7677966">Perrine et al., 1993</a>). The trial with butyrate was based on the observation by <a href="#54" class="mim-tip-reference" title="Perrine, S. P., Greene, M. F., Faller, D. V. &lt;strong&gt;Delay in the fetal globin switch in infants of diabetic mothers.&lt;/strong&gt; New Eng. J. Med. 312: 334-338, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2578609/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2578609&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198502073120602&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2578609">Perrine et al. (1985)</a> that infants who have high plasma levels of alpha-amino-n-butyric acid in the presence of maternal diabetes do not undergo the normal developmental gene switch from the production of predominantly gamma-globin to that of beta-globin before birth. Since other developmental processes were not delayed, the use of butyric acid as a safe and fairly specific agent was suggested. Butyrate may act through sequences near the transcriptional start site to stimulate the activity of the promoter of the gamma-globin genes. <a href="#53" class="mim-tip-reference" title="Perrine, S. P., Ginder, G. D., Faller, D. V., Dover, G. H., Ikuta, T., Witkowska, H. E., Cai, S., Vichinsky, E. P., Olivieri, N. F. &lt;strong&gt;A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders.&lt;/strong&gt; New Eng. J. Med. 328: 81-86, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7677966/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7677966&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199301143280202&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7677966">Perrine et al. (1993)</a> showed that butyrate can significantly and rapidly increase fetal globin production to levels that can ameliorate beta-globin disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6192443+7677965+2578609+7677966+2418898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>On the basis of a double-blind, randomized clinical trial, <a href="#11" class="mim-tip-reference" title="Charache, S., Terrin, M. L., Moore, R. D., Dover, G. J., Barton, F. B., Eckert, S. V., McMahon, R. P., Bonds, D. R., Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. &lt;strong&gt;Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia.&lt;/strong&gt; New Eng. J. Med. 332: 1317-1322, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7715639/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7715639&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199505183322001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7715639">Charache et al. (1995)</a> reported that hydroxyurea therapy can ameliorate the clinical course of sickle cell anemia in adults with 3 or more painful crises per year. Maximal tolerated doses of hydroxyurea may not be necessary to achieve a therapeutic effect. The beneficial effects did not become manifest for several months, and its use must be carefully monitored. The long-term safety of hydroxyurea in patients with sickle cell anemia was uncertain. No neoplastic disorders developed during the study, but hydroxyurea does have a potential for inducing malignancy. This is a nice example of the modulation of expression of endogenous genes to abrogate pathophysiologic processes in the treatment of a genetic disorder. Bone marrow or hematopoietic stem cell transplantation are proven methods of treatment which may be considered a reasonable alternative to long-term drug therapy in some patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7715639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Charache, S., Barton, F. B., Moore, R. D., Terrin, M. L., Steinberg, M. H., Dover, G. J., Ballas, S. K., McMahon, R. P., Castro, O., Orringer, E. P. &lt;strong&gt;Hydroxyurea and sickle cell anemia: clinical utility of a myelosuppressive &#x27;switching&#x27; agent.&lt;/strong&gt; Medicine 75: 300-326, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8982148/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8982148&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00005792-199611000-00002&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8982148">Charache et al. (1996)</a> gave a comprehensive report on the results of a multicenter study of hydroxyurea in sickle cell anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8982148" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#73" class="mim-tip-reference" title="Steinberg, M. H. &lt;strong&gt;Management of sickle cell disease.&lt;/strong&gt; New Eng. J. Med. 340: 1021-1030, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10099145/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10099145&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199904013401307&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10099145">Steinberg (1999)</a> provided a detailed and highly useful exposition on the management of sickle cell disease. Hydroxyurea, properly used and monitored, is an established form of therapy. Early interruption of the vasoocclusive process that underlies the clinical manifestations of sickle cell disease may prevent damage to the central nervous system, lungs, kidneys, and bones. Two important caveats tempered this hope. The long-term effects of hydroxyurea are unknown. Is it mutagenic, carcinogenic, or leukemogenic? <a href="#73" class="mim-tip-reference" title="Steinberg, M. H. &lt;strong&gt;Management of sickle cell disease.&lt;/strong&gt; New Eng. J. Med. 340: 1021-1030, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10099145/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10099145&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199904013401307&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10099145">Steinberg (1999)</a> stated that leukemia or cancer had not occurred in patients with sickle cell anemia who had been treated with hydroxyurea, but fewer than 300 patients had been treated for 5 years. It is also not known whether its use in children will have an adverse effect on growth and development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10099145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Treatment with hydroxyurea is associated with cutaneous side effects. <a href="#7" class="mim-tip-reference" title="Chaine, B., Neonato, M.-G., Girot, R., Aractingi, S. &lt;strong&gt;Cutaneous adverse reactions to hydroxyurea in patients with sickle cell disease.&lt;/strong&gt; Arch. Derm. 137: 467-470, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11295927/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11295927&lt;/a&gt;]" pmid="11295927">Chaine et al. (2001)</a> evaluated 17 adult patients with sickle cell disease who were undergoing long-term treatment with hydroxyurea. They found that 5 (29%) had disabling leg ulcers. Four of the 5 had a history of leg ulcers prior to initiating hydroxyurea treatment. <a href="#7" class="mim-tip-reference" title="Chaine, B., Neonato, M.-G., Girot, R., Aractingi, S. &lt;strong&gt;Cutaneous adverse reactions to hydroxyurea in patients with sickle cell disease.&lt;/strong&gt; Arch. Derm. 137: 467-470, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11295927/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11295927&lt;/a&gt;]" pmid="11295927">Chaine et al. (2001)</a> concluded that caution should be observed when giving hydroxyurea to patients with sickle cell disease with previous ulcers as well as in older patients with sickle cell disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11295927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Ferster, A., Tahriri, P., Vermylen, C., Sturbois, G., Corazza, F., Fondu, P., Devalck, C., Dresse, M. F., Feremans, W., Hunninck, K., Toppet, M., Phillippet, P., Van Geet, C., Sariban, E. &lt;strong&gt;Five years of experience with hydroxyurea in children and young adults with sickle cell disease.&lt;/strong&gt; Blood 97: 3628-3632, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11369660/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11369660&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood.v97.11.3628&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11369660">Ferster et al. (2001)</a> reported results in the treatment of sickle cell disease in children and young adults with hydroxyurea, based on a Belgian registry. The median follow-up of the 93 patients was 3.5 years. On hydroxyurea, the number of hospitalizations and days hospitalized dropped significantly. Analysis of the 22 patients with a minimum of 5 years of follow-up confirmed a significant difference in the number of hospitalizations and days in hospital throughout the treatment when compared to prior to hydroxyurea therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11369660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a phase 3 trial, <a href="#45" class="mim-tip-reference" title="Niihara, Y., Miller, S. T., Kanter, J., Lanzkron, S., Smith, W. R., Hsu, L. L., Gordeuk, V. R., Viswanathan, K., Sarnaik, S., Osunkwo, I., Guillaume, E., Sadanandan, S., and 11 others. &lt;strong&gt;A phase 3 trial of l-glutamine in sickle cell disease.&lt;/strong&gt; New Eng. J. Med. 379: 226-235, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30021096/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30021096&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa1715971&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30021096">Niihara et al. (2018)</a> tested the efficacy of oral glutamine in reducing the incidences of pain crises in patients with sickle cell anemia or sickle beta-zero-thalassemia who had had 2 or more pain crises in the previous year. Of 230 patients aged 5 to 58 years, 152 received L-glutamine and 78 patients received placebo, for a treatment period of 48 weeks. The patients in the L-glutamine group had significantly fewer pain crises than those in the placebo group (p = 0.005), with a median of 3.0 in the L-glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the L-glutamine group than in the placebo group (p = 0.005), with a median of 2.0 in the L-glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the L-glutamine group than in the placebo group. <a href="#45" class="mim-tip-reference" title="Niihara, Y., Miller, S. T., Kanter, J., Lanzkron, S., Smith, W. R., Hsu, L. L., Gordeuk, V. R., Viswanathan, K., Sarnaik, S., Osunkwo, I., Guillaume, E., Sadanandan, S., and 11 others. &lt;strong&gt;A phase 3 trial of l-glutamine in sickle cell disease.&lt;/strong&gt; New Eng. J. Med. 379: 226-235, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30021096/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30021096&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa1715971&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30021096">Niihara et al. (2018)</a> concluded that among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with L-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30021096" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To investigate the feasibility, safety, and benefits of hydroxyurea treatment for children with sickle cell anemia in sub-Saharan Africa, <a href="#76" class="mim-tip-reference" title="Tshilolo, L., Tomlinson, G., Williams, T. N., Santos, B., Olupot-Olupot, P., Lane, A., Aygun, B., Stuber, S. E., Latham, T. S., McGann, P. T., Ware, R. E. &lt;strong&gt;Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa.&lt;/strong&gt; New Eng. J. Med. 380: 121-131, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30501550/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30501550&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=30501550[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa1813598&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30501550">Tshilolo et al. (2019)</a> enrolled 635 children with sickle cell anemia ranging in age from 1 to 10 years from 4 sub-Saharan countries. Children received hydroxyurea at a dose of 15 to 20 mg per kilogram of body weight per day for 6 months, followed by dose escalation. Hematologic dose-limiting toxic events during the first 3 months of treatment (the primary safety end point) occurred in only a small number of participants (5.1%). No serious adverse events or deaths were considered by the investigators to have been related to hydroxyurea treatment. Hydroxyurea therapy led to significant increases in both the hemoglobin and fetal hemoglobin levels. Hydroxyurea use reduced the incidence of vasoocclusive events, infections, malaria, transfusions, and death, which supported the need for wider access to treatment. <a href="#76" class="mim-tip-reference" title="Tshilolo, L., Tomlinson, G., Williams, T. N., Santos, B., Olupot-Olupot, P., Lane, A., Aygun, B., Stuber, S. E., Latham, T. S., McGann, P. T., Ware, R. E. &lt;strong&gt;Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa.&lt;/strong&gt; New Eng. J. Med. 380: 121-131, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30501550/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30501550&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=30501550[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa1813598&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30501550">Tshilolo et al. (2019)</a> concluded that hydroxyurea treatment is feasible and safe in children with sickle cell anemia living in sub-Saharan Africa. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30501550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#78" class="mim-tip-reference" title="Vichinsky, E., Hoppe, C. C., Ataga, K. I., Ware, R. E., Nduba, V., El-Beshlawy, A., Hassab, H., Achebe, M. M., Alkindi, S., Brown, R. C., Diuguid, D. L., Telfer, P., and 11 others. &lt;strong&gt;A phase 3 randomized trial of voxelotor in sickle cell disease.&lt;/strong&gt; New Eng. J. Med. 381: 509-519, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31199090/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31199090&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa1903212&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31199090">Vichinsky et al. (2019)</a> reported a multicenter phase 3, double-blind, randomized, placebo-controlled trial comparing the efficacy and safety of 2 dose levels of voxelotor with placebo in 274 persons with sickle cell disease randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose. Most participants had sickle cell anemia, and approximately two-thirds were receiving hydroxyurea at baseline. Among those receiving the 1500 mg dose of voxelotor, 51% had an increase of more than 1.0 g/dl of hemoglobin from baseline to week 24 versus only 7% in the placebo group. Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. Adverse events of at least grade 3 occurred in 23 to 26% of each of the treatment or placebo groups. Most adverse events were not related to the trial drug or placebo as determined by the investigators. <a href="#78" class="mim-tip-reference" title="Vichinsky, E., Hoppe, C. C., Ataga, K. I., Ware, R. E., Nduba, V., El-Beshlawy, A., Hassab, H., Achebe, M. M., Alkindi, S., Brown, R. C., Diuguid, D. L., Telfer, P., and 11 others. &lt;strong&gt;A phase 3 randomized trial of voxelotor in sickle cell disease.&lt;/strong&gt; New Eng. J. Med. 381: 509-519, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31199090/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31199090&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa1903212&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31199090">Vichinsky et al. (2019)</a> concluded that voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings were consistent with inhibition of HbS polymerization and indicated a disease-modifying potential. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31199090" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Gene Therapy</em></strong></p><p>
The genetic basis of sickle cell disease is an A-to-T transversion in the sixth codon of the HBB gene. The intricacies of globin gene expression make the development of treatments for hemoglobinopathies based on gene therapy difficult. <a href="#33" class="mim-tip-reference" title="Lan, N., Howrey, R. P., Lee, S.-W., Smith, C. A., Sullenger, B. A. &lt;strong&gt;Ribozyme-mediated repair of sickle beta-globin mRNAs in erythrocyte precursors.&lt;/strong&gt; Science 280: 1593-1596, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9616120/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9616120&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.280.5369.1593&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9616120">Lan et al. (1998)</a> used an alternative genetic approach to sickle cell therapy based on RNA repair. They used a trans-splicing group I ribozyme to alter mutant beta-globin transcripts in erythrocyte precursors derived from peripheral blood from individuals with sickle cell disease. Sickle beta-globin transcripts were converted into mRNAs encoding the anti-sickling protein gamma-globin. In this splicing reaction, the ribozyme recognized the sickle beta-globin transcript by basepairing to an accessible region of the RNA upstream of the mutant nucleotide via an internal guide sequence (IGS), cleaved the sickle beta-globin RNA, released the cleavage product containing the mutation, and spliced on the revised sequence for the globin transcript. <a href="#33" class="mim-tip-reference" title="Lan, N., Howrey, R. P., Lee, S.-W., Smith, C. A., Sullenger, B. A. &lt;strong&gt;Ribozyme-mediated repair of sickle beta-globin mRNAs in erythrocyte precursors.&lt;/strong&gt; Science 280: 1593-1596, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9616120/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9616120&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.280.5369.1593&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9616120">Lan et al. (1998)</a> generated erythrocyte precursors from normal umbilical cord blood and from peripheral blood from patients with sickle cell disease by culturing the blood cells in medium without serum supplemented with erythropoietin, FLT3 (<a href="/entry/600007">600007</a>), and IL3 (<a href="/entry/147740">147740</a>). RNA repair may be a particularly appropriate genetic approach with which to treat sickle cell disease because the process should restore the regulated expression of anti-sickling versions of beta-globin and simultaneously reduce the production of sickle beta-globin. The efficiency of beta-globin RNA repair probably does not have to be 100% to benefit patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9616120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#49" class="mim-tip-reference" title="Pawliuk, R., Westerman, K. A., Fabry, M. E., Payen, E., Tighe, R., Bouhassira, E. E., Acharya, S. A., Ellis, J., London, I. M., Eaves, C. J., Humphries, R. K., Beuzard, Y., Nagel, R. L., Leboulch, P. &lt;strong&gt;Correction of sickle cell disease in transgenic mouse models by gene therapy.&lt;/strong&gt; Science 294: 2368-2371, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11743206/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11743206&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1065806&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11743206">Pawliuk et al. (2001)</a> designed a beta-A globin gene variant that prevents HbS polymerization and introduced it into a lentiviral vector that they optimized for transfer to hematopoietic stem cells and gene expression in the adult red blood cell lineage. Long-term expression (up to 10 months) was achieved without preselection in all transplanted mice with erythroid-specific accumulation of the antisickling protein in up to 52% of total Hb and 99% of circulating red blood cells. In 2 mouse sickle cell disease models, Berkeley and SAD, inhibition of red blood cell dehydration and sickling was achieved with correction of hematologic parameters, splenomegaly, and prevention of the characteristic urine concentration defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Esrick, E. B., Lehmann, L. E., Biffi, A., Achebe, M., Brendel, C., Ciuculescu, M. F., Daley, H., MacKinnon, B., Morris, E., Federico, A., Abriss, D., Boardman, K., and 13 others. &lt;strong&gt;Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease.&lt;/strong&gt; New Eng. J. Med. 384: 205-215, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/33283990/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;33283990&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa2029392&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="33283990">Esrick et al. (2021)</a> performed a single-center, open-label pilot study of 6 patients with sickle cell disease with severe manifestations (including stroke, priapism, and vasoocclusive episodes requiring treatment with either transfusions or hydroxyurea) who received infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA targeting BCL11 (<a href="/entry/606557">606557</a>) mRNA embedded in a microRNA (shmiR), allowing erythroid lineage-specific knockdown. At the time of the report, the patients had been followed for a median of 18 months (range 7 to 29 months). All patients had engraftment, and the adverse events were consistent with the effects of the preparatory chemotherapy. All patients had robust and stable HbF induction (HbF 20 to 41%). Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33283990" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Kanter, J., Walters, M. C., Krishnamurti, L., Mapara, M. Y., Kwiatkowski, J. L., Rifkin-Zenenberg, S., Aygun, B., Kasow, K. A., Pierciey, F. J., Bonner, M., Miller, A., Zhang, X., Lynch, J., Kim, D., Ribeil, J. A., Asmal, M., Goyal, S., Thompson, A. A., Tisdale, J. F. &lt;strong&gt;Biologic and clinical efficacy of LentiGlobin for sickle cell disease.&lt;/strong&gt; New Eng. J. Med. 386: 617-628, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34898139/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;34898139&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa2117175&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="34898139">Kanter et al. (2022)</a> reported the results of an ongoing phase 1-2 study of LentiGlobin, a gene therapy that consists of autologous transplantation of hematopoietic stem and progenitor cells transduced with a lentiviral vector encoding a modified beta-globin gene, which produces an antisickling hemoglobin (HbA T87Q). To be included, patients needed to have had at least 4 severe vasoocclusive events in the 24 months before enrollment. Among the 35 enrolled patients with sufficient follow-up data, engraftment occurred in all patients. Median follow-up was 17.3 months. Median total hemoglobin level increased from 8.5 g/deciliter at baseline to 11 g/deciliter or more at 6 months and was sustained for 36 months postinfusion. The antisickling hemoglobin contributed at least 40% of the total hemoglobin, with a mean of 85% of red blood cells estimated to contain the antisickling hemoglobin at 24 months. Markers of hemolysis were reduced. Among the 25 patients with at least 6 months of follow-up after infusion, no severe vasoocclusive events were reported, compared to a median of 3.5 events per year in the 24 months before infusion. Adverse events attributed to the LentiGlobin infusion were seen in 3 patients; all adverse events resolved within 1 week after onset. No hematologic cancers were seen during up to 37.6 months of follow-up. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34898139" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Frangoul, H., Locatelli, F., Sharma, A., Bhatia, M., Mapara, M., Molinari, L., Wall, D., Liem, R. I., Telfer, P., Shah, A. J., Cavazzana, M., Corbacioglu, S., and 17 others. &lt;strong&gt;Exagamglogene autotemcel for severe sickle cell disease.&lt;/strong&gt; New Eng. J. Med. 390: 1649-1662, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/38661449/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;38661449&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa2309676&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="38661449">Frangoul et al. (2024)</a> conducted a phase 3, single-group, open-label study of exagamglogene (exa-cel), a nonviral cell therapy designed to reactivate fetal hemoglobin, in 44 patients aged 12 to 35 years with sickle cell disease who had had at least 2 severe vasoocclusive crises in each of the 2 years before screening. The BCL11A (<a href="/entry/606557">606557</a>) locus of CD34+ hematopoietic stem and progenitor cells (HSPCs) was edited using CRISPR-Cas9. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary endpoint was freedom from severe vasoocclusive crises for at least 12 consecutive months. A key secondary endpoint was freedom from inpatient hospitalization for severe vasoocclusive crises for at least 12 consecutive months. The safety of exa-cel was also assessed. Over a median of 19.3 months (range, 0.8 to 48.1) of follow-up, all patients had neutrophil and platelet engraftment. Of 30 patients with sufficient follow-up to be evaluated, 29 (97%, 95% CI 88-100) were free from vasoocclusive crises for at least 12 months and none required hospitalization for vasoocclusive crises. The safety profile of exa-cel was consistent with that of myeloablative busulfan and autologous HSPC transplantation. No cancers occurred. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38661449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>HbS (<a href="/entry/141900#0243">141900.0243</a>) has a lower oxygen affinity than normal Hb and polymerizes upon deoxygenation, creating red blood cells that are distorted, resulting in a sickled appearance; adherent, leading to vasoocclusion; and fragile, leading to hemolysis. The clinical consequences of the vascular occlusion are variable, but include bone pain, deep venous thrombosis, acute chest syndrome, and stroke. In an aortic ring bioassay, <a href="#51" class="mim-tip-reference" title="Pawloski, J. R., Hess, D. T., Stamler, J. S. &lt;strong&gt;Impaired vasodilation by red blood cells in sickle cell disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 102: 2531-2536, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15699345/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15699345&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15699345[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0409876102&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15699345">Pawloski et al. (2005)</a> found that red blood cells derived from patients with severe sickle cell disease did not induce vasodilation under hypoxic conditions when stimulated with nitric oxide (NO) (see NOS3, <a href="/entry/163729">163729</a>), whereas these conditions did induce vasodilation when tested with normal red blood cells and those from patients with mild disease. <a href="#50" class="mim-tip-reference" title="Pawloski, J. R., Hess, D. T., Stamler, J. S. &lt;strong&gt;Export by red blood cells of nitric oxide bioactivity.&lt;/strong&gt; Nature 409: 622-626, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11214321/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11214321&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/35054560&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11214321">Pawloski et al. (2001)</a> had previously shown that vasodilatory activity can be generated by red blood cells through membrane hemoglobin-derived S-nitrosothiol (SNO) that is formed from transfer of NO to the red cell membrane anion exchanger AE1 (SLC4A1; <a href="/entry/109270">109270</a>) from SNO-Hb. <a href="#51" class="mim-tip-reference" title="Pawloski, J. R., Hess, D. T., Stamler, J. S. &lt;strong&gt;Impaired vasodilation by red blood cells in sickle cell disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 102: 2531-2536, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15699345/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15699345&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15699345[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0409876102&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15699345">Pawloski et al. (2005)</a> demonstrated that sickle cell red blood cells had decreased levels of membrane-bound SNO resulting from intrinsic defects in the processing of NO by sickle cells. Sickle cells showed defects in intramolecular transfer of NO from heme iron to SNO, possibly due to redox potential changes, as well as in transfer of the NO moiety from SNO-HbS to the RBC membrane. Substantial amounts of HbS were disulfide-linked to AE1 in sickle cell membranes, resulting in a loss of free AE1 thiols. The magnitudes of these impairments correlated with clinical severity of disease. <a href="#51" class="mim-tip-reference" title="Pawloski, J. R., Hess, D. T., Stamler, J. S. &lt;strong&gt;Impaired vasodilation by red blood cells in sickle cell disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 102: 2531-2536, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15699345/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15699345&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15699345[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0409876102&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15699345">Pawloski et al. (2005)</a> concluded that abnormal red blood cell vasoactivity contributes to the vasoocclusive pathophysiology of sickle cell anemia, which may also explain phenotypic variation in expression of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11214321+15699345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<p>The most common cause of sickle cell anemia is HbS (<a href="/entry/141900#0243">141900.0243</a>), with hemoglobin SS disease being most prevalent in Africans. <a href="#59" class="mim-tip-reference" title="Rees, D. C., Williams, T. N., Gladwin, M. T. &lt;strong&gt;Sickle cell disease.&lt;/strong&gt; Lancet 376: 2018-2031, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21131035/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21131035&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(10)61029-X&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21131035">Rees et al. (2010)</a> listed genotypes that had been reported to cause sickle cell disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21131035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Modifier Genes</em></strong></p><p>
Priapism, a vasoocclusive manifestation of sickle cell disease, affects more than 30% of males with the disorder. In sickle cell anemia patients, 148 with priapism and 529 without, <a href="#46" class="mim-tip-reference" title="Nolan, V. G., Baldwin, C., Ma, Q., Wyszynski, D. F., Amirault, Y., Farrell, J. J., Bisbee, A., Embury, S. H., Farrer, L. A., Steinberg, M. H. &lt;strong&gt;Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia.&lt;/strong&gt; Brit. J. Haemat. 128: 266-272, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15638863/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15638863&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1365-2141.2004.05295.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15638863">Nolan et al. (2005)</a> searched SNPs from 44 genes of different functional classes for an association with priapism. By genotypic and haplotype analysis, they found an association between SNPs in the KLOTHO gene (<a href="/entry/604824">604824</a>) and priapism (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2249358;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2249358</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs211239;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs211239</a>; adjusted odds ratio of 2.6 and 1.7, respectively). <a href="#46" class="mim-tip-reference" title="Nolan, V. G., Baldwin, C., Ma, Q., Wyszynski, D. F., Amirault, Y., Farrell, J. J., Bisbee, A., Embury, S. H., Farrer, L. A., Steinberg, M. H. &lt;strong&gt;Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia.&lt;/strong&gt; Brit. J. Haemat. 128: 266-272, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15638863/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15638863&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1365-2141.2004.05295.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15638863">Nolan et al. (2005)</a> noted that the finding may have broader implications in sickle cell disease, as the KL protein regulates vascular functions, including the expression of VEGF (<a href="/entry/192240">192240</a>) and release of endothelial nitric oxide (see <a href="/entry/163729">163729</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15638863" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Sickle cell anemia is phenotypically complex, with different clinical courses ranging from early childhood mortality to a virtually unrecognized condition. Overt stroke is a severe complication affecting 6 to 8% of individuals with sickle cell anemia. Modifier genes might interact to determine the susceptibility to stroke. Using Bayesian networks, <a href="#66" class="mim-tip-reference" title="Sebastiani, P., Ramoni, M. F., Nolan, V., Baldwin, C. T., Steinberg, M. H. &lt;strong&gt;Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia.&lt;/strong&gt; Nature Genet. 37: 435-440, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15778708/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15778708&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15778708[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1533&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15778708">Sebastiani et al. (2005)</a> analyzed 108 SNPs in 39 candidate genes in 1,398 individuals with sickle cell anemia. They found that 31 SNPs in 12 genes interacted with fetal hemoglobin to modulate the risk of stroke. This network of interactions included 3 genes in the TGF-beta pathway (see <a href="/entry/190180">190180</a>) and SELP (<a href="/entry/173610">173610</a>). <a href="#66" class="mim-tip-reference" title="Sebastiani, P., Ramoni, M. F., Nolan, V., Baldwin, C. T., Steinberg, M. H. &lt;strong&gt;Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia.&lt;/strong&gt; Nature Genet. 37: 435-440, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15778708/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15778708&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15778708[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1533&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15778708">Sebastiani et al. (2005)</a> validated their model in a different population by predicting the occurrence of stroke in 114 individuals with 98.2% accuracy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15778708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#77" class="mim-tip-reference" title="Uda, M., Galanello, R., Sanna, S., Lettre, G., Sankaran, V. G., Chen, W., Usala, G., Busonero, F., Maschio, A., Albai, G., Piras, M. G., Sestu, N., and 18 others. &lt;strong&gt;Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia.&lt;/strong&gt; Proc. Nat. Acad. Sci. 105: 1620-1625, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18245381/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18245381&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18245381[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0711566105&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18245381">Uda et al. (2008)</a> found that the C allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11886868;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11886868</a> in the BCL11A gene (<a href="/entry/606557#0002">606557.0002</a>) was associated with an ameliorated phenotype in patients with sickle cell anemia, due to increased production of fetal hemoglobin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18245381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 independent cohorts of patients with sickle cell anemia, <a href="#38" class="mim-tip-reference" title="Lettre, G., Sankaran, V. G., Bezerra, M. A. C., Araujo, A. S., Uda, M., Sanna, S., Cao, A., Schlessinger, D., Costa, F. F., Hirschhorn, J. N. &lt;strong&gt;Orkin, S. H.: DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 105: 11869-11874, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18667698/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18667698&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0804799105&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18667698">Lettre et al. (2008)</a> found a significant association between HbF levels and several SNPs in the HBS1L (<a href="/entry/612450">612450</a>)-MYB (<a href="/entry/189990">189990</a>) region on chromosome 6q23 (HBFQTL2; <a href="/entry/142470">142470</a>). The most significant associations among 1,275 African Americans and 350 Brazilians were with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9399137;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs9399137</a> (p = 5 x 10(-11)) and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4895441;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4895441</a> (p = 4 x 10(-7)), respectively. The associations with different SNPs in this region were independent of one another, but overall could explain 5% of variance in HbF levels. Among the African American individuals, there was also a significant association between HbF and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a> in the HBG2 gene (<a href="/entry/142250#0028">142250.0028</a>) (p = 4 x 10(-7)), which explained 2.2% of the variation in HbF levels. The association with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a> could not be tested in the Brazilian cohort because the variant was monomorphic in this population. Finally, the authors found a significant association between HbF and SNPs in the BCL11A gene on chromosome 2p15 (HBFQTL5; <a href="/entry/142335">142335</a>) in both cohorts. The most significant association among both groups was with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4671393;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4671393</a> (p = 2 x 10(-42) among African Americans, p = 3 x 10(-8) among Brazilians). The BCL11A SNPs could explain 6.7 to 14.1% of variance in HbF levels. Sequence variants at all 3 loci together could explain more than 20% of phenotypic variation in the HbF trait. Further statistical analysis showed an association between the high HbF alleles and reduced pain crisis events in patients with sickle cell disease, which may be used to predict overall morbidity and mortality of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18667698" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To fine map HbF association signals at the BCL11A, HBS1L-MYB, and beta-globin loci, <a href="#20" class="mim-tip-reference" title="Galarneau, G., Palmer, C. D., Sankaran, V. G., Orkin, S. H., Hirschhorn, J. N., Lettre, G. &lt;strong&gt;Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation.&lt;/strong&gt; Nature Genet. 42: 1049-1051, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21057501/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21057501&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.707&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21057501">Galarneau et al. (2010)</a> resequenced 175.2 kb from these loci in 190 individuals including the HapMap European CEU and Nigerian YRI founders and 70 African Americans with sickle cell anemia. The authors discovered 1,489 sequence variants, including 910 previously unreported variants. Using this information and data from HapMap, <a href="#20" class="mim-tip-reference" title="Galarneau, G., Palmer, C. D., Sankaran, V. G., Orkin, S. H., Hirschhorn, J. N., Lettre, G. &lt;strong&gt;Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation.&lt;/strong&gt; Nature Genet. 42: 1049-1051, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21057501/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21057501&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.707&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21057501">Galarneau et al. (2010)</a> selected and genotyped 95 SNPs, including 43 at the beta-globin locus, in 1,032 African Americans with sickle cell anemia. An XmnI polymorphism, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a>, in the proximal promoter of HBG2 marks the Senegal and Arab-Indian haplotypes and is associated with HbF levels in African Americans with sickle cell disease (<a href="#38" class="mim-tip-reference" title="Lettre, G., Sankaran, V. G., Bezerra, M. A. C., Araujo, A. S., Uda, M., Sanna, S., Cao, A., Schlessinger, D., Costa, F. F., Hirschhorn, J. N. &lt;strong&gt;Orkin, S. H.: DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 105: 11869-11874, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18667698/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18667698&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0804799105&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18667698">Lettre et al., 2008</a>). <a href="#20" class="mim-tip-reference" title="Galarneau, G., Palmer, C. D., Sankaran, V. G., Orkin, S. H., Hirschhorn, J. N., Lettre, G. &lt;strong&gt;Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation.&lt;/strong&gt; Nature Genet. 42: 1049-1051, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21057501/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21057501&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.707&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21057501">Galarneau et al. (2010)</a> replicated the association between <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a> and HbF levels (p = 3.7 x 10(-7)). However, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs10128556;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs10128556</a>, a T/C SNP located downstream of HBG1, was more strongly associated with HbF levels than <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a> by 2 orders of magnitude (p = 1.3 x 10(-9)). When conditioned on <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs10128556;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs10128556</a>, the HbF association result for <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a> was not significant, indicating that <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7482144;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7482144</a> is not a causal variant for HbF levels in African Americans with sickle cell anemia. The results of a haplotype analysis of the 43 SNPs in the beta-globin locus using <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs10128556;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs10128556</a> as a covariate were not significant (p = 0.40), indicating that <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs10128556;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs10128556</a> or a marker in linkage disequilibrium with it is the principal HbF-influencing variant at the beta-globin locus in African Americans with sickle cell anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18667698+21057501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In sub-Saharan Africa, 2 hemoglobinopathies occur at particularly high frequencies: sickle cell anemia and alpha(+)-thalassemia. Individually, each is protective against severe Plasmodium falciparum malaria. <a href="#83" class="mim-tip-reference" title="Williams, T. N., Mwangi, T. W., Wambua, S., Peto, T. E. A., Weatherall, D. J., Gupta, S., Recker, M., Penman, B. S., Uyoga, S., Macharia, A., Mwacharo, J. K., Snow, R. W., Marsh, K. &lt;strong&gt;Negative epistasis between the malaria-protective effects of alpha(+)-thalassemia and the sickle cell trait.&lt;/strong&gt; Nature Genet. 37: 1253-1257, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16227994/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16227994&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16227994[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1660&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16227994">Williams et al. (2005)</a> investigated malaria-protective effects when hemoglobin S and alpha-thalassemia are inherited in combination. Studying a population on the coast of Kenya, they found that the protection afforded by each condition inherited alone was lost when the 2 conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with regard to the mutation underlying alpha(+)-thalassemia. Negative epistasis could explain the failure of alpha(+)-thalassemia to reach fixation in any population in sub-Saharan Africa. Possible mechanisms of the interaction of the 2 genetic changes in relation to malaria were discussed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16227994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The estimated number of worldwide annual births of patients with sickle cell anemia is 217,331 and with SC disease is 54,736 (<a href="#42" class="mim-tip-reference" title="Modell, B., Darlison, M. &lt;strong&gt;Global epidemiology of haemoglobin disorders and derived service indicators.&lt;/strong&gt; Bull. World Health Organ. 86: 480-487, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18568278/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18568278&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.2471/blt.06.036673&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18568278">Modell and Darlison, 2008</a> and <a href="#82" class="mim-tip-reference" title="Weatherall, D. J. &lt;strong&gt;The inherited diseases of hemoglobin are an emerging global health burden.&lt;/strong&gt; Blood 115: 4331-4336, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20233970/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20233970&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2010-01-251348&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20233970">Weatherall, 2010</a>). <a href="#55" class="mim-tip-reference" title="Piel, F. B., Steinberg, M. H., Rees, D. C. &lt;strong&gt;Sickle cell disease.&lt;/strong&gt; New Eng. J. Med. 376: 1561-1573, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28423290/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28423290&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMra1510865&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28423290">Piel et al. (2017)</a> stated that the vast majority of the approximately 300,000 yearly births of patients with sickle cell anemia occur in Nigeria, the Democratic Republic of the Congo, and India. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20233970+18568278+28423290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#81" class="mim-tip-reference" title="Wang, Y., Kennedy, J., Caggana, M., Zimmerman, R., Thomas, S., Berninger, J., Harris, K., Green, N. S., Oyeku, S., Hulihan, M., Grant, A. M., Grosse, S. D. &lt;strong&gt;Sickle cell disease incidence among newborns in New York State by maternal race/ethnicity and nativity.&lt;/strong&gt; Genet. Med. 15: 222-228, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23018751/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23018751&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2012.128&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23018751">Wang et al. (2013)</a> analyzed sickle cell disease incidence among newborns in New York State by maternal race/ethnicity and nativity in the period between 2000 and 2008. In that interval, 1,911 New York State newborns were diagnosed with sickle cell disease and matched to the birth certificate files. One in every 1,146 live births was diagnosed with sickle cell disease. Newborns of non-Hispanic black mothers accounted for 86% of sickle cell disease cases, whereas newborns of Hispanic mothers accounted for 12% of cases. The estimated incidence was 1 in 230 live births for non-Hispanic black mothers, 1 in 2,320 births for Hispanic mothers, and 1 in 41,647 births for non-Hispanic white mothers. Newborns of foreign-born non-Hispanic black mothers had a 2-fold higher incidence of sickle cell disease than those born to US-born non-Hispanic black mothers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23018751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 1,121 African Americans screened for sickle cell disease/beta-thalassemia carrier status, <a href="#37" class="mim-tip-reference" title="Lazarin, G. A., Haque, I. S., Nazareth, S., Iori, K., Patterson, A. S., Jacobson, J. L., Marshall, J. R., Seltzer, W. K., Patrizio, P., Evans, E. A., Srinivasan, B. S. &lt;strong&gt;An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.&lt;/strong&gt; Genet. Med. 15: 178-186, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22975760/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22975760&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2012.114&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22975760">Lazarin et al. (2013)</a> found a carrier frequency of approximately 1 in 10. Eighty-nine individuals were heterozygous for the HB S mutation and 27 were heterozygous for beta-thalassemia. Among 469 individuals of Middle Eastern origin, a carrier frequency of 1 in 5 was found. Among 21,360 ethnically diverse individuals screened for sickle cell disease carrier status, <a href="#37" class="mim-tip-reference" title="Lazarin, G. A., Haque, I. S., Nazareth, S., Iori, K., Patterson, A. S., Jacobson, J. L., Marshall, J. R., Seltzer, W. K., Patrizio, P., Evans, E. A., Srinivasan, B. S. &lt;strong&gt;An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.&lt;/strong&gt; Genet. Med. 15: 178-186, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22975760/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22975760&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2012.114&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22975760">Lazarin et al. (2013)</a> identified 307 carriers (1.4%), for an estimated carrier frequency of approximately 1 in 70. Ten 'carrier couples' were identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22975760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#70" class="mim-tip-reference" title="Shesely, E. G., Kim, H.-S., Shehee, W. R., Papayannopoulou, T., Smithies, O., Popovich, B. W. &lt;strong&gt;Correction of a human beta-S-globin gene by gene targeting.&lt;/strong&gt; Proc. Nat. Acad. Sci. 88: 4294-4298, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2034673/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2034673&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.88.10.4294&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2034673">Shesely et al. (1991)</a> corrected the human beta-S-globin gene by homologous recombination in a mouse-human hybrid cell line that is derived from a mouse erythroleukemia cell line and carries a single human chromosome 11 with the beta-S-globin allele. The corrected gene retained the proper regulation of induction of human beta-globin expression. The targeting construct contained 1.2 kb of prokaryotic sequence 5-prime to the normal beta-A-globin sequence for use in selecting and identifying targeted clones. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2034673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Fabry, M. E., Kennan, R. P., Paszty, C., Costantini, F., Rubin, E. M., Gore, J. C., Nagel, R. L. &lt;strong&gt;Magnetic resonance evidence of hypoxia in a homozygous alpha-knockout of a transgenic mouse model for sickle cell disease.&lt;/strong&gt; J. Clin. Invest. 98: 2450-2455, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8958206/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8958206&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI119062&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8958206">Fabry et al. (1996)</a> succeeded in creating an improved transgenic mouse model for sickle cell disease. Previous transgenic models had expressed residual levels of mouse globins which complicated the interpretation of experimental results. They reported on a mouse expressing high levels of human sickle beta chains and 100% human alpha-globin. These mice were created by breeding the alpha-globin-knockout mouse and the mouse with deletion of the beta(major)-deletion to homozygosity, the same mice expressing human alpha- and beta(S)-transgenes (see <a href="/entry/141900#0243">141900.0243</a>). The animals were considered important for testing strategies for gene therapy and for testing new noninvasive diagnostic procedures such as magnetic resonance imaging techniques. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8958206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#62" class="mim-tip-reference" title="Ryan, T. M., Ciavatta, D. J., Townes, T. M. &lt;strong&gt;Knockout-transgenic mouse model of sickle cell disease.&lt;/strong&gt; Science 278: 873-876, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9346487/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9346487&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.278.5339.873&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9346487">Ryan et al. (1997)</a> and <a href="#48" class="mim-tip-reference" title="Paszty, C., Brion, C. M., Manci, E., Witkowska, H. E., Stevens, M. E., Mohandas, N., Rubin, E. M. &lt;strong&gt;Transgenic knockout mice with exclusively human sickle hemoglobin and sickle cell disease.&lt;/strong&gt; Science 278: 876-878, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9346488/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9346488&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.278.5339.876&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9346488">Paszty et al. (1997)</a> created transgenic knockout mouse models of sickle cell disease. In both cases the model was produced by mating transgenic mice that expressed human sickle hemoglobin with mice having knockout mutations of the mouse alpha- and beta-globin genes. Similar to human patients with sickle cell disease, the mice developed hemolytic anemia and extensive organ pathology. Although chronically anemic, most animals survived 2 to 9 months and were fertile. Thus, this mouse model of sickle cell disease should be useful for trial of drug and genetic therapies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9346488+9346487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Chang, J. C., Lu, R., Lin, C., Xu, S.-M., Kan, Y. W., Porcu, S., Carlson, E., Kitamura, M., Yang, S., Flebbe-Rehwaldt, L., Gaensler, K. M. L. &lt;strong&gt;Transgenic knockout mice exclusively expressing human hemoglobin S after transfer of a 240-kb beta-S-globin yeast artificial chromosome: a mouse model of sickle cell anemia.&lt;/strong&gt; Proc. Nat. Acad. Sci. 95: 14886-14890, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9843985/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9843985&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=9843985[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.95.25.14886&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9843985">Chang et al. (1998)</a> created transgenic knockout mice expressing human hemoglobin S by transfer of a 240-kb yeast artificial chromosome carrying the beta-sickle gene. The transgenic lines were produced by coinjection of human alpha-, gamma-, and beta-globin constructs. Thus, all of the transgenes were integrated at a single chromosomal site. Studies in transgenic mice had demonstrated that the normal gene order and spatial organization of the members of the human beta-globin gene family are required for appropriate developmental and stage-restricted expression of the genes. The mice produced by transfer of the YAC had hemolytic anemia, 10% irreversibly sickled cells in their peripheral blood, reticulocytosis, and other phenotypic features of sickle cell anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843985" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#58" class="mim-tip-reference" title="Popp, R. A., Popp, D. M., Shinpock, S. G., Yang, M. Y., Mural, J. G., Aguinaga, M. P., Kopsombut, P., Roa, P. D., Turner, E. A., Rubin, E. M. &lt;strong&gt;A transgenic mouse model of hemoglobin S Antilles disease.&lt;/strong&gt; Blood 89: 4204-4212, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9166865/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9166865&lt;/a&gt;]" pmid="9166865">Popp et al. (1997)</a> bred 2 homozygous viable HbS Antilles transgene insertions into a strain of mice that produce hemoglobins with a higher affinity for oxygen than normal mouse Hb. The rationale was that the high oxygen affinity hemoglobin, the lower oxygen affinity of HbS Antilles, and the lower solubility of deoxygenated HbS Antilles than HbS would favor deoxygenation and polymerization of human HbS Antilles in the red cells of the high-oxygen-affinity mice. The investigators found that the mice produced a high and balanced expression of human alpha and human beta (S Antilles) globins, that 25 to 35% of their RBCs were misshapen in vivo, and that in vitro deoxygenation of their blood induced 30 to 50% of the RBCs to form classic elongated sickle cells with pointed ends. The mice exhibited reticulocytosis, an elevated white blood cell count, and lung and kidney pathology commonly found in sickle cell patients, which should make these mice useful for experimental studies on possible therapeutic intervention of sickle cell disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9166865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a transgenic mouse model of sickle cell disease, <a href="#5" class="mim-tip-reference" title="Blouin, M.-J., Beauchemin, H., Wright, A., De Paepe, M., Sorette, M., Bleau, A.-M., Nakamoto, B., Ou, C.-N., Stamatoyannopoulos, G., Trudel, M. &lt;strong&gt;Genetic correction of sickle cell disease: insights using transgenic mouse models.&lt;/strong&gt; Nature Med. 6: 177-182, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10655106/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10655106&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/72279&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10655106">Blouin et al. (2000)</a> assessed in vivo the potential curative threshold of fetal hemoglobin using mating with mice expressing the human fetal A-gamma-globin gene (HBG1; <a href="/entry/142200">142200</a>). With increasing levels of HbF, the transgenic mice showed considerable improvement in all hematologic parameters, morphopathologic features, and life span/survival. Correction was observed by increasing fetal hemoglobin to about 9 to 16% in this mouse model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10655106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="He, Z., Russell, J. E. &lt;strong&gt;Antisickling effects of an endogenous human alpha-like globin.&lt;/strong&gt; Nature Med. 10: 365-367, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15034572/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15034572&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nm1022&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15034572">He and Russell (2004)</a> generated complex transgenic knockout mice expressing human hemoglobin-S, either exclusively (S-alpha mice) or in the presence of human zeta-globin (S-zeta mice), an endogenous, developmentally silenced, non-beta-like globin. Sickle-cell disease-related deficits in erythrocyte number, hematocrit, and total hemoglobin were significantly improved in S-zeta mice. They also had reduced spleen size and improved urine concentrating ability compared with S-alpha mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15034572" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Hanna, J., Wernig, M., Markoulaki, S., Sun, C.-W., Meissner, A., Cassady, J. P., Beard, C., Brambrink, T., Wu, L.-C., Townes, T. M., Jaenisch, R. &lt;strong&gt;Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin.&lt;/strong&gt; Science 318: 1920-1923, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18063756/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18063756&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1152092&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18063756">Hanna et al. (2007)</a> used a humanized sickle cell anemia mouse model to show that mice can be rescued after transplantation with hematopoietic progenitors obtained in vitro from autologous induced pluripotent stem (iPS) cells. This was achieved after correction of the human sickle hemoglobin allele by gene-specific targeting. <a href="#24" class="mim-tip-reference" title="Hanna, J., Wernig, M., Markoulaki, S., Sun, C.-W., Meissner, A., Cassady, J. P., Beard, C., Brambrink, T., Wu, L.-C., Townes, T. M., Jaenisch, R. &lt;strong&gt;Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin.&lt;/strong&gt; Science 318: 1920-1923, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18063756/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18063756&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1152092&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18063756">Hanna et al. (2007)</a> concluded that their results provided proof of principle for using transcription factor-induced reprogramming combined with gene and cell therapy for disease treatment in mice. The authors pointed out the problems associated with using retroviruses and oncogenes for reprogramming need to be resolved before iPS cells can be considered for human therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18063756" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#84" class="mim-tip-reference" title="Xu, J., Peng, C., Sankaran, V. G., Shao, Z., Esrick, E. B., Chong, B. G., Ippolito, G. C., Fujiwara, Y., Ebert, B. L., Tucker, P. W., Orkin, S. H. &lt;strong&gt;Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing.&lt;/strong&gt; Science 334: 993-996, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21998251/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21998251&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21998251[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1211053&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21998251">Xu et al. (2011)</a> showed that the repressor BCL11A (<a href="/entry/606557">606557</a>) is required in vivo for silencing of gamma-globin expression in adult animals, yet dispensable for red cell production. BCL11A serves as a barrier to HbF reactivation by known HbF inducing agents. In a proof-of-principle test of BCL11A as a potential therapeutic target, <a href="#84" class="mim-tip-reference" title="Xu, J., Peng, C., Sankaran, V. G., Shao, Z., Esrick, E. B., Chong, B. G., Ippolito, G. C., Fujiwara, Y., Ebert, B. L., Tucker, P. W., Orkin, S. H. &lt;strong&gt;Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing.&lt;/strong&gt; Science 334: 993-996, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21998251/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21998251&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21998251[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1211053&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21998251">Xu et al. (2011)</a> demonstrated that inactivation of BCL11A in sickle cell disease transgenic mice corrects the hematologic and pathologic defects associated with sickle cell disease through high-level pancellular HbF induction. Thus, <a href="#84" class="mim-tip-reference" title="Xu, J., Peng, C., Sankaran, V. G., Shao, Z., Esrick, E. B., Chong, B. G., Ippolito, G. C., Fujiwara, Y., Ebert, B. L., Tucker, P. W., Orkin, S. H. &lt;strong&gt;Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing.&lt;/strong&gt; Science 334: 993-996, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21998251/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21998251&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21998251[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1211053&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21998251">Xu et al. (2011)</a> concluded that interference with HbF silencing by manipulation of a single target protein is sufficient to reverse sickle cell disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21998251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#64" class="mim-tip-reference" title="Savitt, T. L., Goldberg, M. F. &lt;strong&gt;Herrick&#x27;s 1910 case report of sickle cell anemia: the rest of the story.&lt;/strong&gt; JAMA 261: 266-271, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2642320/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2642320&lt;/a&gt;]" pmid="2642320">Savitt and Goldberg (1989)</a> gave an interesting account of investigations into the story of Walter Clement Noel, the first-to-be-described case of sickle cell anemia (<a href="#28" class="mim-tip-reference" title="Herrick, J. B. &lt;strong&gt;Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia.&lt;/strong&gt; Arch. Intern. Med. 5: 517-521, 1910. Note: Reprint. Classics of Biology and Medicine. Yale J. Biol. Med. 74: 179-184, 2001."None>Herrick, 1910</a>). Noel, a first-year dental student at the Chicago College of Dental Surgery, was admitted to the Presbyterian Hospital in late 1904 where Ernest E. Irons, a 27-year-old intern, obtained a history and performed routine physical, blood, and urine examinations. He noticed that Noel's blood smear contained 'many pear-shaped and elongated forms' and alerted his attending physician, James B. Herrick, to the unusual blood findings. Irons drew a rough sketch of these erythrocytes in the hospital record. Herrick and Irons followed Noel over the next 2.5 years through several episodes of severe illness as he continued his dental studies. Thereafter, Noel returned to Grenada to practice dentistry. He died 9 years later at the age of 32. Curiously, Irons, who lived from 1877 to 1959, was not included by Herrick, who lived from 1861 to 1964, in the authorship. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2642320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Conner, B. J., Reyes, A. A., Morin, C., Itakura, K., Teplitz, R. L., Wallace, R. B. &lt;strong&gt;Detection of sickle cell beta(S)-globin allele by hybridization with synthetic oligonucleotides.&lt;/strong&gt; Proc. Nat. Acad. Sci. 80: 278-282, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6572002/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6572002&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.80.1.278&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6572002">Conner et al. (1983)</a> synthesized two 19-base-long oligonucleotides, 1 complementary to the 5-prime end of the normal beta-globin gene and 1 complementary to the sickle cell gene. DNA from normal homozygotes showed hybridization only for the first probe; DNA from persons with sickle cell anemia showed hybridization only with the second; DNA from sickle cell anemia heterozygotes showed hybridization with both. Allele-specific hybridization of oligonucleotides was proposed as a general method for diagnosis of any genetic disease which involves a point mutation in a single-copy gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6572002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#63" class="mim-tip-reference" title="Saiki, R. K., Scharf, S., Faloona, F., Mullis, K. B., Horn, G. T., Erlich, H. A., Arnheim, N. &lt;strong&gt;Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia.&lt;/strong&gt; Science 230: 1350-1354, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2999980/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2999980&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.2999980&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2999980">Saiki et al. (1985)</a> developed a method for rapid and sensitive diagnosis of sickle cell anemia that has potential use in connection with other genetic diseases. It combines 2 methods: primer-mediated enzymatic amplification (about 220,000 times) of specific beta-globin target sequences in genomic DNA and restriction endonuclease digestion of an end-labeled oligonucleotide probe hybridized in solution to the amplified beta-globin sequences. In less than a day and with much less than a microgram of DNA, the diagnosis can be made. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2999980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Adams1995" class="mim-anchor"></a>
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Adams, R. J.
<strong>Sickle cell disease and stroke. (Editorial)</strong>
J. Child Neurol. 10: 75-76, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7782612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7782612</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7782612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1177/088307389501000201" target="_blank">Full Text</a>]
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<a id="Adler2001" class="mim-anchor"></a>
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Adler, B. K., Salzman, D. E., Carabasi, M. H., Vaughan, W. P., Reddy, V. V. B., Prchal, J. T.
<strong>Fatal sickle cell crisis after granulocyte colony-stimulating factor administration. (Letter)</strong>
Blood 97: 3313-3314, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11368061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11368061</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11368061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1182/blood.v97.10.3313" target="_blank">Full Text</a>]
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<a id="Ashley-Koch2001" class="mim-anchor"></a>
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Ashley-Koch, A., Murphy, C. C., Khoury, M. J., Boyle, C. A.
<strong>Contribution of sickle cell disease to the occurrence of developmental disabilities: a population-based study.</strong>
Genet. Med. 3: 181-186, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11388758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11388758</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11388758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1097/00125817-200105000-00006" target="_blank">Full Text</a>]
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<a id="Ballas1982" class="mim-anchor"></a>
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Ballas, S. K., Lewis, C. N., Noone, A. M., Krasnow, S. H., Kamarulzaman, E., Burka, E. R.
<strong>Clinical, hematological, and biochemical features of Hb SC disease.</strong>
Am. J. Hemat. 13: 37-51, 1982.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7137165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7137165</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7137165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajh.2830130106" target="_blank">Full Text</a>]
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<a id="Blouin2000" class="mim-anchor"></a>
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Blouin, M.-J., Beauchemin, H., Wright, A., De Paepe, M., Sorette, M., Bleau, A.-M., Nakamoto, B., Ou, C.-N., Stamatoyannopoulos, G., Trudel, M.
<strong>Genetic correction of sickle cell disease: insights using transgenic mouse models.</strong>
Nature Med. 6: 177-182, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655106</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10655106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/72279" target="_blank">Full Text</a>]
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<a id="Booth2010" class="mim-anchor"></a>
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Booth, C., Inusa, B., Obaro, S. K.
<strong>Infection in sickle cell disease: a review.</strong>
Int. J. Infect. Dis. 14: e2-e12, 2010. Note: Electronic Article.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19497774/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19497774</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19497774" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ijid.2009.03.010" target="_blank">Full Text</a>]
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<a id="Chaine2001" class="mim-anchor"></a>
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Chaine, B., Neonato, M.-G., Girot, R., Aractingi, S.
<strong>Cutaneous adverse reactions to hydroxyurea in patients with sickle cell disease.</strong>
Arch. Derm. 137: 467-470, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11295927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11295927</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11295927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Chang1998" class="mim-anchor"></a>
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Chang, J. C., Lu, R., Lin, C., Xu, S.-M., Kan, Y. W., Porcu, S., Carlson, E., Kitamura, M., Yang, S., Flebbe-Rehwaldt, L., Gaensler, K. M. L.
<strong>Transgenic knockout mice exclusively expressing human hemoglobin S after transfer of a 240-kb beta-S-globin yeast artificial chromosome: a mouse model of sickle cell anemia.</strong>
Proc. Nat. Acad. Sci. 95: 14886-14890, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843985</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9843985[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843985" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.95.25.14886" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
<a id="Charache1996" class="mim-anchor"></a>
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Charache, S., Barton, F. B., Moore, R. D., Terrin, M. L., Steinberg, M. H., Dover, G. J., Ballas, S. K., McMahon, R. P., Castro, O., Orringer, E. P.
<strong>Hydroxyurea and sickle cell anemia: clinical utility of a myelosuppressive 'switching' agent.</strong>
Medicine 75: 300-326, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8982148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8982148</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8982148" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1097/00005792-199611000-00002" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="10" class="mim-anchor"></a>
<a id="Charache1983" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Charache, S., Dover, G., Smith, K., Talbot, C. C., Jr., Moyer, M., Boyer, S.
<strong>Treatment of sickle cell anemia with 5-azacytidine results in increased fetal hemoglobin production and is associated with nonrandom hypomethylation of DNA around the gamma-delta-beta-globin gene complex.</strong>
Proc. Nat. Acad. Sci. 80: 4842-4846, 1983.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6192443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6192443</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6192443" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.80.15.4842" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="11" class="mim-anchor"></a>
<a id="Charache1995" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Charache, S., Terrin, M. L., Moore, R. D., Dover, G. J., Barton, F. B., Eckert, S. V., McMahon, R. P., Bonds, D. R., Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia.
<strong>Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia.</strong>
New Eng. J. Med. 332: 1317-1322, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7715639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7715639</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7715639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM199505183322001" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="12" class="mim-anchor"></a>
<a id="Cheung1996" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Cheung, M.-C., Goldberg, J. D., Kan, Y. W.
<strong>Prenatal diagnosis of sickle cell anaemia and thalassaemia by analysis of fetal cells in maternal blood.</strong>
Nature Genet. 14: 264-268, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896554</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8896554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng1196-264" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="13" class="mim-anchor"></a>
<a id="Conner1983" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Conner, B. J., Reyes, A. A., Morin, C., Itakura, K., Teplitz, R. L., Wallace, R. B.
<strong>Detection of sickle cell beta(S)-globin allele by hybridization with synthetic oligonucleotides.</strong>
Proc. Nat. Acad. Sci. 80: 278-282, 1983.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6572002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6572002</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6572002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.80.1.278" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="14" class="mim-anchor"></a>
<a id="Dover1986" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Dover, G. J., Humphries, R. K., Moore, J. G., Ley, T. J., Young, N. S., Charache, S., Nienhuis, A. W.
<strong>Hydroxyurea induction of hemoglobin F production in sickle cell disease: relationship between cytotoxicity and F cell production.</strong>
Blood 67: 735-738, 1986.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2418898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2418898</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2418898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="15" class="mim-anchor"></a>
<a id="Esrick2021" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Esrick, E. B., Lehmann, L. E., Biffi, A., Achebe, M., Brendel, C., Ciuculescu, M. F., Daley, H., MacKinnon, B., Morris, E., Federico, A., Abriss, D., Boardman, K., and 13 others.
<strong>Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease.</strong>
New Eng. J. Med. 384: 205-215, 2021.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33283990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33283990</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33283990" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMoa2029392" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="16" class="mim-anchor"></a>
<a id="Fabry1996" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Fabry, M. E., Kennan, R. P., Paszty, C., Costantini, F., Rubin, E. M., Gore, J. C., Nagel, R. L.
<strong>Magnetic resonance evidence of hypoxia in a homozygous alpha-knockout of a transgenic mouse model for sickle cell disease.</strong>
J. Clin. Invest. 98: 2450-2455, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8958206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8958206</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8958206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI119062" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="17" class="mim-anchor"></a>
<a id="Ferster2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ferster, A., Tahriri, P., Vermylen, C., Sturbois, G., Corazza, F., Fondu, P., Devalck, C., Dresse, M. F., Feremans, W., Hunninck, K., Toppet, M., Phillippet, P., Van Geet, C., Sariban, E.
<strong>Five years of experience with hydroxyurea in children and young adults with sickle cell disease.</strong>
Blood 97: 3628-3632, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11369660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11369660</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11369660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1182/blood.v97.11.3628" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="18" class="mim-anchor"></a>
<a id="Frangoul2024" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Frangoul, H., Locatelli, F., Sharma, A., Bhatia, M., Mapara, M., Molinari, L., Wall, D., Liem, R. I., Telfer, P., Shah, A. J., Cavazzana, M., Corbacioglu, S., and 17 others.
<strong>Exagamglogene autotemcel for severe sickle cell disease.</strong>
New Eng. J. Med. 390: 1649-1662, 2024.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38661449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38661449</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38661449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMoa2309676" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="19" class="mim-anchor"></a>
<a id="Friedman1981" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Friedman, M. J., Trager, W.
<strong>The biochemistry of resistance to malaria.</strong>
Sci. Am. 244(3): 154-164, 1981.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6163210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6163210</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6163210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/scientificamerican0381-154" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="20" class="mim-anchor"></a>
<a id="Galarneau2010" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Galarneau, G., Palmer, C. D., Sankaran, V. G., Orkin, S. H., Hirschhorn, J. N., Lettre, G.
<strong>Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation.</strong>
Nature Genet. 42: 1049-1051, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21057501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21057501</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21057501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng.707" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="21" class="mim-anchor"></a>
<a id="Gladwin2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gladwin, M. T., Sachdev, V., Jison, M. L., Shizukuda, Y., Plehn, J. F., Minter, K., Brown, B., Coles, W. A., Nichols, J. S., Ernst, I., Hunter, L. A., Blackwelder, W. C., Schechter, A. N., Rodgers, G. P., Castro, O., Ognibene, F. P.
<strong>Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.</strong>
New Eng. J. Med. 350: 886-895, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14985486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14985486</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14985486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMoa035477" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="22" class="mim-anchor"></a>
<a id="Gladwin2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gladwin, M. T.
<strong>Unraveling the hemolytic subphenotype of sickle cell disease.</strong>
Blood 106: 2925-2926, 2005.
</p>
</div>
</li>
<li>
<a id="23" class="mim-anchor"></a>
<a id="Gupta1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gupta, A. K., Kirchner, K. A., Nicholson, R., Adams, J. G., III, Schechter, A. N., Noguchi, C. T., Steinberg, M. H.
<strong>Effects of alpha-thalassemia and sickle polymerization tendency on the urine-concentrating defect of individuals with sickle cell trait.</strong>
J. Clin. Invest. 88: 1963-1968, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1752955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1752955</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1752955" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI115521" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="24" class="mim-anchor"></a>
<a id="Hanna2007" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hanna, J., Wernig, M., Markoulaki, S., Sun, C.-W., Meissner, A., Cassady, J. P., Beard, C., Brambrink, T., Wu, L.-C., Townes, T. M., Jaenisch, R.
<strong>Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin.</strong>
Science 318: 1920-1923, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18063756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18063756</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18063756" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.1152092" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="25" class="mim-anchor"></a>
<a id="He2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
He, Z., Russell, J. E.
<strong>Antisickling effects of an endogenous human alpha-like globin.</strong>
Nature Med. 10: 365-367, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034572</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15034572" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/nm1022" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="26" class="mim-anchor"></a>
<a id="Hebbel1997" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hebbel, R. P.
<strong>Adhesive interactions of sickle erythrocytes with endothelium.</strong>
J. Clin. Invest. 99: 2561-2564, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9169483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9169483</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9169483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI119442" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="27" class="mim-anchor"></a>
<a id="Hebbel2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hebbel, R. P.
<strong>Blockade of adhesion of sickle cells to endothelium by monoclonal antibodies. (Editorial)</strong>
New Eng. J. Med. 342: 1910-1912, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861330</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
</div>
</li>
<li>
<a id="28" class="mim-anchor"></a>
<a id="Herrick1910" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Herrick, J. B.
<strong>Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia.</strong>
Arch. Intern. Med. 5: 517-521, 1910. Note: Reprint. Classics of Biology and Medicine. Yale J. Biol. Med. 74: 179-184, 2001.
</p>
</div>
</li>
<li>
<a id="29" class="mim-anchor"></a>
<a id="Kanter2022" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Kanter, J., Walters, M. C., Krishnamurti, L., Mapara, M. Y., Kwiatkowski, J. L., Rifkin-Zenenberg, S., Aygun, B., Kasow, K. A., Pierciey, F. J., Bonner, M., Miller, A., Zhang, X., Lynch, J., Kim, D., Ribeil, J. A., Asmal, M., Goyal, S., Thompson, A. A., Tisdale, J. F.
<strong>Biologic and clinical efficacy of LentiGlobin for sickle cell disease.</strong>
New Eng. J. Med. 386: 617-628, 2022.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34898139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34898139</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34898139" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMoa2117175" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="30" class="mim-anchor"></a>
<a id="Kark1987" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Kark, J. A., Posey, D. M., Schumacher, H. R., Ruehle, C. J.
<strong>Sickle-cell trait as a risk factor for sudden death in physical training.</strong>
New Eng. J. Med. 317: 781-787, 1987.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3627196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3627196</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3627196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
</div>
</li>
<li>
<a id="31" class="mim-anchor"></a>
<a id="Kaul2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Kaul, D. K., Tsai, H. M., Liu, X. D., Nakada, M. T., Nagel, R. L., Coller, B. S.
<strong>Monoclonal antibodies to alpha-v-beta-3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor.</strong>
Blood 95: 368-374, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10627437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10627437</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10627437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="32" class="mim-anchor"></a>
<a id="Kodish1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Kodish, E., Lantos, J., Stocking, C., Singer, P. A., Siegler, M., Johnson, F. L.
<strong>Bone marrow transplantation for sickle cell disease: a study of parents' decisions.</strong>
New Eng. J. Med. 325: 1349-1353, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1922237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1922237</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1922237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
</div>
</li>
<li>
<a id="33" class="mim-anchor"></a>
<a id="Lan1998" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Lan, N., Howrey, R. P., Lee, S.-W., Smith, C. A., Sullenger, B. A.
<strong>Ribozyme-mediated repair of sickle beta-globin mRNAs in erythrocyte precursors.</strong>
Science 280: 1593-1596, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9616120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9616120</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9616120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.280.5369.1593" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="34" class="mim-anchor"></a>
<a id="Lane1985" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Lane, P. A., Githens, J. H.
<strong>Splenic syndrome at mountain altitudes in sickle cell trait: its occurrence in nonblack persons.</strong>
JAMA 253: 2251-2254, 1985.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3974118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3974118</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3974118" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="35" class="mim-anchor"></a>
<a id="Lane1994" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Lane, P. A., Rogers, Z. R., Woods, G. M., Wang, W. C., Wilimas, J. A., Miller, S. T., Khakoo, Y., Buchanan, G. R.
<strong>Fatal pneumococcal septicemia in hemoglobin SC disease.</strong>
J. Pediat. 124: 859-862, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8201467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8201467</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8201467" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0022-3476(05)83171-3" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="36" class="mim-anchor"></a>
<a id="Langdown1989" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Langdown, J. V., Williamson, D., Knight, C. B., Rubenstein, D., Carrell, R. W.
<strong>A new doubly substituted sickling haemoglobin: HbS-Oman.</strong>
Brit. J. Haemat. 71: 443-444, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2930724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2930724</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2930724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1365-2141.1989.tb04304.x" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="37" class="mim-anchor"></a>
<a id="Lazarin2013" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Lazarin, G. A., Haque, I. S., Nazareth, S., Iori, K., Patterson, A. S., Jacobson, J. L., Marshall, J. R., Seltzer, W. K., Patrizio, P., Evans, E. A., Srinivasan, B. S.
<strong>An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.</strong>
Genet. Med. 15: 178-186, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22975760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22975760</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22975760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/gim.2012.114" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="38" class="mim-anchor"></a>
<a id="Lettre2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Lettre, G., Sankaran, V. G., Bezerra, M. A. C., Araujo, A. S., Uda, M., Sanna, S., Cao, A., Schlessinger, D., Costa, F. F., Hirschhorn, J. N.
<strong>Orkin, S. H.: DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease.</strong>
Proc. Nat. Acad. Sci. 105: 11869-11874, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18667698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18667698</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18667698" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.0804799105" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="39" class="mim-anchor"></a>
<a id="Luzzatto1989" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Luzzatto, L., Goodfellow, P.
<strong>Sickle cell anemia: a simple disease with no cure.</strong>
Nature 337: 17-18, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2909889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2909889</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2909889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/337017a0" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="40" class="mim-anchor"></a>
<a id="Manci2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Manci, E. A., Culberson, D. E., Yang, Y.-M., Gardner, T. M., Powell, R., Haynes, J., Jr., Shah, A. K., Mankad, V. N., Investigators of the Cooperative Study of Sickle Cell Disease.
<strong>Causes of death in sickle cell disease: an autopsy study.</strong>
Brit. J. Haemat. 123: 359-365, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14531921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14531921</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14531921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1046/j.1365-2141.2003.04594.x" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="41" class="mim-anchor"></a>
<a id="Milner1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Milner, P. F., Kraus, A. P., Sebes, J. I., Sleeper, L. A., Dukes, K. A., Embury, S. H., Bellevue, R., Koshy, M., Moohr, J. W., Smith, J.
<strong>Sickle cell disease as a cause of osteonecrosis of the femoral head.</strong>
New Eng. J. Med. 325: 1476-1481, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1944426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1944426</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1944426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM199111213252104" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="42" class="mim-anchor"></a>
<a id="Modell2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Modell, B., Darlison, M.
<strong>Global epidemiology of haemoglobin disorders and derived service indicators.</strong>
Bull. World Health Organ. 86: 480-487, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18568278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18568278</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18568278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.2471/blt.06.036673" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="43" class="mim-anchor"></a>
<a id="Monk1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Monk, M., Kenealy, M.-R., Mohadjerani, S.
<strong>Detection of both the normal and mutant alleles in single cells of individuals heterozygous for the sickle cell mutation--prelude to preimplantation diagnosis.</strong>
Prenatal Diag. 13: 45-53, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8446570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8446570</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8446570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/pd.1970130107" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="44" class="mim-anchor"></a>
<a id="Morris1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Morris, J., Dunn, D., Beckford, M., Grandison, Y., Mason, K., Higgs, D., De Ceulaer, K., Serjeant, B., Serjeant, G.
<strong>The haematology of homozygous sickle cell disease after the age of 40 years.</strong>
Brit. J. Haemat. 77: 382-385, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1707292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1707292</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1707292" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1365-2141.1991.tb08588.x" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="45" class="mim-anchor"></a>
<a id="Niihara2018" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Niihara, Y., Miller, S. T., Kanter, J., Lanzkron, S., Smith, W. R., Hsu, L. L., Gordeuk, V. R., Viswanathan, K., Sarnaik, S., Osunkwo, I., Guillaume, E., Sadanandan, S., and 11 others.
<strong>A phase 3 trial of l-glutamine in sickle cell disease.</strong>
New Eng. J. Med. 379: 226-235, 2018.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30021096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30021096</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30021096" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMoa1715971" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="46" class="mim-anchor"></a>
<a id="Nolan2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Nolan, V. G., Baldwin, C., Ma, Q., Wyszynski, D. F., Amirault, Y., Farrell, J. J., Bisbee, A., Embury, S. H., Farrer, L. A., Steinberg, M. H.
<strong>Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia.</strong>
Brit. J. Haemat. 128: 266-272, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15638863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15638863</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15638863" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1365-2141.2004.05295.x" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="47" class="mim-anchor"></a>
<a id="Nolan2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Nolan, V. G., Wyszynski, D. F., Farrer, L. A., Steinberg, M. H.
<strong>Hemolysis-associated priapism in sickle cell disease.</strong>
Blood 106: 3264-3267, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15985542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15985542</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15985542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1182/blood-2005-04-1594" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="48" class="mim-anchor"></a>
<a id="Paszty1997" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Paszty, C., Brion, C. M., Manci, E., Witkowska, H. E., Stevens, M. E., Mohandas, N., Rubin, E. M.
<strong>Transgenic knockout mice with exclusively human sickle hemoglobin and sickle cell disease.</strong>
Science 278: 876-878, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9346488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9346488</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9346488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.278.5339.876" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="49" class="mim-anchor"></a>
<a id="Pawliuk2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Pawliuk, R., Westerman, K. A., Fabry, M. E., Payen, E., Tighe, R., Bouhassira, E. E., Acharya, S. A., Ellis, J., London, I. M., Eaves, C. J., Humphries, R. K., Beuzard, Y., Nagel, R. L., Leboulch, P.
<strong>Correction of sickle cell disease in transgenic mouse models by gene therapy.</strong>
Science 294: 2368-2371, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743206</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.1065806" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="50" class="mim-anchor"></a>
<a id="Pawloski2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Pawloski, J. R., Hess, D. T., Stamler, J. S.
<strong>Export by red blood cells of nitric oxide bioactivity.</strong>
Nature 409: 622-626, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11214321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11214321</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11214321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/35054560" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="51" class="mim-anchor"></a>
<a id="Pawloski2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Pawloski, J. R., Hess, D. T., Stamler, J. S.
<strong>Impaired vasodilation by red blood cells in sickle cell disease.</strong>
Proc. Nat. Acad. Sci. 102: 2531-2536, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15699345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15699345</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15699345[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15699345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.0409876102" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="52" class="mim-anchor"></a>
<a id="Pearson1985" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Pearson, H. A., Gallagher, D., Chilcote, R., Sullivan, E., Wilimas, J., Espeland, M., Ritchey, A. K., Cooperative Study of Sickle Cell Disease.
<strong>Developmental pattern of splenic dysfunction in sickle cell disorders.</strong>
Pediatrics 76: 392-397, 1985.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2412200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2412200</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2412200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="53" class="mim-anchor"></a>
<a id="Perrine1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Perrine, S. P., Ginder, G. D., Faller, D. V., Dover, G. H., Ikuta, T., Witkowska, H. E., Cai, S., Vichinsky, E. P., Olivieri, N. F.
<strong>A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders.</strong>
New Eng. J. Med. 328: 81-86, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7677966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7677966</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7677966" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM199301143280202" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="54" class="mim-anchor"></a>
<a id="Perrine1985" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Perrine, S. P., Greene, M. F., Faller, D. V.
<strong>Delay in the fetal globin switch in infants of diabetic mothers.</strong>
New Eng. J. Med. 312: 334-338, 1985.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2578609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2578609</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2578609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM198502073120602" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="55" class="mim-anchor"></a>
<a id="Piel2017" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Piel, F. B., Steinberg, M. H., Rees, D. C.
<strong>Sickle cell disease.</strong>
New Eng. J. Med. 376: 1561-1573, 2017.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28423290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28423290</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28423290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMra1510865" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="56" class="mim-anchor"></a>
<a id="Platt1994" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Platt, O. S., Brambilla, B. J., Rosse, W. F., Milner, P. F., Castro, O., Steinberg, M. H., Klug, P. P.
<strong>Mortality in sickle cell disease: life expectancy and risk factors for early death.</strong>
New Eng. J. Med. 330: 1639-1644, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7993409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7993409</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7993409" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM199406093302303" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="57" class="mim-anchor"></a>
<a id="Platt2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Platt, O. S.
<strong>The acute chest syndrome of sickle cell disease. (Editorial)</strong>
New Eng. J. Med. 342: 1904-1907, 2000. Note: Erratum: New Eng. J. Med. 343: 591 only, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861328</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM200006223422510" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="58" class="mim-anchor"></a>
<a id="Popp1997" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Popp, R. A., Popp, D. M., Shinpock, S. G., Yang, M. Y., Mural, J. G., Aguinaga, M. P., Kopsombut, P., Roa, P. D., Turner, E. A., Rubin, E. M.
<strong>A transgenic mouse model of hemoglobin S Antilles disease.</strong>
Blood 89: 4204-4212, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9166865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9166865</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9166865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="59" class="mim-anchor"></a>
<a id="Rees2010" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rees, D. C., Williams, T. N., Gladwin, M. T.
<strong>Sickle cell disease.</strong>
Lancet 376: 2018-2031, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21131035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21131035</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21131035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/S0140-6736(10)61029-X" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="60" class="mim-anchor"></a>
<a id="Rey1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rey, K. S., Unger, C. A., Rao, S. P., Miller, S. T.
<strong>Sickle cell-hemoglobin E disease: clinical findings and implications.</strong>
J. Pediat. 119: 949-951, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1960615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1960615</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1960615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0022-3476(05)83053-7" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="61" class="mim-anchor"></a>
<a id="Rodgers1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rodgers, G. P., Dover, G. J., Uyesaka, N., Noguchi, C. T., Schechter, A. N., Nienhuis, A. W.
<strong>Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease.</strong>
New Eng. J. Med. 328: 73-80, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7677965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7677965</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7677965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM199301143280201" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="62" class="mim-anchor"></a>
<a id="Ryan1997" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ryan, T. M., Ciavatta, D. J., Townes, T. M.
<strong>Knockout-transgenic mouse model of sickle cell disease.</strong>
Science 278: 873-876, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9346487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9346487</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9346487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.278.5339.873" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="63" class="mim-anchor"></a>
<a id="Saiki1985" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Saiki, R. K., Scharf, S., Faloona, F., Mullis, K. B., Horn, G. T., Erlich, H. A., Arnheim, N.
<strong>Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia.</strong>
Science 230: 1350-1354, 1985.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2999980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2999980</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2999980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.2999980" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="64" class="mim-anchor"></a>
<a id="Savitt1989" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Savitt, T. L., Goldberg, M. F.
<strong>Herrick's 1910 case report of sickle cell anemia: the rest of the story.</strong>
JAMA 261: 266-271, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2642320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2642320</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2642320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="65" class="mim-anchor"></a>
<a id="Scriver1930" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Scriver, J. B., Waugh, T. R.
<strong>Studies on a case of sickle-cell anaemia.</strong>
Canad. Med. Assoc. J. 23: 375-380, 1930.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20317973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20317973</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20317973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="66" class="mim-anchor"></a>
<a id="Sebastiani2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Sebastiani, P., Ramoni, M. F., Nolan, V., Baldwin, C. T., Steinberg, M. H.
<strong>Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia.</strong>
Nature Genet. 37: 435-440, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15778708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15778708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15778708[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15778708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng1533" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="67" class="mim-anchor"></a>
<a id="Serjeant2007" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Serjeant, G. R., Higgs, D. R., Hambleton, I. R.
<strong>Elderly survivors with homozygous sickle cell disease. (Letter)</strong>
New Eng. J. Med. 356: 642-643, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17287491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17287491</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17287491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMc066547" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="68" class="mim-anchor"></a>
<a id="Serjeant1968" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Serjeant, G. R., Richards, R., Barbor, P. R. H., Milner, P. F.
<strong>Relatively benign sickle cell anaemia in 60 patients aged over 30 in the West Indies.</strong>
Brit. Med. J. 3: 86-91, 1968.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4232783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4232783</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4232783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
</div>
</li>
<li>
<a id="69" class="mim-anchor"></a>
<a id="Shear1998" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Shear, H. L., Grinberg, L., Gilman, J., Fabry, M. E., Stamatoyannopoulos, G., Goldberg, D. E., Nagel, R. L.
<strong>Transgenic mice expressing human fetal globin are protected from malaria by a novel mechanism.</strong>
Blood 92: 2520-2526, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9746793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9746793</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9746793" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="70" class="mim-anchor"></a>
<a id="Shesely1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Shesely, E. G., Kim, H.-S., Shehee, W. R., Papayannopoulou, T., Smithies, O., Popovich, B. W.
<strong>Correction of a human beta-S-globin gene by gene targeting.</strong>
Proc. Nat. Acad. Sci. 88: 4294-4298, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2034673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2034673</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2034673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
</div>
</li>
<li>
<a id="71" class="mim-anchor"></a>
<a id="Steinberg1995" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Steinberg, M. H., Ballas, S. K., Brunson, C. Y., Bookchin, R.
<strong>Sickle cell anemia in septuagenarians. (Letter)</strong>
Blood 86: 3997-4002, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7579371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7579371</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7579371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="72" class="mim-anchor"></a>
<a id="Steinberg1989" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Steinberg, M. H.
<strong>Sickle cell anemia in a septuagenarian.</strong>
Brit. J. Haemat. 71: 297-298, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2923816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2923816</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2923816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1365-2141.1989.tb04274.x" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="73" class="mim-anchor"></a>
<a id="Steinberg1999" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Steinberg, M. H.
<strong>Management of sickle cell disease.</strong>
New Eng. J. Med. 340: 1021-1030, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10099145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10099145</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10099145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
</div>
</li>
<li>
<a id="74" class="mim-anchor"></a>
<a id="Thomas2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Thomas, P. W., Singhal, A., Hemmings-Kelly, M., Serjeant, G. R.
<strong>Height and weight reference curves for homozygous sickle cell disease.</strong>
Arch. Dis. Child. 82: 204-208, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10685921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10685921</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10685921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
</div>
</li>
<li>
<a id="75" class="mim-anchor"></a>
<a id="Trompeter2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Trompeter, S., Roberts, I.
<strong>Haemoglobin F modulation in childhood sickle cell disease.</strong>
Brit. J. Haemat. 144: 308-316, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19036119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19036119</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19036119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
</div>
</li>
<li>
<a id="76" class="mim-anchor"></a>
<a id="Tshilolo2019" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Tshilolo, L., Tomlinson, G., Williams, T. N., Santos, B., Olupot-Olupot, P., Lane, A., Aygun, B., Stuber, S. E., Latham, T. S., McGann, P. T., Ware, R. E.
<strong>Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa.</strong>
New Eng. J. Med. 380: 121-131, 2019.
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</p>
</div>
</li>
<li>
<a id="77" class="mim-anchor"></a>
<a id="Uda2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Uda, M., Galanello, R., Sanna, S., Lettre, G., Sankaran, V. G., Chen, W., Usala, G., Busonero, F., Maschio, A., Albai, G., Piras, M. G., Sestu, N., and 18 others.
<strong>Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia.</strong>
Proc. Nat. Acad. Sci. 105: 1620-1625, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18245381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18245381</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18245381[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18245381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
</div>
</li>
<li>
<a id="78" class="mim-anchor"></a>
<a id="Vichinsky2019" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Vichinsky, E., Hoppe, C. C., Ataga, K. I., Ware, R. E., Nduba, V., El-Beshlawy, A., Hassab, H., Achebe, M. M., Alkindi, S., Brown, R. C., Diuguid, D. L., Telfer, P., and 11 others.
<strong>A phase 3 randomized trial of voxelotor in sickle cell disease.</strong>
New Eng. J. Med. 381: 509-519, 2019.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31199090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31199090</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31199090" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMoa1903212" target="_blank">Full Text</a>]
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<a id="79" class="mim-anchor"></a>
<a id="Vichinsky2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Vichinsky, E. P., Neumayr, L. D., Earles, A. N., Williams, R., Lennette, E. T., Dean, D., Nickerson, B., Orringer, E., McKie, V., Bellevue, R., Daeschner, C., Manci, E. A.
<strong>Causes and outcomes of the acute chest syndrome in sickle cell disease.</strong>
New Eng. J. Med. 342: 1855-1865, 2000. Note: Erratum: New Eng. J. Med. 343: 824 only, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861320</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM200006223422502" target="_blank">Full Text</a>]
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<a id="80" class="mim-anchor"></a>
<a id="Walker2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Walker, T. M., Hambleton, I. R., Serjeant, G. R.
<strong>Gallstones in sickle cell disease: observations from the Jamaican Cohort Study.</strong>
J. Pediat. 136: 80-85, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10636979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10636979</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10636979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0022-3476(00)90054-4" target="_blank">Full Text</a>]
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<a id="81" class="mim-anchor"></a>
<a id="Wang2013" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wang, Y., Kennedy, J., Caggana, M., Zimmerman, R., Thomas, S., Berninger, J., Harris, K., Green, N. S., Oyeku, S., Hulihan, M., Grant, A. M., Grosse, S. D.
<strong>Sickle cell disease incidence among newborns in New York State by maternal race/ethnicity and nativity.</strong>
Genet. Med. 15: 222-228, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23018751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23018751</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23018751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/gim.2012.128" target="_blank">Full Text</a>]
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<a id="82" class="mim-anchor"></a>
<a id="Weatherall2010" class="mim-anchor"></a>
<div class="">
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Weatherall, D. J.
<strong>The inherited diseases of hemoglobin are an emerging global health burden.</strong>
Blood 115: 4331-4336, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20233970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20233970</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20233970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1182/blood-2010-01-251348" target="_blank">Full Text</a>]
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<a id="83" class="mim-anchor"></a>
<a id="Williams2005" class="mim-anchor"></a>
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Williams, T. N., Mwangi, T. W., Wambua, S., Peto, T. E. A., Weatherall, D. J., Gupta, S., Recker, M., Penman, B. S., Uyoga, S., Macharia, A., Mwacharo, J. K., Snow, R. W., Marsh, K.
<strong>Negative epistasis between the malaria-protective effects of alpha(+)-thalassemia and the sickle cell trait.</strong>
Nature Genet. 37: 1253-1257, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16227994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16227994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16227994[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16227994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng1660" target="_blank">Full Text</a>]
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<a id="84" class="mim-anchor"></a>
<a id="Xu2011" class="mim-anchor"></a>
<div class="">
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Xu, J., Peng, C., Sankaran, V. G., Shao, Z., Esrick, E. B., Chong, B. G., Ippolito, G. C., Fujiwara, Y., Ebert, B. L., Tucker, P. W., Orkin, S. H.
<strong>Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing.</strong>
Science 334: 993-996, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21998251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21998251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21998251[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21998251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.1211053" target="_blank">Full Text</a>]
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<a id="85" class="mim-anchor"></a>
<a id="Xu1999" class="mim-anchor"></a>
<div class="">
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Xu, K., Shi, Z. M., Veeck, L. L., Hughes, M. R., Rosenwaks, Z.
<strong>First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia.</strong>
JAMA 281: 1701-1706, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10328069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10328069</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10328069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/jama.281.18.1701" target="_blank">Full Text</a>]
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<a id="86" class="mim-anchor"></a>
<a id="Yawn2014" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Yawn, B. P., Buchanan, G. R., Afenyi-Annan, A. N., Ballas, S. K., Hassell, K. L., James, A. H., Jordan, L., Lanzkron, S. M., Lottenberg, R., Savage, W. J., Tanabe, P. J., Ware, R. E., and 6 others.
<strong>Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members.</strong>
JAMA 312: 1033-1048, 2014. Note: Erratum: JAMA 312: 1932 only, 2014. Erratum: JAMA 313: 729 only, 2015.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25203083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25203083</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25203083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/jama.2014.10517" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 05/14/2024
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Sonja A. Rasmussen - updated : 07/26/2022<br>Ada Hamosh - updated : 03/08/2021<br>Ada Hamosh - updated : 09/19/2019<br>Ada Hamosh - updated : 02/05/2019<br>Ada Hamosh - updated : 09/14/2018<br>Carol A. Bocchini - updated : 05/12/2017<br>Anne M. Stumpf - updated : 4/19/2013<br>Ada Hamosh - updated : 4/17/2013<br>Cassandra L. Kniffin - updated : 2/14/2013<br>Ada Hamosh - updated : 12/20/2011<br>Carol A. Bocchini - updated : 2/1/2011<br>Cassandra L. Kniffin - updated : 9/30/2010<br>Cassandra L. Kniffin - updated : 6/22/2009<br>Cassandra L. Kniffin - updated : 6/3/2009<br>Cassandra L. Kniffin - updated : 2/20/2008<br>Ada Hamosh - updated : 2/11/2008<br>Victor A. McKusick - updated : 6/20/2006<br>Victor A. McKusick - updated : 11/1/2005<br>Cassandra L. Kniffin - updated : 6/16/2005<br>Victor A. McKusick - updated : 5/12/2005<br>Victor A. McKusick -updated : 3/29/2005<br>Victor A. McKusick - updated : 4/7/2004<br>Ada Hamosh - updated : 3/30/2004<br>Victor A. McKusick - updated : 12/8/2003<br>Gary A. Bellus - updated : 4/8/2002<br>Ada Hamosh - updated : 1/9/2002<br>Ada Hamosh - updated : 12/18/2001<br>Victor A. McKusick - updated : 10/12/2001<br>Victor A. McKusick - updated : 8/23/2001<br>Victor A. McKusick - updated : 2/26/2001<br>Ada Hamosh - updated : 9/15/2000<br>Paul Brennan - updated : 5/3/2000<br>Victor A. McKusick - updated : 4/11/2000<br>Victor A. McKusick - updated : 7/7/1999
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Ada Hamosh : 6/13/1999
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carol : 05/15/2024
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alopez : 05/14/2024<br>carol : 02/10/2023<br>carol : 07/26/2022<br>alopez : 03/08/2021<br>alopez : 09/19/2019<br>alopez : 05/23/2019<br>carol : 05/17/2019<br>alopez : 02/05/2019<br>alopez : 09/14/2018<br>carol : 05/12/2017<br>carol : 10/18/2016<br>carol : 05/27/2016<br>carol : 1/29/2015<br>carol : 12/1/2014<br>joanna : 11/26/2014<br>alopez : 4/19/2013<br>alopez : 4/19/2013<br>alopez : 4/19/2013<br>alopez : 4/17/2013<br>carol : 4/1/2013<br>terry : 3/14/2013<br>alopez : 2/20/2013<br>ckniffin : 2/14/2013<br>alopez : 1/4/2012<br>terry : 12/20/2011<br>mgross : 11/17/2011<br>terry : 11/11/2011<br>carol : 9/13/2011<br>alopez : 7/18/2011<br>carol : 5/19/2011<br>carol : 2/1/2011<br>wwang : 9/30/2010<br>ckniffin : 9/30/2010<br>terry : 1/20/2010<br>wwang : 9/9/2009<br>wwang : 7/21/2009<br>ckniffin : 6/22/2009<br>carol : 6/17/2009<br>terry : 6/4/2009<br>terry : 6/3/2009<br>ckniffin : 6/3/2009<br>joanna : 3/3/2009<br>wwang : 3/6/2008<br>ckniffin : 2/20/2008<br>alopez : 2/14/2008<br>terry : 2/11/2008<br>mgross : 7/5/2007<br>alopez : 3/21/2007<br>wwang : 6/20/2006<br>terry : 6/20/2006<br>alopez : 11/2/2005<br>terry : 11/1/2005<br>wwang : 7/5/2005<br>ckniffin : 6/16/2005<br>wwang : 6/7/2005<br>wwang : 5/12/2005<br>tkritzer : 4/6/2005<br>tkritzer : 4/4/2005<br>terry : 3/29/2005<br>tkritzer : 4/7/2004<br>alopez : 4/2/2004<br>alopez : 3/30/2004<br>terry : 3/30/2004<br>tkritzer : 12/11/2003<br>terry : 12/8/2003<br>alopez : 4/8/2002<br>alopez : 1/10/2002<br>terry : 1/9/2002<br>alopez : 1/2/2002<br>terry : 12/18/2001<br>carol : 10/12/2001<br>mcapotos : 8/29/2001<br>mcapotos : 8/23/2001<br>carol : 2/26/2001<br>mcapotos : 9/20/2000<br>mcapotos : 9/18/2000<br>mcapotos : 9/18/2000<br>terry : 9/15/2000<br>alopez : 5/3/2000<br>mcapotos : 5/2/2000<br>mcapotos : 5/2/2000<br>mcapotos : 4/27/2000<br>mcapotos : 4/27/2000<br>terry : 4/11/2000<br>jlewis : 8/5/1999<br>carol : 7/19/1999<br>terry : 7/7/1999<br>carol : 7/2/1999<br>carol : 6/27/1999
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<h3>
<span class="mim-font">
<strong>#</strong> 603903
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<span class="mim-font">
SICKLE CELL DISEASE
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<em>Alternative titles; symbols</em>
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SICKLE CELL ANEMIA
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<strong>SNOMEDCT:</strong> 127040003, 417357006; &nbsp;
<strong>ICD10CM:</strong> D57, D57.1; &nbsp;
<strong>ICD9CM:</strong> 282.6, 282.60; &nbsp;
<strong>ORPHA:</strong> 232; &nbsp;
<strong>DO:</strong> 0081445; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<th>
Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<td>
<span class="mim-font">
11p15.4
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Sickle cell disease
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<span class="mim-font">
603903
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Autosomal recessive
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3
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HBB
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141900
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<span class="mim-font">
<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because sickle cell disease is the result of mutant beta globin (HBB; 141900) in which the mutation causes sickling of hemoglobin.</p>
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<h4>
<span class="mim-font">
<strong>Description</strong>
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<p>Sickle cell disease is a multisystem disease associated with episodes of acute illness and progressive organ damage. Hemoglobin polymerization, leading to erythrocyte rigidity and vasoocclusion, is central to the pathophysiology of the disease, but the importance of chronic anemia, hemolysis, and vasculopathy has been established. The most common cause of sickle cell anemia is the HbS variant (141900.0243), with hemoglobin SS disease being most prevalent in Africans (review by Rees et al., 2010). </p><p>See review of infection in sickle cell disease by Booth et al. (2010). </p><p>Piel et al. (2017) reviewed the genetic and nongenetic modifiers of the severity of sickle cell disease. </p>
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<h4>
<span class="mim-font">
<strong>Clinical Features</strong>
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<p>Scriver and Waugh (1930) reported detailed studies of a 7-year-old child with sickle cell anemia. Her main complaints were cough, night sweats, vague pains in the legs and joints, occasional abdominal pain, poor appetite, and increasing fatigue. In a series of clever experiments that involved taking venous blood from the arm under different circumstances, the authors showed a correlation between oxygen tension and sickling of the red blood cells in vivo. Increased sickling was observed when oxygen pressure fell below 40 to 45 mm Hg. Scriver and Waugh (1930) concluded that large aggregations of sickle cells seen in sinuses, vessels, and organs of sickle cell patients at autopsy reflected lowered oxygen tension resulting from death. </p><p>In many children with sickle cell anemia, functional asplenia develops during the first year of life and septicemia is the leading cause of death in childhood. The risk of septicemia in sickle cell anemia is greatest during the first 3 years of life and is reduced markedly by prophylactic penicillin therapy. Less is known about splenic dysfunction and the risk of overwhelming sepsis in children with sickle cell-hemoglobin C disease (see HbC; 141900.0038), although functional asplenia has been documented by radionuclide liver-spleen scans in some adult patients (Ballas et al., 1982) and an elevated erythrocyte pit count, a finding that indicates functional asplenia in children with sickle cell anemia, also has been found in some children with SC disease (Pearson et al., 1985). Lane et al. (1994) reported 7 fatal cases of pneumococcal septicemia in children with SC disease. The earliest death occurred in a 1-year-old child who had cyanotic congenital heart; the other children were aged 3.5 to 15 years. Only 1 child had received pneumococcal vaccine or prophylactic penicillin therapy. All 7 children had an acute febrile illness and rapid deterioration despite parenterally administered antibiotic therapy and intensive medical support. Erythrocyte pit counts in 2 patients were 40.3 and 41.7%, respectively (normal, less than 3.6%). Autopsy findings in 5 cases included splenic congestion without infarction in 5, splenomegaly in 4, and bilateral adrenal hemorrhage in 3. Lane et al. (1994) concluded that pneumococcal vaccine should be administered in all children with SC disease. The routine use of prophylactic penicillin therapy in infants and children with SC disease remained controversial. </p><p>Morris et al. (1991) reported hematologic findings in 181 patients, aged 40 to 73 years, with hemoglobin SS disease. The studies showed a downward age-related trend in hemoglobin and platelets and falling reticulocyte count consistent with progressive bone marrow failure which could not be explained by renal impairment. Kodish et al. (1991) concluded that despite current rates of mortality and morbidity with bone marrow transplantation, a substantial minority of parents of children with sickle cell disease would consent to bone marrow transplantation for their children. </p><p>Adams (1995) reviewed the literature on sickle cell disease and stroke. Previous studies had shown clinically evident cerebral vascular disease in 7 to 8% of cohorts followed during the first 2 weeks of life. However, MRI series demonstrated 11 to 24% of cerebral vascular accidents in patients with sickle cell disease, indicating a large proportion of silent infarctions. </p><p>The defect in urine concentrating ability in persons with sickle cell trait is thought to result from intracellular polymerization of Hb S in erythrocytes, leading to microvascular occlusion, in the vasa recta of the renal medulla. Reasoning that the severity of the concentration defect might be related to the percentage of sickle hemoglobin present in erythrocytes, Gupta et al. (1991) studied urine concentrating ability in 3 classes of A/S individuals, those with a normal alpha-globin genotype and those who were either heterozygous or homozygous for the gene-deletion type of alpha-thalassemia. They found a correlation between urine concentrating ability and the percentage of sickle hemoglobin, which was highest in the individuals with normal alpha-globin genotype and lowest in those homozygous for the deletion. </p><p>Steinberg (1989) described a 73-year-old black man in Mississippi who had hematologically and genotypically typical sickle cell anemia with, however, very mild clinical manifestations. He had had cholecystectomy for asymptomatic cholelithiasis at the age of about 47. He had had partial priapism. In a large study involving 2,590 patients over 5 years of age at entry and followed for an average of 5.6 years, Milner et al. (1991) found an overall prevalence of osteonecrosis of the femoral head of about 10%. Patients with the hemoglobin SS genotype and alpha-thalassemia and those with frequent painful crises were at highest risk. Osteonecrosis was found in patients as young as 5 years old. </p><p>Steinberg et al. (1995) presented 5 cases of sickle cell anemia in individuals in their 70s. They concluded that 'We do not understand why some patients with sickle cell anemia survive their peers by decades just as we have little insight into why occasional normal individuals live far beyond the average number of years.' Sickle cell patients that express gamma-globin at 10 to 20% of the level of sickle globin in most of their red blood cells have greatly improved clinical prognoses (Lan et al., 1998). </p><p>Langdown et al. (1989) described a doubly substituted sickling hemoglobin, called HbS (Oman) (141900.0245). The higher expressors of HbS (Oman) had a sickle cell anemia clinical syndrome of moderate intensity, whereas the lower expressors had no clinical syndrome and were comparable to the solitary case first described in Oman. </p><p>Popp et al. (1997) stated that the sickle cell anemia syndrome produced by HbS Antilles (141900.0244) is a more severe phenotype than that produced by HbS. Humans heterozygous for HbS have RBCs that contain approximately 40% HbS, but do not exhibit clinical symptoms of sickle cell disease. In comparison, humans heterozygous for HbS Antilles have RBCs that contain approximately 40% HbS Antilles, but these individuals exhibit clinical symptoms of sickle cell disease that are similar in severity to those in persons who are homozygous for HbS. This is because Hb S Antilles is less soluble and has a right shift in its oxygen association-dissociation curve, properties that favor deoxygenation and polymerization of Hb S Antilles. </p><p>Rey et al. (1991) described sickle cell/hemoglobin E (SE) disease (141900.0071) in 3 black American children of Haitian origin. They pointed out that the disorder is probably more benign than SC disease, SC (Arab) disease (141900.0202), and SC (Harlem) disease (141900.0039), all of which have increased risk of the complications of sickling including pneumococcal sepsis. </p><p>Walker et al. (2000) studied the prevalence, incidence, risk factors, clinical associations, and morbidity of gallstones in 311 patients with homozygous sickle cell disease and 167 patients with sickle cell-hemoglobin C disease in a cohort studied from birth. Gallstones developed in 96 patients with hemoglobin SS disease and 18 patients with SC disease; specific symptoms necessitating cholecystectomy occurred in only 7 patients with homozygous SS disease. </p><p>Adler et al. (2001) described a patient with mild HbSC disease who, after administration of granulocyte colony-stimulating factor (GCSF; 138970) for collection of peripheral stem cells, developed sickle cell crisis and died within 36 hours. The case strongly suggested a role for granulocytes in acute sickle cell complications and a need for caution in the use of GCSF in this disorder. The patient was a 47-year-old African American woman who had learned she had HbSC disease only 6 weeks earlier. She had no history of sickle cell crisis. HbSC disease was diagnosed after a hemoglobinopathy evaluation at the time of HLA typing, done in preparation for her to become a stem cell donor for her sister, who had chronic myeloid leukemia and mild HbSC disease. The patient was the only sib and had a 6 of 6 antigen match. </p><p>Thomas et al. (2000) presented growth curves for children aged 0-18 years with homozygous sickle cell disease. These were derived from 315 participants in a longitudinal cohort study in Kingston, Jamaica. </p><p>Ashley-Koch et al. (2001) performed population-based surveillance of children aged 3 to 10 years from metropolitan Atlanta to determine if stroke-related neurologic damage in children with sickle cell disease is associated with developmental disabilities. Children with sickle cell disease had an increased risk for developmental disabilities of 3.2, with a P value of less than 0.0001, particularly mental retardation (RR = 2.7, P = 0.0005) and cerebral palsy (RR = 10.8, P less than 0.0001). This risk was confined to developmental disabilities associated with stroke (RR = 130, P less than 0.0001; for developmental disabilities without stroke the relative risk was only 1.3 with a P value of 0.23). </p><p>Gladwin et al. (2004) demonstrated that pulmonary hypertension, diagnosed by doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. </p><p>Priapism, although uncommon in the general population, is one of the most serious complications associated with sickle cell disease. Nolan et al. (2005) assembled 273 patients with sickle cell disease and priapism and 979 control subjects with sickle cell disease and no priapism. Case subjects, compared with controls, had significantly lower hemoglobin levels, higher levels of lactate dehydrogenase, bilirubin, and aspartate aminotransferase, and higher reticulocyte, white blood cell, and platelet counts. The findings suggested an association of priapism with increased hemolysis. Hemolysis decreases the availability of circulating nitric oxide, which plays an important role in erectile function. </p><p>Gladwin (2005) discussed the hemolytic subphenotype of sickle cell disease. He pointed out that hemolytic anemia, while silent from a vasoocclusive pain crisis standpoint, leads to sustained nitric oxide depletion, oxidant stress, vasoconstriction, and proliferative vasculopathy in a number of organ systems, ultimately contributing to the development of priapism, cutaneous leg ulceration, pulmonary hypertension, sudden death, and possibly stroke.</p><p>In a Jamaican study, Serjeant et al. (1968) described 60 patients with homozygous sickle cell disease who were 30 years of age or older, and Platt et al. (1994) estimated a median survival of 42 to 48 years. Serjeant et al. (2007) stated that the sickle cell clinic at the University of West Indies had treated 102 patients (64.7% women) who survived beyond their 60th birthday. None of the patients received hydroxyurea, and only 2 patients with renal impairment received regular transfusions. The ages of the patients ranged from 60.2 to 85.6 years. Measurement of fetal hemoglobin levels suggested that higher fetal hemoglobin levels probably conferred protection in childhood. The major clinical problems emerging with age were renal impairment and decreased levels of hemoglobin. </p><p><strong><em>Malaria Resistance</em></strong></p><p>
Friedman and Trager (1981) reviewed the mechanism of resistance of SA cells to falciparum malaria (see 611162). The cell infected by the falciparum but not by the other malarial parasites develops knobs in its surface which leads to its sticking to the endothelium of small blood vessels such as those in the brain. In such sequestered sites sickling takes place because of the low oxygen concentration. Perforation of the membranes of the parasite as a result of physical injury and perforation of the red cell membrane occur with loss of potassium. In an in vitro test system, death of the parasites can be prevented by high potassium in the medium. The infected red cell is more acidic than the uninfected cell so that the rate of sickling is increased by this factor also. </p><p>Studying transgenic mice expressing the human A-gamma and G-gamma globin chains and challenged with rodent malaria, Shear et al. (1998) found that the mice cleared the infection and survived even if splenectomy had been performed. Light microscopy showed that intraerythrocytic parasites developed slowly in HbF erythrocytes, and electron microscopy showed that hemozoin formation was defective in transgenic mice. Digestion studies of HbF by recombinant plasmepsin II demonstrated that HbF is digested only half as well as hemoglobin A (HBA). Shear et al. (1998) concluded that HbF provides protection from Plasmodium falciparum malaria by the retardation of parasite growth. The mechanism involves resistance to digestion by malarial hemoglobinases based on the data presented and with the well-known properties of HbF as a super stable tetramer. In addition, the resistance of normal neonates for malaria can now be explained a by double mechanism: increased malaria invasion rates, reported in neonatal RBC, will direct parasites to fetal cells, as well as F cells, and less to the approximately 20% of cells that contain HbA, thus amplifying the antimalarial effects of HbF. </p><p><strong><em>Sickle Trait</em></strong></p><p>
In Denver, Lane and Githens (1985) observed the splenic syndrome (severe left-upper-quadrant abdominal pain) in 6 nonblack men with sickle cell trait who developed symptoms within 48 hours of arrival in Colorado from lower altitudes. The authors discussed the possibility that nonblacks may be at greater risk of trouble because of lack of other genetic make-up that through evolution has come to ameliorate the effects of the sickle gene in Africans. </p><p>Kark et al. (1987) studied the frequency of sudden unexplained death among enlisted recruits during basic training in the U.S. Armed Forces from 1977 to 1981. They found that death rates per 100,000 were 32.2 for sudden unexplained deaths, 2.7 for sudden explained deaths, and zero for nonsudden deaths among black recruits with hemoglobin AS, as compared with 1.2, 1.2, and 0.7 among black recruits without hemoglobin S and 0.7, 0.5 and 1.1 among nonblack recruits without hemoglobin S. Among black recruits the relative risk of sudden unexplained death (hemoglobin AS vs nonhemoglobin S) was 27.6, whereas among all recruits this risk was 39.8. </p><p><strong><em>Acute Chest Syndrome</em></strong></p><p>
The acute chest syndrome is a leading cause of death among patients with sickle cell disease. In a 30-center study, Vichinsky et al. (2000) analyzed 671 episodes of the acute chest syndrome in 538 patients with sickle cell disease to determine the cause, outcome, and response to therapy. They found that among patients with sickle cell disease, the acute chest syndrome is commonly precipitated by fat embolism and infection, especially community-acquired pneumonia. Among older patients and those with neurologic symptoms, the syndrome often progressed to respiratory failure. Treatment with transfusions and bronchodilators improved oxygenation, and with aggressive treatment most patients who had respiratory failure recovered. </p><p>Platt (2000) commented on the acute chest syndrome in sickle cell disease. A good working definition of the acute chest syndrome is the presence of a new pulmonary infiltrate, not atelectasis, involving at least one complete lung segment, with chest pain, a temperature of more than 38.5 degrees C, tachypnea, wheezing, or cough in a patient with sickle cell disease. As reported by Charache et al. (1995), there is a 50% reduction in both painful crises and episodes of the acute chest syndrome with long-term treatment with hydroxyurea which results in increased production of fetal hemoglobin and decreased polymerization. The positive effect on the acute chest syndrome probably results from the fact that there are fewer episodes of bone marrow ischemia and embolization. Another explanation may be that the small reduction in white cell count associated with hydroxyurea therapy enhances the effect of increased fetal hemoglobin by dampening the inflammatory response that promotes polymerization. </p><p>As indicated by Hebbel (1997), a factor contributing to the vasoocclusive process in sickle cell disease is abnormal adhesion of sickle cells (even oxygenated ones) to the vascular endothelium. Kaul et al. (2000) explored experimentally in animals the use of monoclonal antibodies to block adhesion of sickle cells to endothelium. This approach was evaluated by Hebbel (2000). </p><p>Manci et al. (2003) studied the morphologic evidence of the cause of death in 306 autopsies of sickle cell disease, accrued between 1929 and 1996. The most common cause of death for all sickle variants and for all age groups was infection (33 to 48%). Other causes of death included stroke (9.8%), complications of therapy (7%), splenic sequestration (6.6%), pulmonary emboli/thrombi (4.9%), renal failure (4.1%), pulmonary hypertension (2.9%), hepatic failure (0.8%), massive hemolysis/red cell aplasia (0.4%), and left ventricular failure (0.4%). Death was frequently sudden and unexpected (40.8%) or occurred within 24 hours after presentation (28.4%), and was usually associated with acute events (63.3%). The study showed that the first 24 hours after presentation for medical care is an especially perilous time for patients with sickle cell disease and an acute event. </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Diagnosis</strong>
</span>
</h4>
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<span class="mim-text-font">
<p><strong><em>Prenatal Diagnosis</em></strong></p><p>
As a preliminary step to preimplantation diagnosis of sickle cell disease in unfertilized eggs or 8-cell embryos of heterozygous parents, Monk et al. (1993) established quality control by detection of the mutant and normal alleles of the HBB gene using single buccal cells. Efficient PCR amplification of a 680-bp sequence of the HBB gene spanning the site of the HbS mutation was obtained for 79% of single heterozygous cells. In 71% of cases, both alleles were detected. Monk et al. (1993) predicted that with that level of efficiency, a clinical preimplantation diagnosis at the 8-cell embryo stage could be carried out safely and reliably for a couple at risk of transmitting sickle cell disease to their children. </p><p>As a substitute for obtaining fetal cells for genetic diagnosis by the invasive procedures of amniocentesis, chorionic villus sampling, and fetal blood sampling, Cheung et al. (1996) reported a method for detecting point mutations in single gene disorders by enriching fetal cells from maternal blood by magnetic cell sorting followed by isolation of pure fetal cells by microdissection. In 2 pregnancies at risk for sickle cell anemia and beta-thalassemia, they successfully identified the fetal genotypes. </p><p>Xu et al. (1999) performed preimplantation genetic diagnosis (PGD) for sickle cell anemia on 7 embryos produced by in vitro fertilization for a couple who were both carriers of the sickle cell gene. PGD indicated that 4 were normal and 2 were carriers; diagnosis was not possible in 1. The embryos were transferred to the uterus on the fourth day after oocyte retrieval. A twin pregnancy was confirmed by ultrasonography, and subsequent amniocentesis showed that both fetuses were unaffected and were not carriers of the sickle cell mutation. The patient delivered healthy twins at 39 weeks' gestation. </p>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Management</strong>
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</h4>
</div>
<span class="mim-text-font">
<p>Yawn et al. (2014) summarized evidence-based recommendations for the management of sickle cell disease based on a review by an expert panel of 34 years of published studies. </p><p>Trompeter and Roberts (2008) provided a review of agents that increase fetal hemoglobin production and of the therapeutic use of such agents, including hydroxycarbamide, decitabine, and butyrate, in children with sickle cell disease. </p><p>In a report on a sickle cell workshop, Luzzatto and Goodfellow (1989) reviewed current treatment of this disease. The lessons learned from sickle cell anemia will be applicable in other genetic diseases. </p><p>Stimulating fetal hemoglobin by increasing gamma-globin synthesis in patients with sickle cell disease would be expected, if the production of sickle hemoglobin is decreased concomitantly, to reduce the formation of intracellular S polymer and improve the acute and chronic hemolytic and vasoocclusive complications of the disease. Azacytidine and hydroxyurea have been shown to increase fetal hemoglobin levels in some patients with sickle cell disease (Charache et al., 1983; Dover et al., 1986). Rodgers et al. (1993) found that administration of intravenous recombinant erythropoietin with iron supplementation alternating with hydroxyurea elevated fetal hemoglobin levels more than hydroxyurea alone. The increases reduced intracellular polymerization of hemoglobin S. The program reduced the myelotoxic effects of hydroxyurea and was beneficial in patients who had not been helped by hydroxyurea alone. Not only does fetal hemoglobin inhibit the polymerization of hemoglobin S but it also can function as a substitute for the beta-globin chains that are defective or absent in patients with the beta-thalassemias. Butyrate has also been tried for the stimulation of fetal hemoglobin synthesis (Perrine et al., 1993). The trial with butyrate was based on the observation by Perrine et al. (1985) that infants who have high plasma levels of alpha-amino-n-butyric acid in the presence of maternal diabetes do not undergo the normal developmental gene switch from the production of predominantly gamma-globin to that of beta-globin before birth. Since other developmental processes were not delayed, the use of butyric acid as a safe and fairly specific agent was suggested. Butyrate may act through sequences near the transcriptional start site to stimulate the activity of the promoter of the gamma-globin genes. Perrine et al. (1993) showed that butyrate can significantly and rapidly increase fetal globin production to levels that can ameliorate beta-globin disorders. </p><p>On the basis of a double-blind, randomized clinical trial, Charache et al. (1995) reported that hydroxyurea therapy can ameliorate the clinical course of sickle cell anemia in adults with 3 or more painful crises per year. Maximal tolerated doses of hydroxyurea may not be necessary to achieve a therapeutic effect. The beneficial effects did not become manifest for several months, and its use must be carefully monitored. The long-term safety of hydroxyurea in patients with sickle cell anemia was uncertain. No neoplastic disorders developed during the study, but hydroxyurea does have a potential for inducing malignancy. This is a nice example of the modulation of expression of endogenous genes to abrogate pathophysiologic processes in the treatment of a genetic disorder. Bone marrow or hematopoietic stem cell transplantation are proven methods of treatment which may be considered a reasonable alternative to long-term drug therapy in some patients. </p><p>Charache et al. (1996) gave a comprehensive report on the results of a multicenter study of hydroxyurea in sickle cell anemia. </p><p>Steinberg (1999) provided a detailed and highly useful exposition on the management of sickle cell disease. Hydroxyurea, properly used and monitored, is an established form of therapy. Early interruption of the vasoocclusive process that underlies the clinical manifestations of sickle cell disease may prevent damage to the central nervous system, lungs, kidneys, and bones. Two important caveats tempered this hope. The long-term effects of hydroxyurea are unknown. Is it mutagenic, carcinogenic, or leukemogenic? Steinberg (1999) stated that leukemia or cancer had not occurred in patients with sickle cell anemia who had been treated with hydroxyurea, but fewer than 300 patients had been treated for 5 years. It is also not known whether its use in children will have an adverse effect on growth and development. </p><p>Treatment with hydroxyurea is associated with cutaneous side effects. Chaine et al. (2001) evaluated 17 adult patients with sickle cell disease who were undergoing long-term treatment with hydroxyurea. They found that 5 (29%) had disabling leg ulcers. Four of the 5 had a history of leg ulcers prior to initiating hydroxyurea treatment. Chaine et al. (2001) concluded that caution should be observed when giving hydroxyurea to patients with sickle cell disease with previous ulcers as well as in older patients with sickle cell disease. </p><p>Ferster et al. (2001) reported results in the treatment of sickle cell disease in children and young adults with hydroxyurea, based on a Belgian registry. The median follow-up of the 93 patients was 3.5 years. On hydroxyurea, the number of hospitalizations and days hospitalized dropped significantly. Analysis of the 22 patients with a minimum of 5 years of follow-up confirmed a significant difference in the number of hospitalizations and days in hospital throughout the treatment when compared to prior to hydroxyurea therapy. </p><p>In a phase 3 trial, Niihara et al. (2018) tested the efficacy of oral glutamine in reducing the incidences of pain crises in patients with sickle cell anemia or sickle beta-zero-thalassemia who had had 2 or more pain crises in the previous year. Of 230 patients aged 5 to 58 years, 152 received L-glutamine and 78 patients received placebo, for a treatment period of 48 weeks. The patients in the L-glutamine group had significantly fewer pain crises than those in the placebo group (p = 0.005), with a median of 3.0 in the L-glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the L-glutamine group than in the placebo group (p = 0.005), with a median of 2.0 in the L-glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the L-glutamine group than in the placebo group. Niihara et al. (2018) concluded that among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with L-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. </p><p>To investigate the feasibility, safety, and benefits of hydroxyurea treatment for children with sickle cell anemia in sub-Saharan Africa, Tshilolo et al. (2019) enrolled 635 children with sickle cell anemia ranging in age from 1 to 10 years from 4 sub-Saharan countries. Children received hydroxyurea at a dose of 15 to 20 mg per kilogram of body weight per day for 6 months, followed by dose escalation. Hematologic dose-limiting toxic events during the first 3 months of treatment (the primary safety end point) occurred in only a small number of participants (5.1%). No serious adverse events or deaths were considered by the investigators to have been related to hydroxyurea treatment. Hydroxyurea therapy led to significant increases in both the hemoglobin and fetal hemoglobin levels. Hydroxyurea use reduced the incidence of vasoocclusive events, infections, malaria, transfusions, and death, which supported the need for wider access to treatment. Tshilolo et al. (2019) concluded that hydroxyurea treatment is feasible and safe in children with sickle cell anemia living in sub-Saharan Africa. </p><p>Vichinsky et al. (2019) reported a multicenter phase 3, double-blind, randomized, placebo-controlled trial comparing the efficacy and safety of 2 dose levels of voxelotor with placebo in 274 persons with sickle cell disease randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose. Most participants had sickle cell anemia, and approximately two-thirds were receiving hydroxyurea at baseline. Among those receiving the 1500 mg dose of voxelotor, 51% had an increase of more than 1.0 g/dl of hemoglobin from baseline to week 24 versus only 7% in the placebo group. Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. Adverse events of at least grade 3 occurred in 23 to 26% of each of the treatment or placebo groups. Most adverse events were not related to the trial drug or placebo as determined by the investigators. Vichinsky et al. (2019) concluded that voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings were consistent with inhibition of HbS polymerization and indicated a disease-modifying potential. </p><p><strong><em>Gene Therapy</em></strong></p><p>
The genetic basis of sickle cell disease is an A-to-T transversion in the sixth codon of the HBB gene. The intricacies of globin gene expression make the development of treatments for hemoglobinopathies based on gene therapy difficult. Lan et al. (1998) used an alternative genetic approach to sickle cell therapy based on RNA repair. They used a trans-splicing group I ribozyme to alter mutant beta-globin transcripts in erythrocyte precursors derived from peripheral blood from individuals with sickle cell disease. Sickle beta-globin transcripts were converted into mRNAs encoding the anti-sickling protein gamma-globin. In this splicing reaction, the ribozyme recognized the sickle beta-globin transcript by basepairing to an accessible region of the RNA upstream of the mutant nucleotide via an internal guide sequence (IGS), cleaved the sickle beta-globin RNA, released the cleavage product containing the mutation, and spliced on the revised sequence for the globin transcript. Lan et al. (1998) generated erythrocyte precursors from normal umbilical cord blood and from peripheral blood from patients with sickle cell disease by culturing the blood cells in medium without serum supplemented with erythropoietin, FLT3 (600007), and IL3 (147740). RNA repair may be a particularly appropriate genetic approach with which to treat sickle cell disease because the process should restore the regulated expression of anti-sickling versions of beta-globin and simultaneously reduce the production of sickle beta-globin. The efficiency of beta-globin RNA repair probably does not have to be 100% to benefit patients. </p><p>Pawliuk et al. (2001) designed a beta-A globin gene variant that prevents HbS polymerization and introduced it into a lentiviral vector that they optimized for transfer to hematopoietic stem cells and gene expression in the adult red blood cell lineage. Long-term expression (up to 10 months) was achieved without preselection in all transplanted mice with erythroid-specific accumulation of the antisickling protein in up to 52% of total Hb and 99% of circulating red blood cells. In 2 mouse sickle cell disease models, Berkeley and SAD, inhibition of red blood cell dehydration and sickling was achieved with correction of hematologic parameters, splenomegaly, and prevention of the characteristic urine concentration defect. </p><p>Esrick et al. (2021) performed a single-center, open-label pilot study of 6 patients with sickle cell disease with severe manifestations (including stroke, priapism, and vasoocclusive episodes requiring treatment with either transfusions or hydroxyurea) who received infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA targeting BCL11 (606557) mRNA embedded in a microRNA (shmiR), allowing erythroid lineage-specific knockdown. At the time of the report, the patients had been followed for a median of 18 months (range 7 to 29 months). All patients had engraftment, and the adverse events were consistent with the effects of the preparatory chemotherapy. All patients had robust and stable HbF induction (HbF 20 to 41%). Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period. </p><p>Kanter et al. (2022) reported the results of an ongoing phase 1-2 study of LentiGlobin, a gene therapy that consists of autologous transplantation of hematopoietic stem and progenitor cells transduced with a lentiviral vector encoding a modified beta-globin gene, which produces an antisickling hemoglobin (HbA T87Q). To be included, patients needed to have had at least 4 severe vasoocclusive events in the 24 months before enrollment. Among the 35 enrolled patients with sufficient follow-up data, engraftment occurred in all patients. Median follow-up was 17.3 months. Median total hemoglobin level increased from 8.5 g/deciliter at baseline to 11 g/deciliter or more at 6 months and was sustained for 36 months postinfusion. The antisickling hemoglobin contributed at least 40% of the total hemoglobin, with a mean of 85% of red blood cells estimated to contain the antisickling hemoglobin at 24 months. Markers of hemolysis were reduced. Among the 25 patients with at least 6 months of follow-up after infusion, no severe vasoocclusive events were reported, compared to a median of 3.5 events per year in the 24 months before infusion. Adverse events attributed to the LentiGlobin infusion were seen in 3 patients; all adverse events resolved within 1 week after onset. No hematologic cancers were seen during up to 37.6 months of follow-up. </p><p>Frangoul et al. (2024) conducted a phase 3, single-group, open-label study of exagamglogene (exa-cel), a nonviral cell therapy designed to reactivate fetal hemoglobin, in 44 patients aged 12 to 35 years with sickle cell disease who had had at least 2 severe vasoocclusive crises in each of the 2 years before screening. The BCL11A (606557) locus of CD34+ hematopoietic stem and progenitor cells (HSPCs) was edited using CRISPR-Cas9. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary endpoint was freedom from severe vasoocclusive crises for at least 12 consecutive months. A key secondary endpoint was freedom from inpatient hospitalization for severe vasoocclusive crises for at least 12 consecutive months. The safety of exa-cel was also assessed. Over a median of 19.3 months (range, 0.8 to 48.1) of follow-up, all patients had neutrophil and platelet engraftment. Of 30 patients with sufficient follow-up to be evaluated, 29 (97%, 95% CI 88-100) were free from vasoocclusive crises for at least 12 months and none required hospitalization for vasoocclusive crises. The safety profile of exa-cel was consistent with that of myeloablative busulfan and autologous HSPC transplantation. No cancers occurred. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>HbS (141900.0243) has a lower oxygen affinity than normal Hb and polymerizes upon deoxygenation, creating red blood cells that are distorted, resulting in a sickled appearance; adherent, leading to vasoocclusion; and fragile, leading to hemolysis. The clinical consequences of the vascular occlusion are variable, but include bone pain, deep venous thrombosis, acute chest syndrome, and stroke. In an aortic ring bioassay, Pawloski et al. (2005) found that red blood cells derived from patients with severe sickle cell disease did not induce vasodilation under hypoxic conditions when stimulated with nitric oxide (NO) (see NOS3, 163729), whereas these conditions did induce vasodilation when tested with normal red blood cells and those from patients with mild disease. Pawloski et al. (2001) had previously shown that vasodilatory activity can be generated by red blood cells through membrane hemoglobin-derived S-nitrosothiol (SNO) that is formed from transfer of NO to the red cell membrane anion exchanger AE1 (SLC4A1; 109270) from SNO-Hb. Pawloski et al. (2005) demonstrated that sickle cell red blood cells had decreased levels of membrane-bound SNO resulting from intrinsic defects in the processing of NO by sickle cells. Sickle cells showed defects in intramolecular transfer of NO from heme iron to SNO, possibly due to redox potential changes, as well as in transfer of the NO moiety from SNO-HbS to the RBC membrane. Substantial amounts of HbS were disulfide-linked to AE1 in sickle cell membranes, resulting in a loss of free AE1 thiols. The magnitudes of these impairments correlated with clinical severity of disease. Pawloski et al. (2005) concluded that abnormal red blood cell vasoactivity contributes to the vasoocclusive pathophysiology of sickle cell anemia, which may also explain phenotypic variation in expression of the disease. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>The most common cause of sickle cell anemia is HbS (141900.0243), with hemoglobin SS disease being most prevalent in Africans. Rees et al. (2010) listed genotypes that had been reported to cause sickle cell disease. </p><p><strong><em>Modifier Genes</em></strong></p><p>
Priapism, a vasoocclusive manifestation of sickle cell disease, affects more than 30% of males with the disorder. In sickle cell anemia patients, 148 with priapism and 529 without, Nolan et al. (2005) searched SNPs from 44 genes of different functional classes for an association with priapism. By genotypic and haplotype analysis, they found an association between SNPs in the KLOTHO gene (604824) and priapism (rs2249358 and rs211239; adjusted odds ratio of 2.6 and 1.7, respectively). Nolan et al. (2005) noted that the finding may have broader implications in sickle cell disease, as the KL protein regulates vascular functions, including the expression of VEGF (192240) and release of endothelial nitric oxide (see 163729). </p><p>Sickle cell anemia is phenotypically complex, with different clinical courses ranging from early childhood mortality to a virtually unrecognized condition. Overt stroke is a severe complication affecting 6 to 8% of individuals with sickle cell anemia. Modifier genes might interact to determine the susceptibility to stroke. Using Bayesian networks, Sebastiani et al. (2005) analyzed 108 SNPs in 39 candidate genes in 1,398 individuals with sickle cell anemia. They found that 31 SNPs in 12 genes interacted with fetal hemoglobin to modulate the risk of stroke. This network of interactions included 3 genes in the TGF-beta pathway (see 190180) and SELP (173610). Sebastiani et al. (2005) validated their model in a different population by predicting the occurrence of stroke in 114 individuals with 98.2% accuracy. </p><p>Uda et al. (2008) found that the C allele of rs11886868 in the BCL11A gene (606557.0002) was associated with an ameliorated phenotype in patients with sickle cell anemia, due to increased production of fetal hemoglobin. </p><p>In 2 independent cohorts of patients with sickle cell anemia, Lettre et al. (2008) found a significant association between HbF levels and several SNPs in the HBS1L (612450)-MYB (189990) region on chromosome 6q23 (HBFQTL2; 142470). The most significant associations among 1,275 African Americans and 350 Brazilians were with rs9399137 (p = 5 x 10(-11)) and rs4895441 (p = 4 x 10(-7)), respectively. The associations with different SNPs in this region were independent of one another, but overall could explain 5% of variance in HbF levels. Among the African American individuals, there was also a significant association between HbF and rs7482144 in the HBG2 gene (142250.0028) (p = 4 x 10(-7)), which explained 2.2% of the variation in HbF levels. The association with rs7482144 could not be tested in the Brazilian cohort because the variant was monomorphic in this population. Finally, the authors found a significant association between HbF and SNPs in the BCL11A gene on chromosome 2p15 (HBFQTL5; 142335) in both cohorts. The most significant association among both groups was with rs4671393 (p = 2 x 10(-42) among African Americans, p = 3 x 10(-8) among Brazilians). The BCL11A SNPs could explain 6.7 to 14.1% of variance in HbF levels. Sequence variants at all 3 loci together could explain more than 20% of phenotypic variation in the HbF trait. Further statistical analysis showed an association between the high HbF alleles and reduced pain crisis events in patients with sickle cell disease, which may be used to predict overall morbidity and mortality of the disease. </p><p>To fine map HbF association signals at the BCL11A, HBS1L-MYB, and beta-globin loci, Galarneau et al. (2010) resequenced 175.2 kb from these loci in 190 individuals including the HapMap European CEU and Nigerian YRI founders and 70 African Americans with sickle cell anemia. The authors discovered 1,489 sequence variants, including 910 previously unreported variants. Using this information and data from HapMap, Galarneau et al. (2010) selected and genotyped 95 SNPs, including 43 at the beta-globin locus, in 1,032 African Americans with sickle cell anemia. An XmnI polymorphism, rs7482144, in the proximal promoter of HBG2 marks the Senegal and Arab-Indian haplotypes and is associated with HbF levels in African Americans with sickle cell disease (Lettre et al., 2008). Galarneau et al. (2010) replicated the association between rs7482144 and HbF levels (p = 3.7 x 10(-7)). However, rs10128556, a T/C SNP located downstream of HBG1, was more strongly associated with HbF levels than rs7482144 by 2 orders of magnitude (p = 1.3 x 10(-9)). When conditioned on rs10128556, the HbF association result for rs7482144 was not significant, indicating that rs7482144 is not a causal variant for HbF levels in African Americans with sickle cell anemia. The results of a haplotype analysis of the 43 SNPs in the beta-globin locus using rs10128556 as a covariate were not significant (p = 0.40), indicating that rs10128556 or a marker in linkage disequilibrium with it is the principal HbF-influencing variant at the beta-globin locus in African Americans with sickle cell anemia. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In sub-Saharan Africa, 2 hemoglobinopathies occur at particularly high frequencies: sickle cell anemia and alpha(+)-thalassemia. Individually, each is protective against severe Plasmodium falciparum malaria. Williams et al. (2005) investigated malaria-protective effects when hemoglobin S and alpha-thalassemia are inherited in combination. Studying a population on the coast of Kenya, they found that the protection afforded by each condition inherited alone was lost when the 2 conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with regard to the mutation underlying alpha(+)-thalassemia. Negative epistasis could explain the failure of alpha(+)-thalassemia to reach fixation in any population in sub-Saharan Africa. Possible mechanisms of the interaction of the 2 genetic changes in relation to malaria were discussed. </p><p>The estimated number of worldwide annual births of patients with sickle cell anemia is 217,331 and with SC disease is 54,736 (Modell and Darlison, 2008 and Weatherall, 2010). Piel et al. (2017) stated that the vast majority of the approximately 300,000 yearly births of patients with sickle cell anemia occur in Nigeria, the Democratic Republic of the Congo, and India. </p><p>Wang et al. (2013) analyzed sickle cell disease incidence among newborns in New York State by maternal race/ethnicity and nativity in the period between 2000 and 2008. In that interval, 1,911 New York State newborns were diagnosed with sickle cell disease and matched to the birth certificate files. One in every 1,146 live births was diagnosed with sickle cell disease. Newborns of non-Hispanic black mothers accounted for 86% of sickle cell disease cases, whereas newborns of Hispanic mothers accounted for 12% of cases. The estimated incidence was 1 in 230 live births for non-Hispanic black mothers, 1 in 2,320 births for Hispanic mothers, and 1 in 41,647 births for non-Hispanic white mothers. Newborns of foreign-born non-Hispanic black mothers had a 2-fold higher incidence of sickle cell disease than those born to US-born non-Hispanic black mothers. </p><p>Among 1,121 African Americans screened for sickle cell disease/beta-thalassemia carrier status, Lazarin et al. (2013) found a carrier frequency of approximately 1 in 10. Eighty-nine individuals were heterozygous for the HB S mutation and 27 were heterozygous for beta-thalassemia. Among 469 individuals of Middle Eastern origin, a carrier frequency of 1 in 5 was found. Among 21,360 ethnically diverse individuals screened for sickle cell disease carrier status, Lazarin et al. (2013) identified 307 carriers (1.4%), for an estimated carrier frequency of approximately 1 in 70. Ten 'carrier couples' were identified. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Shesely et al. (1991) corrected the human beta-S-globin gene by homologous recombination in a mouse-human hybrid cell line that is derived from a mouse erythroleukemia cell line and carries a single human chromosome 11 with the beta-S-globin allele. The corrected gene retained the proper regulation of induction of human beta-globin expression. The targeting construct contained 1.2 kb of prokaryotic sequence 5-prime to the normal beta-A-globin sequence for use in selecting and identifying targeted clones. </p><p>Fabry et al. (1996) succeeded in creating an improved transgenic mouse model for sickle cell disease. Previous transgenic models had expressed residual levels of mouse globins which complicated the interpretation of experimental results. They reported on a mouse expressing high levels of human sickle beta chains and 100% human alpha-globin. These mice were created by breeding the alpha-globin-knockout mouse and the mouse with deletion of the beta(major)-deletion to homozygosity, the same mice expressing human alpha- and beta(S)-transgenes (see 141900.0243). The animals were considered important for testing strategies for gene therapy and for testing new noninvasive diagnostic procedures such as magnetic resonance imaging techniques. </p><p>Ryan et al. (1997) and Paszty et al. (1997) created transgenic knockout mouse models of sickle cell disease. In both cases the model was produced by mating transgenic mice that expressed human sickle hemoglobin with mice having knockout mutations of the mouse alpha- and beta-globin genes. Similar to human patients with sickle cell disease, the mice developed hemolytic anemia and extensive organ pathology. Although chronically anemic, most animals survived 2 to 9 months and were fertile. Thus, this mouse model of sickle cell disease should be useful for trial of drug and genetic therapies. </p><p>Chang et al. (1998) created transgenic knockout mice expressing human hemoglobin S by transfer of a 240-kb yeast artificial chromosome carrying the beta-sickle gene. The transgenic lines were produced by coinjection of human alpha-, gamma-, and beta-globin constructs. Thus, all of the transgenes were integrated at a single chromosomal site. Studies in transgenic mice had demonstrated that the normal gene order and spatial organization of the members of the human beta-globin gene family are required for appropriate developmental and stage-restricted expression of the genes. The mice produced by transfer of the YAC had hemolytic anemia, 10% irreversibly sickled cells in their peripheral blood, reticulocytosis, and other phenotypic features of sickle cell anemia. </p><p>Popp et al. (1997) bred 2 homozygous viable HbS Antilles transgene insertions into a strain of mice that produce hemoglobins with a higher affinity for oxygen than normal mouse Hb. The rationale was that the high oxygen affinity hemoglobin, the lower oxygen affinity of HbS Antilles, and the lower solubility of deoxygenated HbS Antilles than HbS would favor deoxygenation and polymerization of human HbS Antilles in the red cells of the high-oxygen-affinity mice. The investigators found that the mice produced a high and balanced expression of human alpha and human beta (S Antilles) globins, that 25 to 35% of their RBCs were misshapen in vivo, and that in vitro deoxygenation of their blood induced 30 to 50% of the RBCs to form classic elongated sickle cells with pointed ends. The mice exhibited reticulocytosis, an elevated white blood cell count, and lung and kidney pathology commonly found in sickle cell patients, which should make these mice useful for experimental studies on possible therapeutic intervention of sickle cell disease. </p><p>Using a transgenic mouse model of sickle cell disease, Blouin et al. (2000) assessed in vivo the potential curative threshold of fetal hemoglobin using mating with mice expressing the human fetal A-gamma-globin gene (HBG1; 142200). With increasing levels of HbF, the transgenic mice showed considerable improvement in all hematologic parameters, morphopathologic features, and life span/survival. Correction was observed by increasing fetal hemoglobin to about 9 to 16% in this mouse model. </p><p>He and Russell (2004) generated complex transgenic knockout mice expressing human hemoglobin-S, either exclusively (S-alpha mice) or in the presence of human zeta-globin (S-zeta mice), an endogenous, developmentally silenced, non-beta-like globin. Sickle-cell disease-related deficits in erythrocyte number, hematocrit, and total hemoglobin were significantly improved in S-zeta mice. They also had reduced spleen size and improved urine concentrating ability compared with S-alpha mice. </p><p>Hanna et al. (2007) used a humanized sickle cell anemia mouse model to show that mice can be rescued after transplantation with hematopoietic progenitors obtained in vitro from autologous induced pluripotent stem (iPS) cells. This was achieved after correction of the human sickle hemoglobin allele by gene-specific targeting. Hanna et al. (2007) concluded that their results provided proof of principle for using transcription factor-induced reprogramming combined with gene and cell therapy for disease treatment in mice. The authors pointed out the problems associated with using retroviruses and oncogenes for reprogramming need to be resolved before iPS cells can be considered for human therapy. </p><p>Xu et al. (2011) showed that the repressor BCL11A (606557) is required in vivo for silencing of gamma-globin expression in adult animals, yet dispensable for red cell production. BCL11A serves as a barrier to HbF reactivation by known HbF inducing agents. In a proof-of-principle test of BCL11A as a potential therapeutic target, Xu et al. (2011) demonstrated that inactivation of BCL11A in sickle cell disease transgenic mice corrects the hematologic and pathologic defects associated with sickle cell disease through high-level pancellular HbF induction. Thus, Xu et al. (2011) concluded that interference with HbF silencing by manipulation of a single target protein is sufficient to reverse sickle cell disease. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Savitt and Goldberg (1989) gave an interesting account of investigations into the story of Walter Clement Noel, the first-to-be-described case of sickle cell anemia (Herrick, 1910). Noel, a first-year dental student at the Chicago College of Dental Surgery, was admitted to the Presbyterian Hospital in late 1904 where Ernest E. Irons, a 27-year-old intern, obtained a history and performed routine physical, blood, and urine examinations. He noticed that Noel's blood smear contained 'many pear-shaped and elongated forms' and alerted his attending physician, James B. Herrick, to the unusual blood findings. Irons drew a rough sketch of these erythrocytes in the hospital record. Herrick and Irons followed Noel over the next 2.5 years through several episodes of severe illness as he continued his dental studies. Thereafter, Noel returned to Grenada to practice dentistry. He died 9 years later at the age of 32. Curiously, Irons, who lived from 1877 to 1959, was not included by Herrick, who lived from 1861 to 1964, in the authorship. </p><p>Conner et al. (1983) synthesized two 19-base-long oligonucleotides, 1 complementary to the 5-prime end of the normal beta-globin gene and 1 complementary to the sickle cell gene. DNA from normal homozygotes showed hybridization only for the first probe; DNA from persons with sickle cell anemia showed hybridization only with the second; DNA from sickle cell anemia heterozygotes showed hybridization with both. Allele-specific hybridization of oligonucleotides was proposed as a general method for diagnosis of any genetic disease which involves a point mutation in a single-copy gene. </p><p>Saiki et al. (1985) developed a method for rapid and sensitive diagnosis of sickle cell anemia that has potential use in connection with other genetic diseases. It combines 2 methods: primer-mediated enzymatic amplification (about 220,000 times) of specific beta-globin target sequences in genomic DNA and restriction endonuclease digestion of an end-labeled oligonucleotide probe hybridized in solution to the amplified beta-globin sequences. In less than a day and with much less than a microgram of DNA, the diagnosis can be made. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Adams, R. J.
<strong>Sickle cell disease and stroke. (Editorial)</strong>
J. Child Neurol. 10: 75-76, 1995.
[PubMed: 7782612]
[Full Text: https://doi.org/10.1177/088307389501000201]
</p>
</li>
<li>
<p class="mim-text-font">
Adler, B. K., Salzman, D. E., Carabasi, M. H., Vaughan, W. P., Reddy, V. V. B., Prchal, J. T.
<strong>Fatal sickle cell crisis after granulocyte colony-stimulating factor administration. (Letter)</strong>
Blood 97: 3313-3314, 2001.
[PubMed: 11368061]
[Full Text: https://doi.org/10.1182/blood.v97.10.3313]
</p>
</li>
<li>
<p class="mim-text-font">
Ashley-Koch, A., Murphy, C. C., Khoury, M. J., Boyle, C. A.
<strong>Contribution of sickle cell disease to the occurrence of developmental disabilities: a population-based study.</strong>
Genet. Med. 3: 181-186, 2001.
[PubMed: 11388758]
[Full Text: https://doi.org/10.1097/00125817-200105000-00006]
</p>
</li>
<li>
<p class="mim-text-font">
Ballas, S. K., Lewis, C. N., Noone, A. M., Krasnow, S. H., Kamarulzaman, E., Burka, E. R.
<strong>Clinical, hematological, and biochemical features of Hb SC disease.</strong>
Am. J. Hemat. 13: 37-51, 1982.
[PubMed: 7137165]
[Full Text: https://doi.org/10.1002/ajh.2830130106]
</p>
</li>
<li>
<p class="mim-text-font">
Blouin, M.-J., Beauchemin, H., Wright, A., De Paepe, M., Sorette, M., Bleau, A.-M., Nakamoto, B., Ou, C.-N., Stamatoyannopoulos, G., Trudel, M.
<strong>Genetic correction of sickle cell disease: insights using transgenic mouse models.</strong>
Nature Med. 6: 177-182, 2000.
[PubMed: 10655106]
[Full Text: https://doi.org/10.1038/72279]
</p>
</li>
<li>
<p class="mim-text-font">
Booth, C., Inusa, B., Obaro, S. K.
<strong>Infection in sickle cell disease: a review.</strong>
Int. J. Infect. Dis. 14: e2-e12, 2010. Note: Electronic Article.
[PubMed: 19497774]
[Full Text: https://doi.org/10.1016/j.ijid.2009.03.010]
</p>
</li>
<li>
<p class="mim-text-font">
Chaine, B., Neonato, M.-G., Girot, R., Aractingi, S.
<strong>Cutaneous adverse reactions to hydroxyurea in patients with sickle cell disease.</strong>
Arch. Derm. 137: 467-470, 2001.
[PubMed: 11295927]
</p>
</li>
<li>
<p class="mim-text-font">
Chang, J. C., Lu, R., Lin, C., Xu, S.-M., Kan, Y. W., Porcu, S., Carlson, E., Kitamura, M., Yang, S., Flebbe-Rehwaldt, L., Gaensler, K. M. L.
<strong>Transgenic knockout mice exclusively expressing human hemoglobin S after transfer of a 240-kb beta-S-globin yeast artificial chromosome: a mouse model of sickle cell anemia.</strong>
Proc. Nat. Acad. Sci. 95: 14886-14890, 1998.
[PubMed: 9843985]
[Full Text: https://doi.org/10.1073/pnas.95.25.14886]
</p>
</li>
<li>
<p class="mim-text-font">
Charache, S., Barton, F. B., Moore, R. D., Terrin, M. L., Steinberg, M. H., Dover, G. J., Ballas, S. K., McMahon, R. P., Castro, O., Orringer, E. P.
<strong>Hydroxyurea and sickle cell anemia: clinical utility of a myelosuppressive &#x27;switching&#x27; agent.</strong>
Medicine 75: 300-326, 1996.
[PubMed: 8982148]
[Full Text: https://doi.org/10.1097/00005792-199611000-00002]
</p>
</li>
<li>
<p class="mim-text-font">
Charache, S., Dover, G., Smith, K., Talbot, C. C., Jr., Moyer, M., Boyer, S.
<strong>Treatment of sickle cell anemia with 5-azacytidine results in increased fetal hemoglobin production and is associated with nonrandom hypomethylation of DNA around the gamma-delta-beta-globin gene complex.</strong>
Proc. Nat. Acad. Sci. 80: 4842-4846, 1983.
[PubMed: 6192443]
[Full Text: https://doi.org/10.1073/pnas.80.15.4842]
</p>
</li>
<li>
<p class="mim-text-font">
Charache, S., Terrin, M. L., Moore, R. D., Dover, G. J., Barton, F. B., Eckert, S. V., McMahon, R. P., Bonds, D. R., Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia.
<strong>Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia.</strong>
New Eng. J. Med. 332: 1317-1322, 1995.
[PubMed: 7715639]
[Full Text: https://doi.org/10.1056/NEJM199505183322001]
</p>
</li>
<li>
<p class="mim-text-font">
Cheung, M.-C., Goldberg, J. D., Kan, Y. W.
<strong>Prenatal diagnosis of sickle cell anaemia and thalassaemia by analysis of fetal cells in maternal blood.</strong>
Nature Genet. 14: 264-268, 1996.
[PubMed: 8896554]
[Full Text: https://doi.org/10.1038/ng1196-264]
</p>
</li>
<li>
<p class="mim-text-font">
Conner, B. J., Reyes, A. A., Morin, C., Itakura, K., Teplitz, R. L., Wallace, R. B.
<strong>Detection of sickle cell beta(S)-globin allele by hybridization with synthetic oligonucleotides.</strong>
Proc. Nat. Acad. Sci. 80: 278-282, 1983.
[PubMed: 6572002]
[Full Text: https://doi.org/10.1073/pnas.80.1.278]
</p>
</li>
<li>
<p class="mim-text-font">
Dover, G. J., Humphries, R. K., Moore, J. G., Ley, T. J., Young, N. S., Charache, S., Nienhuis, A. W.
<strong>Hydroxyurea induction of hemoglobin F production in sickle cell disease: relationship between cytotoxicity and F cell production.</strong>
Blood 67: 735-738, 1986.
[PubMed: 2418898]
</p>
</li>
<li>
<p class="mim-text-font">
Esrick, E. B., Lehmann, L. E., Biffi, A., Achebe, M., Brendel, C., Ciuculescu, M. F., Daley, H., MacKinnon, B., Morris, E., Federico, A., Abriss, D., Boardman, K., and 13 others.
<strong>Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease.</strong>
New Eng. J. Med. 384: 205-215, 2021.
[PubMed: 33283990]
[Full Text: https://doi.org/10.1056/NEJMoa2029392]
</p>
</li>
<li>
<p class="mim-text-font">
Fabry, M. E., Kennan, R. P., Paszty, C., Costantini, F., Rubin, E. M., Gore, J. C., Nagel, R. L.
<strong>Magnetic resonance evidence of hypoxia in a homozygous alpha-knockout of a transgenic mouse model for sickle cell disease.</strong>
J. Clin. Invest. 98: 2450-2455, 1996.
[PubMed: 8958206]
[Full Text: https://doi.org/10.1172/JCI119062]
</p>
</li>
<li>
<p class="mim-text-font">
Ferster, A., Tahriri, P., Vermylen, C., Sturbois, G., Corazza, F., Fondu, P., Devalck, C., Dresse, M. F., Feremans, W., Hunninck, K., Toppet, M., Phillippet, P., Van Geet, C., Sariban, E.
<strong>Five years of experience with hydroxyurea in children and young adults with sickle cell disease.</strong>
Blood 97: 3628-3632, 2001.
[PubMed: 11369660]
[Full Text: https://doi.org/10.1182/blood.v97.11.3628]
</p>
</li>
<li>
<p class="mim-text-font">
Frangoul, H., Locatelli, F., Sharma, A., Bhatia, M., Mapara, M., Molinari, L., Wall, D., Liem, R. I., Telfer, P., Shah, A. J., Cavazzana, M., Corbacioglu, S., and 17 others.
<strong>Exagamglogene autotemcel for severe sickle cell disease.</strong>
New Eng. J. Med. 390: 1649-1662, 2024.
[PubMed: 38661449]
[Full Text: https://doi.org/10.1056/NEJMoa2309676]
</p>
</li>
<li>
<p class="mim-text-font">
Friedman, M. J., Trager, W.
<strong>The biochemistry of resistance to malaria.</strong>
Sci. Am. 244(3): 154-164, 1981.
[PubMed: 6163210]
[Full Text: https://doi.org/10.1038/scientificamerican0381-154]
</p>
</li>
<li>
<p class="mim-text-font">
Galarneau, G., Palmer, C. D., Sankaran, V. G., Orkin, S. H., Hirschhorn, J. N., Lettre, G.
<strong>Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation.</strong>
Nature Genet. 42: 1049-1051, 2010.
[PubMed: 21057501]
[Full Text: https://doi.org/10.1038/ng.707]
</p>
</li>
<li>
<p class="mim-text-font">
Gladwin, M. T., Sachdev, V., Jison, M. L., Shizukuda, Y., Plehn, J. F., Minter, K., Brown, B., Coles, W. A., Nichols, J. S., Ernst, I., Hunter, L. A., Blackwelder, W. C., Schechter, A. N., Rodgers, G. P., Castro, O., Ognibene, F. P.
<strong>Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.</strong>
New Eng. J. Med. 350: 886-895, 2004.
[PubMed: 14985486]
[Full Text: https://doi.org/10.1056/NEJMoa035477]
</p>
</li>
<li>
<p class="mim-text-font">
Gladwin, M. T.
<strong>Unraveling the hemolytic subphenotype of sickle cell disease.</strong>
Blood 106: 2925-2926, 2005.
</p>
</li>
<li>
<p class="mim-text-font">
Gupta, A. K., Kirchner, K. A., Nicholson, R., Adams, J. G., III, Schechter, A. N., Noguchi, C. T., Steinberg, M. H.
<strong>Effects of alpha-thalassemia and sickle polymerization tendency on the urine-concentrating defect of individuals with sickle cell trait.</strong>
J. Clin. Invest. 88: 1963-1968, 1991.
[PubMed: 1752955]
[Full Text: https://doi.org/10.1172/JCI115521]
</p>
</li>
<li>
<p class="mim-text-font">
Hanna, J., Wernig, M., Markoulaki, S., Sun, C.-W., Meissner, A., Cassady, J. P., Beard, C., Brambrink, T., Wu, L.-C., Townes, T. M., Jaenisch, R.
<strong>Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin.</strong>
Science 318: 1920-1923, 2007.
[PubMed: 18063756]
[Full Text: https://doi.org/10.1126/science.1152092]
</p>
</li>
<li>
<p class="mim-text-font">
He, Z., Russell, J. E.
<strong>Antisickling effects of an endogenous human alpha-like globin.</strong>
Nature Med. 10: 365-367, 2004.
[PubMed: 15034572]
[Full Text: https://doi.org/10.1038/nm1022]
</p>
</li>
<li>
<p class="mim-text-font">
Hebbel, R. P.
<strong>Adhesive interactions of sickle erythrocytes with endothelium.</strong>
J. Clin. Invest. 99: 2561-2564, 1997.
[PubMed: 9169483]
[Full Text: https://doi.org/10.1172/JCI119442]
</p>
</li>
<li>
<p class="mim-text-font">
Hebbel, R. P.
<strong>Blockade of adhesion of sickle cells to endothelium by monoclonal antibodies. (Editorial)</strong>
New Eng. J. Med. 342: 1910-1912, 2000.
[PubMed: 10861330]
[Full Text: https://doi.org/10.1056/NEJM200006223422512]
</p>
</li>
<li>
<p class="mim-text-font">
Herrick, J. B.
<strong>Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia.</strong>
Arch. Intern. Med. 5: 517-521, 1910. Note: Reprint. Classics of Biology and Medicine. Yale J. Biol. Med. 74: 179-184, 2001.
</p>
</li>
<li>
<p class="mim-text-font">
Kanter, J., Walters, M. C., Krishnamurti, L., Mapara, M. Y., Kwiatkowski, J. L., Rifkin-Zenenberg, S., Aygun, B., Kasow, K. A., Pierciey, F. J., Bonner, M., Miller, A., Zhang, X., Lynch, J., Kim, D., Ribeil, J. A., Asmal, M., Goyal, S., Thompson, A. A., Tisdale, J. F.
<strong>Biologic and clinical efficacy of LentiGlobin for sickle cell disease.</strong>
New Eng. J. Med. 386: 617-628, 2022.
[PubMed: 34898139]
[Full Text: https://doi.org/10.1056/NEJMoa2117175]
</p>
</li>
<li>
<p class="mim-text-font">
Kark, J. A., Posey, D. M., Schumacher, H. R., Ruehle, C. J.
<strong>Sickle-cell trait as a risk factor for sudden death in physical training.</strong>
New Eng. J. Med. 317: 781-787, 1987.
[PubMed: 3627196]
[Full Text: https://doi.org/10.1056/NEJM198709243171301]
</p>
</li>
<li>
<p class="mim-text-font">
Kaul, D. K., Tsai, H. M., Liu, X. D., Nakada, M. T., Nagel, R. L., Coller, B. S.
<strong>Monoclonal antibodies to alpha-v-beta-3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor.</strong>
Blood 95: 368-374, 2000.
[PubMed: 10627437]
</p>
</li>
<li>
<p class="mim-text-font">
Kodish, E., Lantos, J., Stocking, C., Singer, P. A., Siegler, M., Johnson, F. L.
<strong>Bone marrow transplantation for sickle cell disease: a study of parents&#x27; decisions.</strong>
New Eng. J. Med. 325: 1349-1353, 1991.
[PubMed: 1922237]
[Full Text: https://doi.org/10.1056/NEJM199111073251905]
</p>
</li>
<li>
<p class="mim-text-font">
Lan, N., Howrey, R. P., Lee, S.-W., Smith, C. A., Sullenger, B. A.
<strong>Ribozyme-mediated repair of sickle beta-globin mRNAs in erythrocyte precursors.</strong>
Science 280: 1593-1596, 1998.
[PubMed: 9616120]
[Full Text: https://doi.org/10.1126/science.280.5369.1593]
</p>
</li>
<li>
<p class="mim-text-font">
Lane, P. A., Githens, J. H.
<strong>Splenic syndrome at mountain altitudes in sickle cell trait: its occurrence in nonblack persons.</strong>
JAMA 253: 2251-2254, 1985.
[PubMed: 3974118]
</p>
</li>
<li>
<p class="mim-text-font">
Lane, P. A., Rogers, Z. R., Woods, G. M., Wang, W. C., Wilimas, J. A., Miller, S. T., Khakoo, Y., Buchanan, G. R.
<strong>Fatal pneumococcal septicemia in hemoglobin SC disease.</strong>
J. Pediat. 124: 859-862, 1994.
[PubMed: 8201467]
[Full Text: https://doi.org/10.1016/s0022-3476(05)83171-3]
</p>
</li>
<li>
<p class="mim-text-font">
Langdown, J. V., Williamson, D., Knight, C. B., Rubenstein, D., Carrell, R. W.
<strong>A new doubly substituted sickling haemoglobin: HbS-Oman.</strong>
Brit. J. Haemat. 71: 443-444, 1989.
[PubMed: 2930724]
[Full Text: https://doi.org/10.1111/j.1365-2141.1989.tb04304.x]
</p>
</li>
<li>
<p class="mim-text-font">
Lazarin, G. A., Haque, I. S., Nazareth, S., Iori, K., Patterson, A. S., Jacobson, J. L., Marshall, J. R., Seltzer, W. K., Patrizio, P., Evans, E. A., Srinivasan, B. S.
<strong>An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.</strong>
Genet. Med. 15: 178-186, 2013.
[PubMed: 22975760]
[Full Text: https://doi.org/10.1038/gim.2012.114]
</p>
</li>
<li>
<p class="mim-text-font">
Lettre, G., Sankaran, V. G., Bezerra, M. A. C., Araujo, A. S., Uda, M., Sanna, S., Cao, A., Schlessinger, D., Costa, F. F., Hirschhorn, J. N.
<strong>Orkin, S. H.: DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease.</strong>
Proc. Nat. Acad. Sci. 105: 11869-11874, 2008.
[PubMed: 18667698]
[Full Text: https://doi.org/10.1073/pnas.0804799105]
</p>
</li>
<li>
<p class="mim-text-font">
Luzzatto, L., Goodfellow, P.
<strong>Sickle cell anemia: a simple disease with no cure.</strong>
Nature 337: 17-18, 1989.
[PubMed: 2909889]
[Full Text: https://doi.org/10.1038/337017a0]
</p>
</li>
<li>
<p class="mim-text-font">
Manci, E. A., Culberson, D. E., Yang, Y.-M., Gardner, T. M., Powell, R., Haynes, J., Jr., Shah, A. K., Mankad, V. N., Investigators of the Cooperative Study of Sickle Cell Disease.
<strong>Causes of death in sickle cell disease: an autopsy study.</strong>
Brit. J. Haemat. 123: 359-365, 2003.
[PubMed: 14531921]
[Full Text: https://doi.org/10.1046/j.1365-2141.2003.04594.x]
</p>
</li>
<li>
<p class="mim-text-font">
Milner, P. F., Kraus, A. P., Sebes, J. I., Sleeper, L. A., Dukes, K. A., Embury, S. H., Bellevue, R., Koshy, M., Moohr, J. W., Smith, J.
<strong>Sickle cell disease as a cause of osteonecrosis of the femoral head.</strong>
New Eng. J. Med. 325: 1476-1481, 1991.
[PubMed: 1944426]
[Full Text: https://doi.org/10.1056/NEJM199111213252104]
</p>
</li>
<li>
<p class="mim-text-font">
Modell, B., Darlison, M.
<strong>Global epidemiology of haemoglobin disorders and derived service indicators.</strong>
Bull. World Health Organ. 86: 480-487, 2008.
[PubMed: 18568278]
[Full Text: https://doi.org/10.2471/blt.06.036673]
</p>
</li>
<li>
<p class="mim-text-font">
Monk, M., Kenealy, M.-R., Mohadjerani, S.
<strong>Detection of both the normal and mutant alleles in single cells of individuals heterozygous for the sickle cell mutation--prelude to preimplantation diagnosis.</strong>
Prenatal Diag. 13: 45-53, 1993.
[PubMed: 8446570]
[Full Text: https://doi.org/10.1002/pd.1970130107]
</p>
</li>
<li>
<p class="mim-text-font">
Morris, J., Dunn, D., Beckford, M., Grandison, Y., Mason, K., Higgs, D., De Ceulaer, K., Serjeant, B., Serjeant, G.
<strong>The haematology of homozygous sickle cell disease after the age of 40 years.</strong>
Brit. J. Haemat. 77: 382-385, 1991.
[PubMed: 1707292]
[Full Text: https://doi.org/10.1111/j.1365-2141.1991.tb08588.x]
</p>
</li>
<li>
<p class="mim-text-font">
Niihara, Y., Miller, S. T., Kanter, J., Lanzkron, S., Smith, W. R., Hsu, L. L., Gordeuk, V. R., Viswanathan, K., Sarnaik, S., Osunkwo, I., Guillaume, E., Sadanandan, S., and 11 others.
<strong>A phase 3 trial of l-glutamine in sickle cell disease.</strong>
New Eng. J. Med. 379: 226-235, 2018.
[PubMed: 30021096]
[Full Text: https://doi.org/10.1056/NEJMoa1715971]
</p>
</li>
<li>
<p class="mim-text-font">
Nolan, V. G., Baldwin, C., Ma, Q., Wyszynski, D. F., Amirault, Y., Farrell, J. J., Bisbee, A., Embury, S. H., Farrer, L. A., Steinberg, M. H.
<strong>Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia.</strong>
Brit. J. Haemat. 128: 266-272, 2005.
[PubMed: 15638863]
[Full Text: https://doi.org/10.1111/j.1365-2141.2004.05295.x]
</p>
</li>
<li>
<p class="mim-text-font">
Nolan, V. G., Wyszynski, D. F., Farrer, L. A., Steinberg, M. H.
<strong>Hemolysis-associated priapism in sickle cell disease.</strong>
Blood 106: 3264-3267, 2005.
[PubMed: 15985542]
[Full Text: https://doi.org/10.1182/blood-2005-04-1594]
</p>
</li>
<li>
<p class="mim-text-font">
Paszty, C., Brion, C. M., Manci, E., Witkowska, H. E., Stevens, M. E., Mohandas, N., Rubin, E. M.
<strong>Transgenic knockout mice with exclusively human sickle hemoglobin and sickle cell disease.</strong>
Science 278: 876-878, 1997.
[PubMed: 9346488]
[Full Text: https://doi.org/10.1126/science.278.5339.876]
</p>
</li>
<li>
<p class="mim-text-font">
Pawliuk, R., Westerman, K. A., Fabry, M. E., Payen, E., Tighe, R., Bouhassira, E. E., Acharya, S. A., Ellis, J., London, I. M., Eaves, C. J., Humphries, R. K., Beuzard, Y., Nagel, R. L., Leboulch, P.
<strong>Correction of sickle cell disease in transgenic mouse models by gene therapy.</strong>
Science 294: 2368-2371, 2001.
[PubMed: 11743206]
[Full Text: https://doi.org/10.1126/science.1065806]
</p>
</li>
<li>
<p class="mim-text-font">
Pawloski, J. R., Hess, D. T., Stamler, J. S.
<strong>Export by red blood cells of nitric oxide bioactivity.</strong>
Nature 409: 622-626, 2001.
[PubMed: 11214321]
[Full Text: https://doi.org/10.1038/35054560]
</p>
</li>
<li>
<p class="mim-text-font">
Pawloski, J. R., Hess, D. T., Stamler, J. S.
<strong>Impaired vasodilation by red blood cells in sickle cell disease.</strong>
Proc. Nat. Acad. Sci. 102: 2531-2536, 2005.
[PubMed: 15699345]
[Full Text: https://doi.org/10.1073/pnas.0409876102]
</p>
</li>
<li>
<p class="mim-text-font">
Pearson, H. A., Gallagher, D., Chilcote, R., Sullivan, E., Wilimas, J., Espeland, M., Ritchey, A. K., Cooperative Study of Sickle Cell Disease.
<strong>Developmental pattern of splenic dysfunction in sickle cell disorders.</strong>
Pediatrics 76: 392-397, 1985.
[PubMed: 2412200]
</p>
</li>
<li>
<p class="mim-text-font">
Perrine, S. P., Ginder, G. D., Faller, D. V., Dover, G. H., Ikuta, T., Witkowska, H. E., Cai, S., Vichinsky, E. P., Olivieri, N. F.
<strong>A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders.</strong>
New Eng. J. Med. 328: 81-86, 1993.
[PubMed: 7677966]
[Full Text: https://doi.org/10.1056/NEJM199301143280202]
</p>
</li>
<li>
<p class="mim-text-font">
Perrine, S. P., Greene, M. F., Faller, D. V.
<strong>Delay in the fetal globin switch in infants of diabetic mothers.</strong>
New Eng. J. Med. 312: 334-338, 1985.
[PubMed: 2578609]
[Full Text: https://doi.org/10.1056/NEJM198502073120602]
</p>
</li>
<li>
<p class="mim-text-font">
Piel, F. B., Steinberg, M. H., Rees, D. C.
<strong>Sickle cell disease.</strong>
New Eng. J. Med. 376: 1561-1573, 2017.
[PubMed: 28423290]
[Full Text: https://doi.org/10.1056/NEJMra1510865]
</p>
</li>
<li>
<p class="mim-text-font">
Platt, O. S., Brambilla, B. J., Rosse, W. F., Milner, P. F., Castro, O., Steinberg, M. H., Klug, P. P.
<strong>Mortality in sickle cell disease: life expectancy and risk factors for early death.</strong>
New Eng. J. Med. 330: 1639-1644, 1994.
[PubMed: 7993409]
[Full Text: https://doi.org/10.1056/NEJM199406093302303]
</p>
</li>
<li>
<p class="mim-text-font">
Platt, O. S.
<strong>The acute chest syndrome of sickle cell disease. (Editorial)</strong>
New Eng. J. Med. 342: 1904-1907, 2000. Note: Erratum: New Eng. J. Med. 343: 591 only, 2000.
[PubMed: 10861328]
[Full Text: https://doi.org/10.1056/NEJM200006223422510]
</p>
</li>
<li>
<p class="mim-text-font">
Popp, R. A., Popp, D. M., Shinpock, S. G., Yang, M. Y., Mural, J. G., Aguinaga, M. P., Kopsombut, P., Roa, P. D., Turner, E. A., Rubin, E. M.
<strong>A transgenic mouse model of hemoglobin S Antilles disease.</strong>
Blood 89: 4204-4212, 1997.
[PubMed: 9166865]
</p>
</li>
<li>
<p class="mim-text-font">
Rees, D. C., Williams, T. N., Gladwin, M. T.
<strong>Sickle cell disease.</strong>
Lancet 376: 2018-2031, 2010.
[PubMed: 21131035]
[Full Text: https://doi.org/10.1016/S0140-6736(10)61029-X]
</p>
</li>
<li>
<p class="mim-text-font">
Rey, K. S., Unger, C. A., Rao, S. P., Miller, S. T.
<strong>Sickle cell-hemoglobin E disease: clinical findings and implications.</strong>
J. Pediat. 119: 949-951, 1991.
[PubMed: 1960615]
[Full Text: https://doi.org/10.1016/s0022-3476(05)83053-7]
</p>
</li>
<li>
<p class="mim-text-font">
Rodgers, G. P., Dover, G. J., Uyesaka, N., Noguchi, C. T., Schechter, A. N., Nienhuis, A. W.
<strong>Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease.</strong>
New Eng. J. Med. 328: 73-80, 1993.
[PubMed: 7677965]
[Full Text: https://doi.org/10.1056/NEJM199301143280201]
</p>
</li>
<li>
<p class="mim-text-font">
Ryan, T. M., Ciavatta, D. J., Townes, T. M.
<strong>Knockout-transgenic mouse model of sickle cell disease.</strong>
Science 278: 873-876, 1997.
[PubMed: 9346487]
[Full Text: https://doi.org/10.1126/science.278.5339.873]
</p>
</li>
<li>
<p class="mim-text-font">
Saiki, R. K., Scharf, S., Faloona, F., Mullis, K. B., Horn, G. T., Erlich, H. A., Arnheim, N.
<strong>Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia.</strong>
Science 230: 1350-1354, 1985.
[PubMed: 2999980]
[Full Text: https://doi.org/10.1126/science.2999980]
</p>
</li>
<li>
<p class="mim-text-font">
Savitt, T. L., Goldberg, M. F.
<strong>Herrick&#x27;s 1910 case report of sickle cell anemia: the rest of the story.</strong>
JAMA 261: 266-271, 1989.
[PubMed: 2642320]
</p>
</li>
<li>
<p class="mim-text-font">
Scriver, J. B., Waugh, T. R.
<strong>Studies on a case of sickle-cell anaemia.</strong>
Canad. Med. Assoc. J. 23: 375-380, 1930.
[PubMed: 20317973]
</p>
</li>
<li>
<p class="mim-text-font">
Sebastiani, P., Ramoni, M. F., Nolan, V., Baldwin, C. T., Steinberg, M. H.
<strong>Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia.</strong>
Nature Genet. 37: 435-440, 2005.
[PubMed: 15778708]
[Full Text: https://doi.org/10.1038/ng1533]
</p>
</li>
<li>
<p class="mim-text-font">
Serjeant, G. R., Higgs, D. R., Hambleton, I. R.
<strong>Elderly survivors with homozygous sickle cell disease. (Letter)</strong>
New Eng. J. Med. 356: 642-643, 2007.
[PubMed: 17287491]
[Full Text: https://doi.org/10.1056/NEJMc066547]
</p>
</li>
<li>
<p class="mim-text-font">
Serjeant, G. R., Richards, R., Barbor, P. R. H., Milner, P. F.
<strong>Relatively benign sickle cell anaemia in 60 patients aged over 30 in the West Indies.</strong>
Brit. Med. J. 3: 86-91, 1968.
[PubMed: 4232783]
[Full Text: https://doi.org/10.1136/bmj.3.5610.86]
</p>
</li>
<li>
<p class="mim-text-font">
Shear, H. L., Grinberg, L., Gilman, J., Fabry, M. E., Stamatoyannopoulos, G., Goldberg, D. E., Nagel, R. L.
<strong>Transgenic mice expressing human fetal globin are protected from malaria by a novel mechanism.</strong>
Blood 92: 2520-2526, 1998.
[PubMed: 9746793]
</p>
</li>
<li>
<p class="mim-text-font">
Shesely, E. G., Kim, H.-S., Shehee, W. R., Papayannopoulou, T., Smithies, O., Popovich, B. W.
<strong>Correction of a human beta-S-globin gene by gene targeting.</strong>
Proc. Nat. Acad. Sci. 88: 4294-4298, 1991.
[PubMed: 2034673]
[Full Text: https://doi.org/10.1073/pnas.88.10.4294]
</p>
</li>
<li>
<p class="mim-text-font">
Steinberg, M. H., Ballas, S. K., Brunson, C. Y., Bookchin, R.
<strong>Sickle cell anemia in septuagenarians. (Letter)</strong>
Blood 86: 3997-4002, 1995.
[PubMed: 7579371]
</p>
</li>
<li>
<p class="mim-text-font">
Steinberg, M. H.
<strong>Sickle cell anemia in a septuagenarian.</strong>
Brit. J. Haemat. 71: 297-298, 1989.
[PubMed: 2923816]
[Full Text: https://doi.org/10.1111/j.1365-2141.1989.tb04274.x]
</p>
</li>
<li>
<p class="mim-text-font">
Steinberg, M. H.
<strong>Management of sickle cell disease.</strong>
New Eng. J. Med. 340: 1021-1030, 1999.
[PubMed: 10099145]
[Full Text: https://doi.org/10.1056/NEJM199904013401307]
</p>
</li>
<li>
<p class="mim-text-font">
Thomas, P. W., Singhal, A., Hemmings-Kelly, M., Serjeant, G. R.
<strong>Height and weight reference curves for homozygous sickle cell disease.</strong>
Arch. Dis. Child. 82: 204-208, 2000.
[PubMed: 10685921]
[Full Text: https://doi.org/10.1136/adc.82.3.204]
</p>
</li>
<li>
<p class="mim-text-font">
Trompeter, S., Roberts, I.
<strong>Haemoglobin F modulation in childhood sickle cell disease.</strong>
Brit. J. Haemat. 144: 308-316, 2008.
[PubMed: 19036119]
[Full Text: https://doi.org/10.1111/j.1365-2141.2008.07482.x]
</p>
</li>
<li>
<p class="mim-text-font">
Tshilolo, L., Tomlinson, G., Williams, T. N., Santos, B., Olupot-Olupot, P., Lane, A., Aygun, B., Stuber, S. E., Latham, T. S., McGann, P. T., Ware, R. E.
<strong>Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa.</strong>
New Eng. J. Med. 380: 121-131, 2019.
[PubMed: 30501550]
[Full Text: https://doi.org/10.1056/NEJMoa1813598]
</p>
</li>
<li>
<p class="mim-text-font">
Uda, M., Galanello, R., Sanna, S., Lettre, G., Sankaran, V. G., Chen, W., Usala, G., Busonero, F., Maschio, A., Albai, G., Piras, M. G., Sestu, N., and 18 others.
<strong>Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia.</strong>
Proc. Nat. Acad. Sci. 105: 1620-1625, 2008.
[PubMed: 18245381]
[Full Text: https://doi.org/10.1073/pnas.0711566105]
</p>
</li>
<li>
<p class="mim-text-font">
Vichinsky, E., Hoppe, C. C., Ataga, K. I., Ware, R. E., Nduba, V., El-Beshlawy, A., Hassab, H., Achebe, M. M., Alkindi, S., Brown, R. C., Diuguid, D. L., Telfer, P., and 11 others.
<strong>A phase 3 randomized trial of voxelotor in sickle cell disease.</strong>
New Eng. J. Med. 381: 509-519, 2019.
[PubMed: 31199090]
[Full Text: https://doi.org/10.1056/NEJMoa1903212]
</p>
</li>
<li>
<p class="mim-text-font">
Vichinsky, E. P., Neumayr, L. D., Earles, A. N., Williams, R., Lennette, E. T., Dean, D., Nickerson, B., Orringer, E., McKie, V., Bellevue, R., Daeschner, C., Manci, E. A.
<strong>Causes and outcomes of the acute chest syndrome in sickle cell disease.</strong>
New Eng. J. Med. 342: 1855-1865, 2000. Note: Erratum: New Eng. J. Med. 343: 824 only, 2000.
[PubMed: 10861320]
[Full Text: https://doi.org/10.1056/NEJM200006223422502]
</p>
</li>
<li>
<p class="mim-text-font">
Walker, T. M., Hambleton, I. R., Serjeant, G. R.
<strong>Gallstones in sickle cell disease: observations from the Jamaican Cohort Study.</strong>
J. Pediat. 136: 80-85, 2000.
[PubMed: 10636979]
[Full Text: https://doi.org/10.1016/s0022-3476(00)90054-4]
</p>
</li>
<li>
<p class="mim-text-font">
Wang, Y., Kennedy, J., Caggana, M., Zimmerman, R., Thomas, S., Berninger, J., Harris, K., Green, N. S., Oyeku, S., Hulihan, M., Grant, A. M., Grosse, S. D.
<strong>Sickle cell disease incidence among newborns in New York State by maternal race/ethnicity and nativity.</strong>
Genet. Med. 15: 222-228, 2013.
[PubMed: 23018751]
[Full Text: https://doi.org/10.1038/gim.2012.128]
</p>
</li>
<li>
<p class="mim-text-font">
Weatherall, D. J.
<strong>The inherited diseases of hemoglobin are an emerging global health burden.</strong>
Blood 115: 4331-4336, 2010.
[PubMed: 20233970]
[Full Text: https://doi.org/10.1182/blood-2010-01-251348]
</p>
</li>
<li>
<p class="mim-text-font">
Williams, T. N., Mwangi, T. W., Wambua, S., Peto, T. E. A., Weatherall, D. J., Gupta, S., Recker, M., Penman, B. S., Uyoga, S., Macharia, A., Mwacharo, J. K., Snow, R. W., Marsh, K.
<strong>Negative epistasis between the malaria-protective effects of alpha(+)-thalassemia and the sickle cell trait.</strong>
Nature Genet. 37: 1253-1257, 2005.
[PubMed: 16227994]
[Full Text: https://doi.org/10.1038/ng1660]
</p>
</li>
<li>
<p class="mim-text-font">
Xu, J., Peng, C., Sankaran, V. G., Shao, Z., Esrick, E. B., Chong, B. G., Ippolito, G. C., Fujiwara, Y., Ebert, B. L., Tucker, P. W., Orkin, S. H.
<strong>Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing.</strong>
Science 334: 993-996, 2011.
[PubMed: 21998251]
[Full Text: https://doi.org/10.1126/science.1211053]
</p>
</li>
<li>
<p class="mim-text-font">
Xu, K., Shi, Z. M., Veeck, L. L., Hughes, M. R., Rosenwaks, Z.
<strong>First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia.</strong>
JAMA 281: 1701-1706, 1999.
[PubMed: 10328069]
[Full Text: https://doi.org/10.1001/jama.281.18.1701]
</p>
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<li>
<p class="mim-text-font">
Yawn, B. P., Buchanan, G. R., Afenyi-Annan, A. N., Ballas, S. K., Hassell, K. L., James, A. H., Jordan, L., Lanzkron, S. M., Lottenberg, R., Savage, W. J., Tanabe, P. J., Ware, R. E., and 6 others.
<strong>Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members.</strong>
JAMA 312: 1033-1048, 2014. Note: Erratum: JAMA 312: 1932 only, 2014. Erratum: JAMA 313: 729 only, 2015.
[PubMed: 25203083]
[Full Text: https://doi.org/10.1001/jama.2014.10517]
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Ada Hamosh - updated : 05/14/2024<br>Sonja A. Rasmussen - updated : 07/26/2022<br>Ada Hamosh - updated : 03/08/2021<br>Ada Hamosh - updated : 09/19/2019<br>Ada Hamosh - updated : 02/05/2019<br>Ada Hamosh - updated : 09/14/2018<br>Carol A. Bocchini - updated : 05/12/2017<br>Anne M. Stumpf - updated : 4/19/2013<br>Ada Hamosh - updated : 4/17/2013<br>Cassandra L. Kniffin - updated : 2/14/2013<br>Ada Hamosh - updated : 12/20/2011<br>Carol A. Bocchini - updated : 2/1/2011<br>Cassandra L. Kniffin - updated : 9/30/2010<br>Cassandra L. Kniffin - updated : 6/22/2009<br>Cassandra L. Kniffin - updated : 6/3/2009<br>Cassandra L. Kniffin - updated : 2/20/2008<br>Ada Hamosh - updated : 2/11/2008<br>Victor A. McKusick - updated : 6/20/2006<br>Victor A. McKusick - updated : 11/1/2005<br>Cassandra L. Kniffin - updated : 6/16/2005<br>Victor A. McKusick - updated : 5/12/2005<br>Victor A. McKusick -updated : 3/29/2005<br>Victor A. McKusick - updated : 4/7/2004<br>Ada Hamosh - updated : 3/30/2004<br>Victor A. McKusick - updated : 12/8/2003<br>Gary A. Bellus - updated : 4/8/2002<br>Ada Hamosh - updated : 1/9/2002<br>Ada Hamosh - updated : 12/18/2001<br>Victor A. McKusick - updated : 10/12/2001<br>Victor A. McKusick - updated : 8/23/2001<br>Victor A. McKusick - updated : 2/26/2001<br>Ada Hamosh - updated : 9/15/2000<br>Paul Brennan - updated : 5/3/2000<br>Victor A. McKusick - updated : 4/11/2000<br>Victor A. McKusick - updated : 7/7/1999
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