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Entry
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- #306700 - HEMOPHILIA A; HEMA
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- OMIM
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<p>
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<span class="h4">#306700</span>
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<br />
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<strong>Table of Contents</strong>
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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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<li role="presentation">
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<a href="/clinicalSynopsis/306700"><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="#nomenclature">Nomenclature</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#otherFeatures">Other Features</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=02384&isoform_id=02384_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=HEMOPHILIA A" 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>
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<div><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=17872&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Severe hemophilia A </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=17873&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Moderate hemophilia A </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=17874&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Mild hemophilia A </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=17996&Typ=Pat" title="Bleeding disorder in hemophilia A carriers" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Bleeding disorder in hemop… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=13895&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Hemophilia A </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1404/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=306700[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=169802" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Severe hemophilia A</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=169805" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Moderate hemophilia A</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=169808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Mild hemophilia A</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=177926" title="Bleeding disorder in hemophilia A carriers" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Bleeding disorder in hemop…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98878" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Hemophilia A</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://hadb.org.uk/" title="The Haemophilia A Mutation, Structure, Test & Resource Site (HAMSTeRS)" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">The Haemophilia A Mutation…</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/F8" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">F8 database at LOVD</a></div><div style="margin-left: 0.5em;"><a href="http://www.hemobase.com/en/Base_de_datos_HA.htm" title="F8 Mutation Registry at Hemobase" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">F8 Mutation Registry at He…</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</a>
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</span>
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</span>
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</div>
|
|
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:12134" 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>
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<div><a href="http://www.informatics.jax.org/disease/306700" 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>
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<div><a href="https://omia.org/OMIA000437/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:12134" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<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;">►</div>
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|
<div style="display: table-cell;">Cell Lines</div>
|
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</div>
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:306700" 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>
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</div>
|
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</div>
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</div>
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</div>
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</div>
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</div>
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<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.">
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</span>
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</span>
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</div>
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|
<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">
|
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|
|
<div>
|
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|
|
<a id="title" class="mim-anchor"></a>
|
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|
|
<div>
|
|
<a id="number" class="mim-anchor"></a>
|
|
<div class="text-right">
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|
|
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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|
<strong>SNOMEDCT:</strong> 28293008<br />
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|
<strong>ICD10CM:</strong> D66<br />
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<strong>ICD9CM:</strong> 286.0<br />
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|
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<strong>ORPHA:</strong> 169802, 169805, 169808, 177926, 98878<br />
|
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<strong>DO:</strong> 12134<br />
|
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">ICD+</a>
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</div>
|
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<div>
|
|
<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
|
|
<span class="text-danger"><strong>#</strong></span>
|
|
306700
|
|
</span>
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
|
<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
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|
|
HEMOPHILIA A; HEMA
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</span>
|
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</h3>
|
|
</div>
|
|
<div>
|
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<br />
|
|
</div>
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<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">
|
|
HEMOPHILIA, CLASSIC
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<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/X/878?start=-3&limit=10&highlight=878">
|
|
Xq28
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hemophilia A
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/306700"> 306700 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</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">
|
|
F8
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/300841"> 300841 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/306700" 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>
|
|
|
|
|
|
|
|
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|
|
|
|
|
|
|
|
|
<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/306700" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/306700" 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">
|
|
|
|
- X-linked recessive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845977&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845977</a>, <a href="https://bioportal.bioontology.org/search?q=C1279481&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1279481</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
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|
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|
|
|
|
|
|
|
|
|
|
|
<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">
|
|
|
|
- Hemarthroses <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/81808003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">81808003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M25.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M25.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/719.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">719.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/719.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">719.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018924&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018924</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005261" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005261</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005261" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005261</a>]</span><br /> -
|
|
Degenerative joint disease <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/225655006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">225655006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/396275006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">396275006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M15-M19" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M15-M19</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M19.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M19.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M19.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M19.90</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/715.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">715.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029408&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029408</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002758" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002758</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002758" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002758</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Ecchymoses common <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844370&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844370</a>]</span><br /> -
|
|
Petechiae and purpura do not occur <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844371&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844371</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
|
|
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|
|
|
|
|
</div>
|
|
|
|
</div>
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
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- Factor VIII deficiency <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/234440005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">234440005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/28293008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">28293008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D66" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D66</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/286.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">286.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019069&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019069</a>, <a href="https://bioportal.bioontology.org/search?q=C3494187&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3494187</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003125" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003125</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003125" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003125</a>]</span><br /> -
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PTT prolonged <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/409675001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">409675001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240671&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240671</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003645" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003645</a>]</span><br /> -
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PT normal <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844369&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844369</a>]</span><br /> -
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Bleeding time normal <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0855391&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0855391</a>]</span><br /> -
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Platelet count normal <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165555003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165555003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0427564&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427564</a>]</span><br /> -
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Platelet function normal <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0855741&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0855741</a>]</span><br />
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- Partial factor VIII deficiency in heterozygous carriers<br /> -
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Persistent bleeding after trauma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844374&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844374</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001934" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001934</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001934" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001934</a>]</span><br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the coagulation factor VIII gene (F8, <a href="/entry/300841#0001">300841.0001</a>)<br />
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because classic hemophilia, or hemophilia A (HEMA), is caused by mutation in the gene encoding coagulation factor VIII (F8; <a href="/entry/300841">300841</a>) on chromosome Xq28.</p>
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<p>Hemophilia A (HEMA) is an X-linked recessive bleeding disorder caused by a deficiency in the activity of coagulation factor VIII. The disorder is clinically heterogeneous with variable severity, depending on the plasma levels of coagulation factor VIII: mild, with levels 6 to 30% of normal; moderate, with levels 2 to 5% of normal; and severe, with levels less than 1% of normal. Patients with mild hemophilia usually bleed excessively only after trauma or surgery, whereas those with severe hemophilia have an annual average of 20 to 30 episodes of spontaneous or excessive bleeding after minor trauma, particularly into joints and muscles. These symptoms differ substantially from those of bleeding disorders due to platelet defects or von Willebrand disease (<a href="/entry/193400">193400</a>), in which mucosal bleeding predominates (review by <a href="#85" class="mim-tip-reference" title="Mannucci, P. M., Tuddenham, E. G. D. <strong>The hemophilias--from royal genes to gene therapy.</strong> New Eng. J. Med. 344: 1773-1779, 2001. Note: Erratum: New Eng. J. Med. 345: 384 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11396445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11396445</a>] [<a href="https://doi.org/10.1056/NEJM200106073442307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11396445">Mannucci and Tuddenham, 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11396445" 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>The term 'hemophilia' is used in reference to hemophilia A (factor VIII deficiency); hemophilia B or Christmas disease (factor IX deficiency; <a href="/entry/306900">306900</a>) and von Willebrand disease (von Willebrand factor deficiency; <a href="/entry/193400">193400</a>). Hemophilia A and B are X-linked recessive disorders; von Willebrand disease has an autosomal dominant, or in some cases an autosomal recessive mode of inheritance (review by <a href="#85" class="mim-tip-reference" title="Mannucci, P. M., Tuddenham, E. G. D. <strong>The hemophilias--from royal genes to gene therapy.</strong> New Eng. J. Med. 344: 1773-1779, 2001. Note: Erratum: New Eng. J. Med. 345: 384 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11396445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11396445</a>] [<a href="https://doi.org/10.1056/NEJM200106073442307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11396445">Mannucci and Tuddenham, 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11396445" 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 Features</strong>
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<p>The severity and frequency of bleeding in hemophilia A is inversely related to the amount of residual factor VIII in the plasma: less than 1% factor VIII results in severe bleeding, 2 to 6% results in moderate bleeding, and 6 to 30% results in mild bleeding. The proportion of cases that are severe, moderate, and mild are about 50, 10, and 40%, respectively, The joints are frequently affected, causing swelling, pain, decreased function, and degenerative arthritis. Similarly, muscle hemorrhage can cause necrosis, contractures, and neuropathy by entrapment. Hematuria occurs occasionally and is usually painless. Intracranial hemorrhage, while uncommon, can occur after even mild head trauma and lead to severe complications. Bleeding from tongue or lip lacerations is often persistent (review by <a href="#2" class="mim-tip-reference" title="Antonarakis, S. E., Kazazian, H. H., Tuddenham, G. D. <strong>Molecular etiology of factor VIII deficiency in hemophilia A.</strong> Hum. Mutat. 5: 1-22, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7728145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7728145</a>] [<a href="https://doi.org/10.1002/humu.1380050102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7728145">Antonarakis et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7728145" 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 clinical hallmarks of hemophilia A are joint and muscle hemorrhages, easy bruising, and prolonged hemorrhage after surgery or trauma, but no excessive bleeding after minor cuts or abrasions. Affected individuals may have little bleeding during the first year of life, but develop hemarthroses when beginning to walk. The most frequently affected joints are the knees, elbows, ankles, shoulders, and hips. Hemophilic arthropathy can be a progressive inflammatory condition which may result in limitation of motion and permanent disability (review by <a href="#60" class="mim-tip-reference" title="Hoyer, L. W. <strong>Hemophilia A.</strong> New Eng. J. Med. 330: 38-47, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8259143/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8259143</a>] [<a href="https://doi.org/10.1056/NEJM199401063300108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8259143">Hoyer, 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8259143" 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>Female Carriers</em></strong></p><p>
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<a href="#117" class="mim-tip-reference" title="Rapaport, S. I., Patch, M. J., Moore, F. J. <strong>Anti-hemophilic globulin levels in carriers of hemophilia A.</strong> J. Clin. Invest. 39: 1619-1625, 1960.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13739554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13739554</a>] [<a href="https://doi.org/10.1172/JCI104184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13739554">Rapaport et al. (1960)</a> demonstrated a partial deficiency of factor VIII in heterozygous female carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13739554" 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>Most heterozygous female carriers of hemophilia A or hemophilia B (<a href="/entry/306900">306900</a>) have concentrations of clotting factor VIII or IX (F9; <a href="/entry/300746">300746</a>) of about 50% of normal, respectively, and in most cases have mildly decreased coagulability without clinical signs. <a href="#136" class="mim-tip-reference" title="Sramek, A., Kriek, M., Rosendaal, F. R. <strong>Decreased mortality of ischaemic heart disease among carriers of haemophilia.</strong> Lancet 362: 351-354, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12907007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12907007</a>] [<a href="https://doi.org/10.1016/s0140-6736(03)14021-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12907007">Sramek et al. (2003)</a> followed up a cohort of 1,012 mothers of all known people with hemophilia in the Netherlands from birth to death, or the end-of-study date (41,984 person years of follow-up). Overall mortality was decreased by 22%. Deaths from ischemic heart disease were reduced by 36%. No decrease in mortality was observed for cerebral stroke (ischemic and hemorrhagic combined). Women in the cohort had an increased risk of deaths from extra cranial hemorrhage; however, the number of deaths from this cause was much lower than that for ischemic heart disease. The results were interpreted as showing that a mild decrease in coagulability has a protective effect against fatal ischemic heart disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12907007" 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 population-based survey in the Netherlands, <a href="#114" class="mim-tip-reference" title="Plug, I., Mauser-Bunschoten, E. P., Brocker-Vriends, A. H. J. T., van Amstel, H. K. P., van der Bom, J. G., van Diemen-Homan, J. E. M., Willemse, J., Rosendaal, F. R. <strong>Bleeding in carriers of hemophilia.</strong> Blood 108: 52-56, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16551972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16551972</a>] [<a href="https://doi.org/10.1182/blood-2005-09-3879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16551972">Plug et al. (2006)</a> found that female carriers of hemophilia A and B bled more frequently than noncarrier women, especially after medical procedures, such as tooth extraction or tonsillectomy. Reduced clotting factor levels correlated with a mild hemophilia phenotype. Variation in clotting levels was attributed to lyonization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16551972" 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="#124" class="mim-tip-reference" title="Rosendaal, F. R., Briet, E., Stibbe, J., van Herpen, G., Gevers Leuven, J. A., Hofman, A., Vandenbroucke, J. P. <strong>Haemophilia protects against ischaemic heart disease: a study of risk factors.</strong> Brit. J. Haemat. 75: 525-530, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2207003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2207003</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1990.tb07793.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2207003">Rosendaal et al. (1990)</a> presented evidence supporting their earlier findings that mortality due to ischemic heart disease is lower in hemophilia patients than in the general male population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2207003" 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>Chronic synovitis occurs in about 10% of Indian patients with severe hemophilia. <a href="#42" class="mim-tip-reference" title="Ghosh, K., Shankarkumar, U., Shetty, S., Mohanty, D. <strong>Chronic synovitis and HLA B27 in patients with severe haemophilia.</strong> Lancet 361: 933-934, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12648975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12648975</a>] [<a href="https://doi.org/10.1016/S0140-6736(03)12763-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12648975">Ghosh et al. (2003)</a> reported an association between the development of chronic synovitis in patients with hemophilia and the HLA-B27 allele (<a href="/entry/142830#0001">142830.0001</a>). Twenty-one (64%) of 33 patients with both disorders had HLA-B27, compared to 23 (5%) of 440 with severe hemophilia without synovitis (odds ratio of 31.6). There were 3 sib pairs with hemophilia in whom only 1 sib had synovitis; all the affected sibs had the HLA-B27 allele, whereas the unaffected sibs did not. Chronic synovitis presented as swelling of the joint with heat and redness and absence of response to treatment with factor concentrate. <a href="#42" class="mim-tip-reference" title="Ghosh, K., Shankarkumar, U., Shetty, S., Mohanty, D. <strong>Chronic synovitis and HLA B27 in patients with severe haemophilia.</strong> Lancet 361: 933-934, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12648975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12648975</a>] [<a href="https://doi.org/10.1016/S0140-6736(03)12763-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12648975">Ghosh et al. (2003)</a> suggested that patients with HLA-B27 may not be able to easily downregulate inflammatory mediators after bleeding in the joints, leading to chronic synovitis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12648975" 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="#1" class="mim-tip-reference" title="Alexander, B., Goldstein, R. <strong>Dual hemostatic defect in pseudohemophilia. (Abstract)</strong> J. Clin. Invest. 32: 551 only, 1953."None>Alexander and Goldstein (1953)</a> first noted low levels of factor VIII in cases of von Willebrand disease (see <a href="/entry/193400">193400</a>). This was confirmed by other workers including <a href="#103" class="mim-tip-reference" title="Nilsson, I. M., Blomback, M., Von Francken, I. <strong>On an inherited autosomal hemorrhagic diathesis with antihemophilic globulin (AHG) deficiency and prolonged bleeding time.</strong> Acta Med. Scand. 159: 35-57, 1957.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13497611/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13497611</a>] [<a href="https://doi.org/10.1111/j.0954-6820.1957.tb00532.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13497611">Nilsson et al. (1957)</a>, who studied von Willebrand's original family in the Aland Islands. Since von Willebrand disease is an autosomal disorder, these findings indicated that an autosomal locus can also cause low factor VIII levels. This overlap in phenotype between hemophilia A and von Willebrand disease is seen in families such as that of <a href="#49" class="mim-tip-reference" title="Graham, J. B., McLendon, W. W., Brinkhous, K. M. <strong>Mild hemophilia: an allelic form of the disease.</strong> Am. J. Med. Sci. 225: 46-53, 1953.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13007695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13007695</a>]" pmid="13007695">Graham et al. (1953)</a> and <a href="#18" class="mim-tip-reference" title="Bond, T. P., Levin, W. C., Celander, D. R., Guest, M. M. <strong>'Mild hemophilia' affecting both males and females.</strong> New Eng. J. Med. 266: 220-223, 1962.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13870925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13870925</a>] [<a href="https://doi.org/10.1056/NEJM196202012660502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13870925">Bond et al. (1962)</a> in which the carrier females showed depression of factor VIII levels, but not as low as in hemizygous affected males and sometimes clinical hemophilia. <a href="#30" class="mim-tip-reference" title="Cooper, H. A., Wagner, R. H. <strong>The defect in hemophilic and Von Willebrand's disease. Plasmas studied by a recombination technique.</strong> J. Clin. Invest. 54: 1093-1099, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4213756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4213756</a>] [<a href="https://doi.org/10.1172/JCI107853" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4213756">Cooper and Wagner (1974)</a> presented evidence that the factor VIII carrier molecule, von Willebrand factor, is normally present in the plasma of hemophilia A patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4213756+13497611+13870925+13007695" 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 F8 antibodies, <a href="#33" class="mim-tip-reference" title="Denson, K. W. E. <strong>Two forms of haemophilia? (Letter)</strong> Lancet 292: 222-223, 1968. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4173441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4173441</a>] [<a href="https://doi.org/10.1016/s0140-6736(68)92661-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4173441">Denson (1968)</a> and <a href="#37" class="mim-tip-reference" title="Feinstein, D., Chong, M. N. Y., Kasper, C. K., Rapaport, S. I. <strong>Hemophilia A: polymorphism detectable by a factor VIII antibody.</strong> Science 163: 1071-1072, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5764870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5764870</a>] [<a href="https://doi.org/10.1126/science.163.3871.1071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5764870">Feinstein et al. (1969)</a> demonstrated that patients with hemophilia A have heterogeneous F8 molecules: plasma from some patients can be neutralized by the antibody, whereas plasma from other patients is not neutralized by the antibody. <a href="#32" class="mim-tip-reference" title="Denson, K. W. E., Biggs, R., Haddon, M. E., Borrett, R., Cobb, K. <strong>Two types of haemophilia (A+ and A-): a study of 48 cases.</strong> Brit. J. Haemat. 17: 163-171, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5306640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5306640</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1969.tb01355.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5306640">Denson et al. (1969)</a> postulated that there are 2 subtypes of hemophilia A: one without any immunologically demonstrable protein and one with immunologically normal, but hemostatically defective protein. <a href="#59" class="mim-tip-reference" title="Hoyer, L. W., Breckenridge, R. T. <strong>Two forms of haemophilia? (Letter)</strong> Lancet 292: 457 only, 1968. Note: Originally Volume II."None>Hoyer and Breckenridge (1968)</a> also found heterogeneity of the F8 protein in hemophilia A. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4173441+5306640+5764870" 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="#138" class="mim-tip-reference" title="Stites, D. P., Hershgold, E. J., Perlman, J. D., Fudenberg, H. H. <strong>Factor VIII detection by hemagglutination inhibition: hemophilia A and von Willebrand's disease.</strong> Science 171: 196-197, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5312959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5312959</a>] [<a href="https://doi.org/10.1126/science.171.3967.196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5312959">Stites et al. (1971)</a> were able to detect F8 immunologically in all of 14 patients with hemophilia A they studied, whereas little or no F8 was identified in patients with von Willebrand disease. <a href="#156" class="mim-tip-reference" title="Zimmerman, T. S., Ratnoff, O. D., Littell, A. S. <strong>Detection of carriers of classic hemophilia using an immunologic assay for antihemophilic factor (factor VIII).</strong> J. Clin. Invest. 50: 255-258, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5543880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5543880</a>] [<a href="https://doi.org/10.1172/JCI106481" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5543880">Zimmerman et al. (1971)</a> found immunoreactive material in all of 22 patients with hemophilia A. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5543880+5312959" 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>Hemophilia A is an X-linked recessive disorder and usually occurs in males. In familial cases, the affected boy has inherited the mutant gene from his carrier mother, but about 30% of cases arise from a spontaneous mutation (review by <a href="#85" class="mim-tip-reference" title="Mannucci, P. M., Tuddenham, E. G. D. <strong>The hemophilias--from royal genes to gene therapy.</strong> New Eng. J. Med. 344: 1773-1779, 2001. Note: Erratum: New Eng. J. Med. 345: 384 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11396445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11396445</a>] [<a href="https://doi.org/10.1056/NEJM200106073442307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11396445">Mannucci and Tuddenham, 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11396445" 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 improved methods of carrier detection, <a href="#17" class="mim-tip-reference" title="Biggs, R., Rizza, C. R. <strong>The sporadic case of haemophilia A.</strong> Lancet 308: 431-433, 1976. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/73739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">73739</a>] [<a href="https://doi.org/10.1016/s0140-6736(76)92523-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="73739">Biggs and Rizza (1976)</a> studied 41 mothers of presumably sporadic cases of hemophilia A and found that 39 were carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=73739" 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="#56" class="mim-tip-reference" title="Hermann, J. <strong>Der Einfluss des Zeugungsalters auf die Mutationen zu Haemophilie A.</strong> Humangenetik 3: 1-16, 1966."None>Hermann (1966)</a> reported an age effect on the mutation rate in hemophilia, but <a href="#8" class="mim-tip-reference" title="Barrai, I., Cann, H. M., Cavalli-Sforza, L. L., de Nicola, P. <strong>The effect of parental age on rates of mutation for hemophilia and evidence for differing mutation rates for hemophilia A and B.</strong> Am. J. Hum. Genet. 20: 175-196, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5657359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5657359</a>]" pmid="5657359">Barrai et al. (1968)</a> concluded that there was no effect of maternal age or maternal grandfather's age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5657359" 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="#144" class="mim-tip-reference" title="Vogel, F. <strong>A probable sex difference in some mutation rates.</strong> Am. J. Hum. Genet. 29: 312-319, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/868880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">868880</a>]" pmid="868880">Vogel (1977)</a> concluded that the mutation rate causing hemophilia A is higher in males than in females; however <a href="#9" class="mim-tip-reference" title="Barrai, I., Cann, H. M., Cavalli-Sforza, L. L. <strong>Segregation analysis of hemophilia A and B. (Letter)</strong> Am. J. Hum. Genet. 31: 226-227, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17948547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17948547</a>]" pmid="17948547">Barrai et al. (1979)</a> did not. Based on carrier detection tests of 21 mothers of isolated cases of severe hemophilia A, <a href="#147" class="mim-tip-reference" title="Winter, R. M., Tuddenham, E. G. D., Goldman, E., Matthews, K. B. <strong>A maximum likelihood estimate of the sex ratio of mutation rates in haemophilia A.</strong> Hum. Genet. 64: 156-159, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6411604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6411604</a>] [<a href="https://doi.org/10.1007/BF00327115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6411604">Winter et al. (1983)</a> derived a maximum likelihood estimate of 9.6 (95% confidence limits 2.2-41.5) for the ratio of male to female mutation. <a href="#14" class="mim-tip-reference" title="Bernardi, F., Marchetti, G., Bertagnolo, V., Faggioli, L., Volinia, S., Patracchini, P., Bartolai, S., Vannini, F., Felloni, L., Rossi, L., Panicucci, F., Conconi, F. <strong>RFLP analysis in families with sporadic hemophilia A: estimate of the mutation ratio in male and female gametes.</strong> Hum. Genet. 76: 253-256, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2885255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2885255</a>] [<a href="https://doi.org/10.1007/BF00283618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2885255">Bernardi et al. (1987)</a> found data consistent with a higher mutation rate in males than in females by using RFLP analysis in families with sporadic hemophilia A, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2885255+868880+17948547+6411604" 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="#124" class="mim-tip-reference" title="Rosendaal, F. R., Briet, E., Stibbe, J., van Herpen, G., Gevers Leuven, J. A., Hofman, A., Vandenbroucke, J. P. <strong>Haemophilia protects against ischaemic heart disease: a study of risk factors.</strong> Brit. J. Haemat. 75: 525-530, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2207003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2207003</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1990.tb07793.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2207003">Rosendaal et al. (1990)</a> collected information by mail on 462 Dutch patients with severe or moderately severe hemophilia A. Pedigree analysis on 189 of these patients who were the first hemophiliacs in their family showed, by the maximum likelihood method, that the ratio of mutation frequencies in males and females was 2.1, with a 95% confidence interval of 0.7-6.7. <a href="#125" class="mim-tip-reference" title="Rosendaal, F. R., Brocker-Vriends, A. H. J. T., van Houwelingen, J. C., Smit, C., Varekamp, I., van Dijck, H., Suurmeijer, T. P. B. M., Vandenbroucke, J. P., Briet, E. <strong>Sex ratio of the mutation frequencies in haemophilia A: estimation and meta-analysis.</strong> Hum. Genet. 86: 139-146, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2148300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2148300</a>] [<a href="https://doi.org/10.1007/BF00197695" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2148300">Rosendaal et al. (1990)</a> performed a meta-analysis of all published studies on the sex ratio of mutation frequencies. From pooling of 6 studies, they estimated that mutations originate 3.1 times more often in males than in females (95% confidence interval 1.9-4.9). This implies that 80% of mothers of an isolated patient are expected to be hemophilia carriers. This estimate of prior risk is required for the application of Bayes theorem to probability calculations in carriership testing. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2148300+2207003" 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="Brocker-Vriends, A. H. J. T., Rosendaal, F. R., van Houwelingen, J. C., Bakker, E., van Ommen, G. J. B., van de Kamp, J. J. P., Briet, E. <strong>Sex ratio of the mutation frequencies in haemophilia A: coagulation assays and RFLP analysis.</strong> J. Med. Genet. 28: 672-680, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1682494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1682494</a>] [<a href="https://doi.org/10.1136/jmg.28.10.672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1682494">Brocker-Vriends et al. (1991)</a> estimated that the mutation rate in males is 5.2 times that in females (95% confidence interval 1.8 to 15.1) suggesting that the probability of carriership for mothers of an isolated case amounts to 86%. Although this would imply that 14% of the mothers are not carriers in the classical sense, they may be mosaic for the mutation and, therefore, at risk of transmitting the mutation more than once. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1682494" 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="Leuer, M., Oldenburg, J., Lavergne, J.-M., Ludwig, M., Fregin, A., Eigel, A., Ljung, R., Goodeve, A., Peake, I., Olek, K. <strong>Somatic mosaicism in hemophilia A: a fairly common event.</strong> Am. J. Hum. Genet. 69: 75-87, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11410838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11410838</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11410838[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/321285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11410838">Leuer et al. (2001)</a> explored the hypothesis that a significant proportion of de novo mutations causing hemophilia A can be attributed to a germline or somatic mosaic originating from a mutation during early embryogenesis. They used allele-specific PCR to analyze 61 families that included members who had sporadic severe hemophilia A and known F8 gene defects. The presence of somatic mosaicism of varying degrees (0.2 to 25%) could be shown in 8 (13%) of the 61 families and was confirmed by a mutation-enrichment procedure. All mosaics were found in families with point mutations (8 of 32 families). In a subgroup of 8 families with CpG transitions, the percentage with mosaicism increased to 50% (4 of 8 families). In contrast, no mosaics were observed in 13 families with small deletions or insertions or in 16 families with intron 22 inversions. These data suggested that mosaicism may represent a fairly common event in hemophilia A. As a consequence, risk assessment in genetic counseling should include consideration of the possibility of somatic mosaicism in families with apparently de novo mutations, especially families with this subtype of point mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11410838" 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>Unusual Inheritance Patterns</em></strong></p><p>
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Hemophilia A can also occur in females because of inheritance of defective F8 genes from both parents or on the basis of an autosome translocation disrupting the structure of the gene (e.g., <a href="#92" class="mim-tip-reference" title="Migeon, B. R., Axelman, J., Jan de Beur, S., Valle, D., Mitchell, G. A., Rosenbaum, K. N. <strong>Selection against lethal alleles in females heterozygous for incontinentia pigmenti.</strong> Am. J. Hum. Genet. 44: 100-106, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2562819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2562819</a>]" pmid="2562819">Migeon et al., 1989</a>). <a href="#115" class="mim-tip-reference" title="Pola, V., Svojitka, J. <strong>Klassische Haemophilie bei Frauen.</strong> Folia Haemat. 75: 43-51, 1957."None>Pola and Svojitka (1957)</a> reported a homozygous affected female who was the daughter of a hemophilic man married to a double first cousin. <a href="#133" class="mim-tip-reference" title="Sie, P., Caranobe, C., Benalioua, M., Boneu, B. <strong>Homozygous hemophilia A in a female. (Letter)</strong> Thromb. Haemost. 54: 728 only, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4089803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4089803</a>]" pmid="4089803">Sie et al. (1985)</a> reported a homozygous female. In these cases, the homozygous female was not more severely affected than the hemizygous male. Theoretically, a female can be homozygous on the basis of uniparental isodisomy. It is also possible, in some cases diagnosed as hemophilia A, that actually von Willebrand disease (see <a href="/entry/193400">193400</a>) is producing the hemorrhagic diathesis with very low levels of factor VIII. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4089803+2562819" 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="Howard, P. L., Hoag, J. B., Bovill, E. G., Heintz, N. H. <strong>Spontaneous mutation in the male gamete as a cause of hemophilia A: clarification of a case using DNA probes.</strong> Am. J. Hemat. 28: 167-169, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2900604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2900604</a>] [<a href="https://doi.org/10.1002/ajh.2830280307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2900604">Howard et al. (1988)</a> showed that the mother of a hemophilic boy carried a mutation in the X chromosome she received from her nonhemophilic father rather than in the X chromosome received from her mother. Thus, the father was a gonadal mosaic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2900604" 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 studies of a sporadic case of hemophilia, <a href="#48" class="mim-tip-reference" title="Gitschier, J. <strong>Maternal duplication associated with gene deletion in sporadic hemophilia.</strong> Am. J. Hum. Genet. 43: 274-279, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2901224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2901224</a>]" pmid="2901224">Gitschier (1988)</a> found that the mother had partial duplication of the F8 gene. Among her 7 children, in addition to the hemophilic male who had partial deletion of factor VIII, there were some who inherited her normal X chromosome and others who inherited her duplicated X chromosome. Possibly the duplication in the mother predisposed to deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2901224" 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="#142" class="mim-tip-reference" title="Vidaud, D., Vidaud, M., Plassa, F., Gazengel, C., Noel, B., Goossens, M. <strong>Father-to-son transmission of hemophilia A due to uniparental disomy. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A226 only, 1989."None>Vidaud et al. (1989)</a> presented evidence that a case of apparent transmission of hemophilia from father to son was due to uniparental disomy. Gamete complementation, involving fertilization of a nullisomic oocyte by a disomic sperm carrying both an X and a Y, was thought to have occurred. More than 15 X-linked DNA markers indicated that the son's X chromosome was inherited from his father.</p><p><a href="#105" class="mim-tip-reference" title="Nisen, P. D., Waber, P. G. <strong>Nonrandom X chromosome DNA methylation patterns in hemophiliac females.</strong> J. Clin. Invest. 83: 1400-1403, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2564852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2564852</a>] [<a href="https://doi.org/10.1172/JCI114028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2564852">Nisen and Waber (1989)</a> studied X-chromosome inactivation patterns, as indicated by DNA methylation, in 3 families with hemophilic daughters. One was a case of severe hemophilia B in a girl referred to in <a href="/entry/306900">306900</a>. The other 2 were cases of hemophilia A. The maternal and paternal X chromosomes were distinguished by RFLPs, and then patterns of methylation of selected genes on the X-chromosome were determined using methylation-sensitive restriction endonucleases. Of the 6 X-chromosome probes tested, only the PGK (<a href="/entry/311800">311800</a>) and HPRT (<a href="/entry/308000">308000</a>) clones were informative. After digestion with HpaII or HhaI, the hybridization intensity of the RFLPs of all 3 mothers and an unaffected sister were diminished by 50%, consistent with random X-chromosome inactivation. The methylation patterns of the X chromosomes of the affected females, however, were clearly nonrandom. Depending on the probe and the patient, HPRT and PGK sequences were either completely methylated or unmethylated. Thus, nonrandom X-chromosome inactivation was the basis for severe hemophilia in these females. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2564852" 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="#27" class="mim-tip-reference" title="Coleman, R., Genet, S. A., Harper, J. I., Wilkie, A. O. M. <strong>Interaction of incontinentia pigmenti and factor VIII mutations in a female with biased X inactivation, resulting in haemophilia.</strong> J. Med. Genet. 30: 497-500, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8326493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8326493</a>] [<a href="https://doi.org/10.1136/jmg.30.6.497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8326493">Coleman et al. (1993)</a> reported another unusual mechanism for full-blown hemophilia A in a female, namely, biased X inactivation. A female infant born to a mother with incontinentia pigmenti (IP; <a href="/entry/308300">308300</a>) and a father with hemophilia A manifested both disorders. Methylation studies of peripheral blood DNA from the infant, her mother, and 2 female relatives with IP showed a highly skewed pattern of X inactivation. Random patterns were observed in the infant's 2 sisters, who did not have IP and had the usual carrier activity of factor VIII. <a href="#27" class="mim-tip-reference" title="Coleman, R., Genet, S. A., Harper, J. I., Wilkie, A. O. M. <strong>Interaction of incontinentia pigmenti and factor VIII mutations in a female with biased X inactivation, resulting in haemophilia.</strong> J. Med. Genet. 30: 497-500, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8326493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8326493</a>] [<a href="https://doi.org/10.1136/jmg.30.6.497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8326493">Coleman et al. (1993)</a> postulated that the usual negative selection against cells with the IP-bearing X chromosome as the active one had unmasked the factor VIII mutation on the infant's other X chromosome. Thus, the infant was functionally hemizygous for the F8 mutation inherited from the father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8326493" 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="#146" class="mim-tip-reference" title="Windsor, S., Lyng, A., Taylor, S. A. M., Ewenstein, B. M., Neufeld, E. J., Lillicrap, D. <strong>Severe haemophilia A in a female resulting from two de novo factor VIII mutations.</strong> Brit. J. Haemat. 90: 906-909, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7669670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7669670</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1995.tb05213.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7669670">Windsor et al. (1995)</a> described another mechanism for severe hemophilia A in a female: the presence of 2 de novo F8 mutations, an X chromosome deletion, and a paternal F8 inversion mutation. Neither parent showed evidence of the mutation in somatic DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7669670" 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="#140" class="mim-tip-reference" title="Valleix, S., Vinciguerra, C., Lavergne, J.-M., Leuer, M., Delpech, M., Negrier, C. <strong>Skewed X-chromosome inactivation in monochorionic diamniotic twin sisters results in severe and mild hemophilia A.</strong> Blood 100: 3034-3036, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12351418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12351418</a>] [<a href="https://doi.org/10.1182/blood-2002-01-0277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12351418">Valleix et al. (2002)</a> described monozygotic twin females who were heterozygous for a tyr16-to-cys mutation in the F8 gene (Y16C; <a href="#0269">306700.0269</a>) which most probably arose in the paternal germline. Both twins showed skewing of X inactivation toward the maternally derived normal X chromosome, the most severely affected twin exhibiting a higher percentage of inactivation of the normal X chromosome. The degree of skewing of X inactivation closely correlated with both the coagulation parameters and the clinical phenotype of the twins. Monozygotic twins may be monochorionic or dichorionic, depending on whether they develop in a single or 2 distinct chorionic sacs. Dichorionic twinning occurs prior to or around the onset of X inactivation and monochorionic twinning occurs later. A discordant X-inactivation pattern might therefore be expected to be seen more frequently in dichorionic twins. As these twins were monochorionic, <a href="#140" class="mim-tip-reference" title="Valleix, S., Vinciguerra, C., Lavergne, J.-M., Leuer, M., Delpech, M., Negrier, C. <strong>Skewed X-chromosome inactivation in monochorionic diamniotic twin sisters results in severe and mild hemophilia A.</strong> Blood 100: 3034-3036, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12351418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12351418</a>] [<a href="https://doi.org/10.1182/blood-2002-01-0277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12351418">Valleix et al. (2002)</a> suggested that the twinning event in this case may have been after the onset of X inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12351418" 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="Bicocchi, M. P., Migeon, B. R., Pasino, M., Lanza, T., Bottini, F., Boeri, E., Molinari, A. C., Corsolini, F., Morerio, C., Acquila, M. <strong>Familial nonrandom inactivation linked to the X inactivation centre in heterozygotes manifesting haemophilia A.</strong> Europ. J. Hum. Genet. 13: 635-640, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15741993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15741993</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201386" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15741993">Bicocchi et al. (2005)</a> reported a 3-generation family in which 3 females were affected with classic hemophilia A due to a heterozygous missense mutation in the F8 gene. All 3 women showed completely skewed X inactivation with expression only of the mutant gene in all tissues analyzed, including leukocytes, skin fibroblasts, uroepithelium, and buccal mucosa. Although no mutations were identified in the XIST gene (<a href="/entry/314670">314670</a>), <a href="#16" class="mim-tip-reference" title="Bicocchi, M. P., Migeon, B. R., Pasino, M., Lanza, T., Bottini, F., Boeri, E., Molinari, A. C., Corsolini, F., Morerio, C., Acquila, M. <strong>Familial nonrandom inactivation linked to the X inactivation centre in heterozygotes manifesting haemophilia A.</strong> Europ. J. Hum. Genet. 13: 635-640, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15741993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15741993</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201386" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15741993">Bicocchi et al. (2005)</a> determined that all 3 women had the same XIST allele, and suggested that an alteration within the X-inactivation center on the chromosome carrying the F8C mutation prevented it from being inactivated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15741993" 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="#121" class="mim-tip-reference" title="Renault, N. K., Dyack, S., Dobson, M. J., Costa, T., Lam, W. L., Greer, W. L. <strong>Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females.</strong> Europ. J. Hum. Genet. 15: 628-637, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17342157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17342157</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17342157">Renault et al. (2007)</a> described a 3-generation family segregating 2 distinct phenotypes, hemophilia A and dramatically skewed X chromosome inactivation, the convergence of which led to the expression of hemophilia A in 3 heterozygous females. All affected males and females had a proximal (type II) IVS22 inversion of the F8 gene. No female carried more than 1 inverted allele. The 3 affected females had skewed X inactivation in favor of the mutant X; 3 unaffected females also had skewed X inactivation, 2 in favor of the normal X, and the third did not carry the mutation. <a href="#121" class="mim-tip-reference" title="Renault, N. K., Dyack, S., Dobson, M. J., Costa, T., Lam, W. L., Greer, W. L. <strong>Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females.</strong> Europ. J. Hum. Genet. 15: 628-637, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17342157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17342157</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17342157">Renault et al. (2007)</a> stated that known causes of skewing were not consistent with their findings in this family, suggesting that the X-chromosome inactivation ratios were genetically influenced (SXI2; <a href="/entry/300179">300179</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17342157" 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>Hemophilia A should be suspected whenever unusual bleeding is encountered in a male patient. Laboratory tests show normal platelet count and prothrombin time (PT), but a prolonged activated partial thromboplastin time (aPTT). Since hemophilia A and B are clinically similar, specific assays of factor VIII and factor IX (F9; <a href="/entry/300746">300746</a>) must be performed. Patients with von Willebrand disease (VWD; <a href="/entry/193400">193400</a>) also have factor VIII deficiency secondary to a deficiency of von Willebrand factor (VWF; <a href="/entry/613160">613160</a>).</p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Baty, B. J., Drayna, D., Leonard, C. O., White, R. <strong>Prenatal diagnosis of factor VIII deficiency to help with the management of pregnancy and delivery. (Letter)</strong> Lancet 327: 207 only, 1986. Note: Originally Volume I.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2868222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2868222</a>] [<a href="https://doi.org/10.1016/s0140-6736(86)90672-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2868222">Baty et al. (1986)</a> demonstrated how DNA diagnosis can be helpful in obstetrical decisions and early care of hemophilia even though the family does not make use of the information for elective abortion. Specifically, Cesarean section was performed and the parents were psychologically prepared. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2868222" 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="#112" class="mim-tip-reference" title="Pecorara, M., Casarino, L., Mori, P. G., Morfini, M., Mancuso, G., Scrivano, A. M., Boeri, E., Molinari, A. C., De Biasi, R., Ciavarella, N., Bencivelli, F., Repa, T., Barbujani, G., Loi, A., Perseu, L., Cao, A., Pirastu, M. <strong>Hemophilia A: carrier detection and prenatal diagnosis by DNA analysis.</strong> Blood 70: 531-535, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3111562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3111562</a>]" pmid="3111562">Pecorara et al. (1987)</a> reported a relatively large experience with carrier detection and prenatal diagnosis by means of RFLP analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3111562" 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="#70" class="mim-tip-reference" title="Kogan, S. C., Doherty, M., Gitschier, J. <strong>An improved method for prenatal diagnosis of genetic diseases by analysis of amplified DNA sequences: application to hemophilia A.</strong> New Eng. J. Med. 317: 985-990, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3657865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3657865</a>] [<a href="https://doi.org/10.1056/NEJM198710153171603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3657865">Kogan et al. (1987)</a> modified the procedure of PCR to use a heat-stable DNA polymerase which allowed the repeated rounds of DNA synthesis to proceed at 63 degrees C. The high sequence specificity of PCR at this temperature enabled detection of restriction-site polymorphisms, contained in PCR products derived from clinical samples to be analyzed by visual inspection of their digestion products on polyacrylamide gels. <a href="#70" class="mim-tip-reference" title="Kogan, S. C., Doherty, M., Gitschier, J. <strong>An improved method for prenatal diagnosis of genetic diseases by analysis of amplified DNA sequences: application to hemophilia A.</strong> New Eng. J. Med. 317: 985-990, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3657865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3657865</a>] [<a href="https://doi.org/10.1056/NEJM198710153171603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3657865">Kogan et al. (1987)</a> used the improved method to detect carriers of hemophilia A and to diagnose hemophilia prenatally. <a href="#36" class="mim-tip-reference" title="Erlich, H. A., Gelfand, D. H., Saiki, R. K. <strong>Specific DNA amplification.</strong> Nature 331: 461-462, 1988."None>Erlich et al. (1988)</a> improved the PCR method using thermostable DNA polymerase from Thermus aquaticus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3657865" 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="#76" class="mim-tip-reference" title="Lavery, S. <strong>Preimplantation genetic diagnosis of haemophilia.</strong> Brit. J. Haemat. 144: 303-307, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19036080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19036080</a>] [<a href="https://doi.org/10.1111/j.1365-2141.2008.07391.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19036080">Lavery (2008)</a> described strategies for preimplantation genetic diagnosis of hemophilia, including embryo sexing, specific mutation analysis, coamplification of polymorphic markers, direct sequencing of F8, and haplotyping after multiple displacement amplification, and discussed the ethical challenges. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19036080" 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>Linkage studies in the early 1960s indicated that hemophilia A and B (<a href="/entry/306900">306900</a>) are not allelic (<a href="#89" class="mim-tip-reference" title="McKusick, V. A. <strong>On the X Chromosome of Man.</strong> Washington, D. C.: Am. Inst. Biol. Sci. (pub.) 1964."None>McKusick, 1964</a>). The independence of the 2 loci was confirmed when <a href="#123" class="mim-tip-reference" title="Robertson, J. H., Trueman, R. G. <strong>Combined hemophilia and Christmas disease.</strong> Blood 24: 281-288, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14214137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14214137</a>]" pmid="14214137">Robertson and Trueman (1964)</a> found a family in which both hemophilia A and hemophilia B were segregating; one male was deficient in both factor VIII and factor IX. From study of another family in which both hemophilia A and hemophilia B were segregating, <a href="#148" class="mim-tip-reference" title="Woodliff, H. J., Jackson, J. M. <strong>Combined haemophilia and Christmas disease: a genetic study of a patient and his relatives.</strong> Med. J. Aust. 53: 658-661, 1966."None>Woodliff and Jackson (1966)</a> concluded that the 2 loci are far apart. Direct studies of linkage between hemophilias A and B in the dog indicated that the 2 loci are at least 50 map units apart (<a href="#22" class="mim-tip-reference" title="Brinkhous, K. M., Davis, P. D., Graham, J. B., Dodds, W. J. <strong>Expression and linkage of genes for X-linked hemophilia A and B in the dog.</strong> Blood 41: 577-585, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4688873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4688873</a>]" pmid="4688873">Brinkhous et al., 1973</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4688873+14214137" 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="#53" class="mim-tip-reference" title="Haldane, J. B. S., Smith, C. A. B. <strong>A new estimate of the linkage between the genes for colour-blindness and haemophilia in man.</strong> Ann. Eugen. 14: 10-31, 1947.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18897933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18897933</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1947.tb02374.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18897933">Haldane and Smith (1947)</a> concluded that there is 5-20% recombination between the color blindness (CBD; <a href="/entry/303800">303800</a>) and hemophilia loci with the most probable value about 10%. However, <a href="#134" class="mim-tip-reference" title="Smith, C. A. B. <strong>Personal Communication.</strong> London 1968."None>Smith (1968)</a> subsequently concluded that the data on which that estimate was based were heterogeneous, with some families (presumably hemophilia A) showing very close linkage and others (presumably hemophilia B) showing no linkage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18897933" 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="#127" class="mim-tip-reference" title="Samama, M., Perrotez, C., Houissa, R., Hafsia, A., Seger, J. <strong>Hemophilia A feminine avec deletion d'une partie du bras long d'un chromosome X.</strong> Pathol. Biol. (Paris) 25 Suppl.: 10-17, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/353654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">353654</a>]" pmid="353654">Samama et al. (1977)</a> confirmed assignment of the hemophilia A locus to the long arm of the X chromosome by demonstration of hemophilia in a girl whose mother was a carrier and one of whose X chromosomes had partial deletion of the long arm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=353654" 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 families of African descent, <a href="#19" class="mim-tip-reference" title="Boyer, S. H., Graham, J. B. <strong>Linkage between the X chromosome loci for glucose-6-phosphate dehydrogenase electrophoretic variation and hemophilia A.</strong> Am. J. Hum. Genet. 17: 320-324, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17948498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17948498</a>]" pmid="17948498">Boyer and Graham (1965)</a> demonstrated close linkage of hemophilia A and the A/B polymorphism of G6PD (<a href="/entry/305900">305900</a>). <a href="#38" class="mim-tip-reference" title="Filippi, G., Mannucci, P. M., Coppola, R., Farris, A., Rinaldi, A., Siniscalco, M. <strong>Studies on hemophilia A in Sardinia bearing on the problems of multiple allelism, carrier detection, and differential mutation rate in the two sexes.</strong> Am. J. Hum. Genet. 36: 44-71, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6421151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6421151</a>]" pmid="6421151">Filippi et al. (1984)</a> stated that 58 scorable sibs, all nonrecombinant for the linkage of HEMA and G6PD, were known by that time. From this, they inferred that the 90% upper limit of meiotic recombination between the 2 loci is less than 4%. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17948498+6421151" 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="#54" class="mim-tip-reference" title="Harper, K., Winter, R. M., Pembrey, M. E., Hartley, D., Davies, K. E., Tuddenham, E. G. D. <strong>A clinically useful DNA probe closely linked to haemophilia A.</strong> Lancet 324: 6-8, 1984. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6145983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6145983</a>] [<a href="https://doi.org/10.1016/s0140-6736(84)91995-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6145983">Harper et al. (1984)</a> did linkage studies with the DNA probe DX13, which had been localized to band Xq28. When DNA is digested with the restriction enzyme BglII, the probe recognizes an RFLP for which 50% of females are heterozygous. No recombination was observed between the HEMA and DX13 loci. The workers concluded that the marker is useful for carrier detection and prenatal diagnosis. About 30% recombination was found between the factor VIII and IX loci. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6145983" 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="#107" class="mim-tip-reference" title="Oberle, I., Camerino, G., Heilig, R., Grunebaum, L., Cazenave, J.-P., Crapanzano, C., Mannucci, P. M., Mandel, J.-L. <strong>Genetic screening for hemophilia A (classic hemophilia) with a polymorphic DNA probe.</strong> New Eng. J. Med. 312: 682-686, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2983207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2983207</a>] [<a href="https://doi.org/10.1056/NEJM198503143121103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2983207">Oberle et al. (1985)</a> observed very close linkage of a polymorphic anonymous DNA probe called St14 (from Strasbourg, France). No recombination (theta=0) was found in 12 families (lod score 9.65). The probe was informative in more than 90% of families, and the authors suggested that it could be used in conjunction with assays of factor VIII to identify carriers with 96% confidence or better. St14 could be used for prenatal diagnosis of disorders such as hemophilia A and adrenoleukodystrophy because of close linkage (<a href="#107" class="mim-tip-reference" title="Oberle, I., Camerino, G., Heilig, R., Grunebaum, L., Cazenave, J.-P., Crapanzano, C., Mannucci, P. M., Mandel, J.-L. <strong>Genetic screening for hemophilia A (classic hemophilia) with a polymorphic DNA probe.</strong> New Eng. J. Med. 312: 682-686, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2983207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2983207</a>] [<a href="https://doi.org/10.1056/NEJM198503143121103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2983207">Oberle et al., 1985</a>). <a href="#64" class="mim-tip-reference" title="Janco, R. L., Phillips, J. A., III, Orlando, P. J., Woodard, M. J., Wion, K. L., Lawn, R. M. <strong>Detection of hemophilia A carriers using intragenic factor VIII:C DNA polymorphisms.</strong> Blood 69: 1539-1541, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2882794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2882794</a>]" pmid="2882794">Janco et al. (1987)</a> used the more accurate intragenic F8 RFLPs to detect hemophilia A carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2983207+2882794" 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 9-year-old Malaysian female with de novo hemophilia A as well as a complex de novo translocation involving one X chromosome and one chromosome 17 (<a href="#95" class="mim-tip-reference" title="Muneer, R. S., Coffman, M. A., Thompson, L. M., Sexauer, C. L., Rennert, O. M. <strong>Classic hemophilia in a female with X/17 complex translocation and partial deletion of the long arm X chromosome (Xq11-13). (Abstract)</strong> Am. J. Hum. Genet. 39: A126, 1986."None>Muneer et al., 1986</a>), <a href="#93" class="mim-tip-reference" title="Migeon, B. R., McGinniss, M. J., Antonarakis, S. E., Axelman, J., Stasiowski, B. A., Youssoufian, H., Kearns, W. G., Chung, A., Pearson, P. L., Kazazian, H. H., Jr., Muneer, R. S. <strong>Severe hemophilia A in a female by cryptic translocation: order and orientation of factor VIII within Xq28.</strong> Genomics 16: 20-25, 1993. Note: Erratum: Genomics 16: 792 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8486358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8486358</a>] [<a href="https://doi.org/10.1006/geno.1993.1134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8486358">Migeon et al. (1993)</a> identified a breakpoint within Xq28 with deletion of the 5-prime end of the factor VIII gene, leaving the more proximal G6PD locus intact on the derivative chromosome 17. As the deleted segment included the 5-prime half of F8C as well as the subtelomeric DXYS64 locus, they concluded that F8 is oriented on the chromosome with its 5-prime region closest to the telomere. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8486358" 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="#118" class="mim-tip-reference" title="Ratnoff, O. D., Bennett, B. <strong>The genetics of hereditary disorders of blood coagulation.</strong> Science 179: 1291-1298, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4568863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4568863</a>] [<a href="https://doi.org/10.1126/science.179.4080.1291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4568863">Ratnoff and Bennett (1973)</a> reviewed the genetics of hereditary disorders of blood coagulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4568863" 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="#45" class="mim-tip-reference" title="Gitschier, J., Drayna, D., Tuddenham, E. G. D., White, R. L., Lawn, R. M. <strong>Genetic mapping and diagnosis of haemophilia A achieved through a BclI polymorphism in the factor VIII gene.</strong> Nature 314: 738-740, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2986011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2986011</a>] [<a href="https://doi.org/10.1038/314738a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2986011">Gitschier et al. (1985)</a> identified truncating mutations in the F8 gene (see, e.g., <a href="/entry/300841#0001">300841.0001</a>-<a href="/entry/300841#0003">300841.0003</a>) as the basis for hemophilia A. A severe hemophiliac with no detectable factor VIIIC activity had an R2307X mutation (<a href="/entry/300841#0001">300841.0001</a>). <a href="#46" class="mim-tip-reference" title="Gitschier, J., Wood, W. I., Shuman, M. A., Lawn, R. M. <strong>Identification of a missense mutation in the factor VIII gene of a mild hemophiliac.</strong> Science 232: 1415-1416, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3012775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3012775</a>] [<a href="https://doi.org/10.1126/science.3012775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3012775">Gitschier et al. (1986)</a> found that the same codon was converted to glutamine (R2307Q; <a href="/entry/300841#0042">300841.0042</a>) in a mild hemophiliac with 10% of normal activity. A diminished level of factor VIII Ag in the latter patient coincided with the level of clotting activity, suggesting that the abnormal factor VIII was relatively unstable. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2986011+3012775" 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 study of 83 patients with hemophilia A, <a href="#154" class="mim-tip-reference" title="Youssoufian, H., Kazazian, H. H., Jr., Phillips, D. G., Aronis, S., Tsiftis, G., Brown, V. A., Antonarakis, S. E. <strong>Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots.</strong> Nature 324: 380-382, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3097553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3097553</a>] [<a href="https://doi.org/10.1038/324380a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3097553">Youssoufian et al. (1986)</a> identified 2 different point mutations, one in exon 18 and one in exon 22, that recurred independently in unrelated families. Each mutation produced a nonsense codon by a change of CG to TG. In the opinion of <a href="#154" class="mim-tip-reference" title="Youssoufian, H., Kazazian, H. H., Jr., Phillips, D. G., Aronis, S., Tsiftis, G., Brown, V. A., Antonarakis, S. E. <strong>Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots.</strong> Nature 324: 380-382, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3097553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3097553</a>] [<a href="https://doi.org/10.1038/324380a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3097553">Youssoufian et al. (1986)</a>, these observations indicated that CpG dinucleotides are mutation hotspots. It had been postulated that methylated cytosines may be mutation hotspots because 5-methylcytosine can spontaneously deaminate to thymine, resulting in a C-to-T transition in DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3097553" 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="#150" class="mim-tip-reference" title="Youssoufian, H., Antonarakis, S. E., Aronis, S., Tsiftis, G., Phillips, D. G., Kazazian, H. H., Jr. <strong>Characterization of five partial deletions of the factor VIII gene.</strong> Proc. Nat. Acad. Sci. 84: 3772-3776, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3035554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3035554</a>] [<a href="https://doi.org/10.1073/pnas.84.11.3772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3035554">Youssoufian et al. (1987)</a> characterized 5 different partial deletions of the F8 gene in 83 patients with hemophilia. None had developed circulating inhibitors. One of the deletions occurred de novo in a germ cell of the maternal grandmother, while a second deletion occurred in a germ cell of a maternal grandfather. The findings indicated that de novo deletions of X-linked genes can occur in either male or female gametes. <a href="#153" class="mim-tip-reference" title="Youssoufian, H., Kasper, C. K., Phillips, D. G., Kazazian, H. H., Jr., Antonarakis, S. E. <strong>Restriction endonuclease mapping of six novel deletions of the factor VIII gene in hemophilia A.</strong> Hum. Genet. 80: 143-148, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3139545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3139545</a>] [<a href="https://doi.org/10.1007/BF00702857" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3139545">Youssoufian et al. (1988)</a> reported 6 other partial F8 gene deletions in severe hemophilia A, bringing to 12 the number of deletions among 240 patients. No association was observed between the size or location of deletions and the presence of inhibitors to factor VIII. Furthermore, no 'hotspots' for deletion breakpoints were identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3139545+3035554" 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="#151" class="mim-tip-reference" title="Youssoufian, H., Antonarakis, S. E., Bell, W., Griffin, A. M., Kazazian, H. H., Jr. <strong>Nonsense and missense mutations in hemophilia A: estimate of the relative mutation rate at CG dinucleotides.</strong> Am. J. Hum. Genet. 42: 718-725, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2833855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2833855</a>]" pmid="2833855">Youssoufian et al. (1988)</a> screened 240 patients with hemophilia A and found CG to TG transitions in an exon in 9. They identified novel missense mutations leading to severe hemophilia A and estimated that the extent of hypermutability of CpG dinucleotides is 10 to 20 times greater than the average mutation rate for hemophilia A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2833855" 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="Cooper, D. N., Youssoufian, H. <strong>The CpG dinucleotide and human genetic disease.</strong> Hum. Genet. 78: 151-155, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3338800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3338800</a>] [<a href="https://doi.org/10.1007/BF00278187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3338800">Cooper and Youssoufian (1988)</a> collated reports of single basepair mutations within gene coding regions causing human genetic disease. They found that 35% of mutations occurred within CpG dinucleotides. Over 90% of these mutations were C-to-T or G-to-A transitions, which thus occur within coding regions at a frequency 42-times higher than that predicted from random mutation. <a href="#29" class="mim-tip-reference" title="Cooper, D. N., Youssoufian, H. <strong>The CpG dinucleotide and human genetic disease.</strong> Hum. Genet. 78: 151-155, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3338800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3338800</a>] [<a href="https://doi.org/10.1007/BF00278187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3338800">Cooper and Youssoufian (1988)</a> believed these findings were consistent with methylation-induced deamination of 5-methylcytosine and suggested that methylation of DNA within coding regions may contribute significantly to the incidence of human genetic disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3338800" 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="Higuchi, M., Kochhan, L., Olek, K. <strong>A somatic mosaic for haemophilia A detected at the DNA level.</strong> Molec. Biol. Med. 5: 23-27, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3131627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3131627</a>]" pmid="3131627">Higuchi et al. (1988)</a> found deletion of about 2,000 bases spanning exon 3 and part of IVS3 of the F8 gene in a patient with severe hemophilia A. The mother was judged to be somatic mosaic because the defective gene could be identified in only a portion of the leukocytes and cultured fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3131627" 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 review, <a href="#2" class="mim-tip-reference" title="Antonarakis, S. E., Kazazian, H. H., Tuddenham, G. D. <strong>Molecular etiology of factor VIII deficiency in hemophilia A.</strong> Hum. Mutat. 5: 1-22, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7728145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7728145</a>] [<a href="https://doi.org/10.1002/humu.1380050102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7728145">Antonarakis et al. (1995)</a> collected the findings of more than 1,000 hemophilia subjects examined for F8 gene mutations. These include point mutations, inversions, deletions, and unidentified mutations which constitute 46%, 42%, 8%, 4%, and 91%, 0%, 0%, and 9%, respectively, of those with severe versus mild to moderate disease, respectively, in selected studies. The 266 point mutations described as of April, 1994 comprised missense (53%), CpG-to-TpG (16%), small deletions (12%), nonsense (9%), small inversions and splicing (3% each), and missense polymorphisms and silent mutations in exons (2% each). In addition to these point mutations 100 different larger deletions and 9 insertion mutations had been reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7728145" 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 study of 147 sporadic cases of severe hemophilia A, <a href="#11" class="mim-tip-reference" title="Becker, J., Schwaab, R., Moller-Taube, A., Schwaab, U., Schmidt, W., Brackmann, H. H., Grimm, T., Olek, K., Oldenburg, J. <strong>Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: family studies indicate a mutation type-dependent sex ratio of mutation frequencies.</strong> Am. J. Hum. Genet. 58: 657-670, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644728</a>]" pmid="8644728">Becker et al. (1996)</a> were able to identify the causative defect in the F8 gene in 126 patients (85.7%). An inversion of the gene was found in 55 patients (37.4%), a point mutation in 47 (32%), a small deletion in 14 (9.5%), a large deletion in 8 (5.4%), and a small insertion in 2 (1.4%). In 4 (2.7%), mutations were localized but not yet sequenced. No mutation was identified in 17 patients (11.6%). The identified mutations occurred in the B domain in 16 (10.9%); 4 of these were located in an adenosine nucleotide stretch at codon 1192, indicating a mutation hotspot. Somatic mosaicism was detected in 3 (3.9%) of 76 patients' mothers, comprising 3 of 16 de novo mutations in the patients' mothers. Investigation of family relatives allowed detection of a de novo mutation in 16 of 76 2-generation and 28 of 34 3-generation families. On the basis of these data, <a href="#11" class="mim-tip-reference" title="Becker, J., Schwaab, R., Moller-Taube, A., Schwaab, U., Schmidt, W., Brackmann, H. H., Grimm, T., Olek, K., Oldenburg, J. <strong>Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: family studies indicate a mutation type-dependent sex ratio of mutation frequencies.</strong> Am. J. Hum. Genet. 58: 657-670, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644728</a>]" pmid="8644728">Becker et al. (1996)</a> estimated the male:female ratio of mutation frequencies (k) to be 3.6. By use of the quotients of mutation origin in maternal grandfather to patients' mother or to maternal grandmother, k values were directly estimated as 15 and 7.5, respectively. Considering each mutation type separately, they found a mutation type-specific sex ratio of mutation frequencies. Point mutations showed a 5-to-10-fold-higher and inversions a more than 10-fold-higher mutation rate in male germ cells, whereas deletions showed a more than 5-fold-higher mutation rate in female germ cells. Consequently, and in accordance with the data of other disorders such as Duchenne muscular dystrophy, the results indicated to <a href="#11" class="mim-tip-reference" title="Becker, J., Schwaab, R., Moller-Taube, A., Schwaab, U., Schmidt, W., Brackmann, H. H., Grimm, T., Olek, K., Oldenburg, J. <strong>Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: family studies indicate a mutation type-dependent sex ratio of mutation frequencies.</strong> Am. J. Hum. Genet. 58: 657-670, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644728</a>]" pmid="8644728">Becker et al. (1996)</a> that at least for X-chromosomal disorders the male:female mutation rate is determined by its proportion of the different mutation types. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8644728" 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 molecular diagnosis of hemophilia A is challenging because of the high number of different causative mutations that are distributed through the large F8 gene. The putative role of the novel mutations, especially missense mutations, may be difficult to interpret as causing hemophilia A. <a href="#52" class="mim-tip-reference" title="Guillet, B., Lambert, T., d'Oiron, R., Proulle, V., Plantier, J.-L., Rafowicz, A., Peynet, J., Costa, J.-M., Bendelac, L., Laurian, Y., Lavergne, J.-M. <strong>Detection of 95 novel mutations in coagulation factor VIII gene F8 responsible for hemophilia A: results from a single institution.</strong> Hum. Mutat. 27: 676-685, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16786531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16786531</a>] [<a href="https://doi.org/10.1002/humu.20345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16786531">Guillet et al. (2006)</a> identified 95 novel mutations out of 180 different mutations found among 515 patients with hemophilia A from 406 unrelated families followed up at a single hemophilia treatment center in a Paris hospital. The 95 novel mutations comprised 55 missense mutations, 12 nonsense mutations, 11 splice site mutations, and 17 small insertions/deletions. They used a strategy in interpreting the causality of novel F8 mutations based on a combination of the familial segregation of the mutation, the resulting biologic and clinical hemophilia A phenotype, and the molecular consequences of the amino acid substitution. For the latter, they studied the putative biochemical modifications: its conservation status with cross-species factor VIII and homologous proteins, its putative location in known factor VIII functional regions, and its spatial position in the available factor VIII 3D structures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16786531" 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 1,410 Italian patients with hemophilia A, <a href="#128" class="mim-tip-reference" title="Santacroce, R., Acquila, M., Belvini, D., Castaldo, G., Garagiola, I., Giacomelli, S. H., Lombardi, A. M., Minuti, B., Riccardi, F., Salviato, R., Tagliabue, L., Grandone, E., Margaglione, M., the AICE-Genetics Study Group. <strong>Identification of 217 unreported mutations in the F8 gene in a group of 1,410 unselected Italian patients with hemophilia A.</strong> J. Hum. Genet. 53: 275-284, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18217193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18217193</a>] [<a href="https://doi.org/10.1007/s10038-007-0238-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18217193">Santacroce et al. (2008)</a> identified 382 different mutations in the F8 gene, 217 (57%) of which had not previously been reported. Mutations leading to a null allele accounted for 82%, 15%, and less than 1% of severe, moderate, or mild hemophilia, respectively. Missense mutations were identified in 16%, 68%, and 81% of severe, moderate, or mild hemophilia, respectively, yielding a good genotype/phenotype correlation useful for treatment and genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18217193" 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 order to establish a national database of F8 mutations, <a href="#50" class="mim-tip-reference" title="Green, P. M., Bagnall, R. D., Waseem, N. H., Giannelli, F. <strong>Haemophilia A mutations in the UK: results of screening one-third of the population.</strong> Brit. J. Haemat. 143: 115-128, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18691168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18691168</a>] [<a href="https://doi.org/10.1111/j.1365-2141.2008.07310.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18691168">Green et al. (2008)</a> identified and cataloged multiple mutations in approximately one-third of the U.K. hemophilia A population. The risk of developing inhibitors for patients with nonsense mutations was greater when the stop codon was in the 3-prime half of the mRNA. The most common change was the intron 22 inversion (<a href="#0067">306700.0067</a>), which accounted for 16.6% of all mutations and for 38% of those causing severe disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18691168" 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>Inversion Mutations in Intron 22 of the F8 Gene</em></strong></p><p>
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Intron 22 of the human F8 gene is hypomethylated on the active X and methylated on the inactive X. <a href="#61" class="mim-tip-reference" title="Inaba, H., Fujimaki, M., Kazazian, H. H., Jr., Antonarakis, S. E. <strong>MspI polymorphic site in intron 22 of the factor VIII gene in the Japanese population.</strong> Hum. Genet. 84: 214-215, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1688823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1688823</a>] [<a href="https://doi.org/10.1007/BF00208947" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1688823">Inaba et al. (1990)</a> described an MspI RFLP in intron 22 of the F8 gene. Japanese showed 45% heterozygosity and Asian Indians showed 13%; polymorphism was not found in American blacks or Caucasians. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1688823" 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="#97" class="mim-tip-reference" title="Naylor, J. A., Green, P. M., Rizza, C. R., Giannelli, F. <strong>Factor VIII gene explains all cases of haemophilia A.</strong> Lancet 340: 1066-1067, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1357455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1357455</a>] [<a href="https://doi.org/10.1016/0140-6736(92)93080-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1357455">Naylor et al. (1992)</a> found an unusual cluster of mutations involving regions of intron 22 not examined earlier and leading to defective joining of exons 22 and 23 in the mRNA (<a href="/entry/300841#0067">300841.0067</a>) as the cause of hemophilia A in 10 of 24 severely affected UK patients. These results confirmed predictions about the efficacy of the mRNA-based method suggested by <a href="#96" class="mim-tip-reference" title="Naylor, J. A., Green, P. M., Montandon, A. J., Rizza, C. R., Giannelli, F. <strong>Detection of three novel mutations in two haemophilia A patients by rapid screening of whole essential region of factor VIII gene.</strong> Lancet 337: 635-639, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671991</a>] [<a href="https://doi.org/10.1016/0140-6736(91)92450-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1671991">Naylor et al. (1991)</a>, and also excluded hypotheses proposing that mutations outside the F8 gene are responsible for a large proportion of severe hemophilia A. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1671991+1357455" 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>Of the 28 patients reported by <a href="#98" class="mim-tip-reference" title="Naylor, J. A., Green, P. M., Rizza, C. R., Giannelli, F. <strong>Analysis of factor VIII mRNA reveals defects in everyone of 28 haemophilia A patients.</strong> Hum. Molec. Genet. 2: 11-17, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490618</a>] [<a href="https://doi.org/10.1093/hmg/2.1.11" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490618">Naylor et al. (1993)</a>, 5 had mild or moderate disease and all had a missense mutation. The other 23 patients were severely affected; unexpectedly, intron 22 seemed to be the target of approximately 40% of the mutations causing severe hemophilia A. <a href="#99" class="mim-tip-reference" title="Naylor, J., Brinke, A., Hassock, S., Green, P. M., Giannelli, F. <strong>Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions.</strong> Hum. Molec. Genet. 2: 1773-1778, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8281136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8281136</a>] [<a href="https://doi.org/10.1093/hmg/2.11.1773" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8281136">Naylor et al. (1993)</a> found that the basis of the unique F8 mRNA defect that prevented PCR amplification across the boundary between exons 22 and 23 was an abnormality in the internal regions of intron 22. They showed that exons 1-22 of the F8 mRNA had become part of a hybrid message containing new multi-exonic sequences expressed in normal cells. The novel sequences were not located in a YAC containing the whole F8 gene. Southern blots from patients probed by novel sequences and clones covering intron 22 showed no obvious abnormalities. <a href="#99" class="mim-tip-reference" title="Naylor, J., Brinke, A., Hassock, S., Green, P. M., Giannelli, F. <strong>Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions.</strong> Hum. Molec. Genet. 2: 1773-1778, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8281136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8281136</a>] [<a href="https://doi.org/10.1093/hmg/2.11.1773" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8281136">Naylor et al. (1993)</a> also suggested that inversions involving intron 22 repeated sequences are the basis of the mRNA defect. These mutations in severely affected patients occur at the surprising rate of approximately 4 x 10(-6) per gene per gamete per generation. Furthermore, it has been shown that these de novo inversions occur more frequently in males than females with a ratio of 302:1 estimated in male:female germ cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8281136+8490618" 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 F8A gene (<a href="/entry/305423">305423</a>) is contained entirely within intron 22 of the F8 gene and is transcript in the reverse orientation from the F8 gene (<a href="#80" class="mim-tip-reference" title="Levinson, B., Kenwrick, S., Lakich, D., Hammonds, G., Gitschier, J. <strong>A transcribed gene in an intron of the human factor VIII gene.</strong> Genomics 7: 1-11, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2110545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2110545</a>] [<a href="https://doi.org/10.1016/0888-7543(90)90512-s" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2110545">Levinson et al., 1990</a>). <a href="#74" class="mim-tip-reference" title="Lakich, D., Kazazian, H. H., Jr., Antonarakis, S. E., Gitschier, J. <strong>Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A.</strong> Nature Genet. 5: 236-241, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8275087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8275087</a>] [<a href="https://doi.org/10.1038/ng1193-236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8275087">Lakich et al. (1993)</a> proposed that many of the previously unidentified mutations resulting in severe hemophilia A are based on recombination between the homologous F8A sequences within intron 22 and upstream of the F8 gene. Such a recombination would lead to an inversion of all intervening DNA and a disruption of the gene. <a href="#74" class="mim-tip-reference" title="Lakich, D., Kazazian, H. H., Jr., Antonarakis, S. E., Gitschier, J. <strong>Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A.</strong> Nature Genet. 5: 236-241, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8275087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8275087</a>] [<a href="https://doi.org/10.1038/ng1193-236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8275087">Lakich et al. (1993)</a> presented evidence to support this model and described a Southern blot assay that detects the inversion. They suggested that this assay should permit genetic prediction of hemophilia A in approximately 45% of families with severe disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8275087+2110545" 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>Inversion mutations resulting from recombinations between DNA sequences in the A gene in intron 22 of the F8 gene and 1 of 2 other A genes upstream to F8 have been shown to cause a large portion of cases. From data on more than 2,000 samples, <a href="#3" class="mim-tip-reference" title="Antonarakis, S. E., Rossiter, J. P., Young, M., Horst, J., de Moerloose, P., Sommer, S. S., Ketterling, R. P., Kazazian, H. H., Jr., Negrier, C., Vinciguerra, C., Gitschier, J., Goossens, M., and 54 others. <strong>Factor VIII inversions in severe hemophilia A: results from an international consortium.</strong> Blood 86: 2206-2212, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7662970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7662970</a>]" pmid="7662970">Antonarakis et al. (1995)</a> concluded that the common inversion mutations are found in 42% of all severe hemophilia A subjects. Whereas 98% of the mothers of those with inversions were carriers of the inversion, only about 1 de novo inversion was found in maternal cells for every 25 mothers of sporadic cases. When the maternal grandparental origin of inversions was examined the ratio of de novo occurrences in male:female germ cells was 69:1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7662970" 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="Brinke, A., Tagliavacca, L., Naylor, J., Green, P., Giangrande, P., Giannelli, F. <strong>Two chimaeric transcription units result from an inversion breaking intron 1 of the factor VIII gene and a region reportedly affected by reciprocal translocations in T-cell leukaemia.</strong> Hum. Molec. Genet. 5: 1945-1951, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968748</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968748">Brinke et al. (1996)</a> reported the presence of a novel inversion in 2 hemophilic monozygotic twins. These patients showed an inversion that affects the first intron of the F8 gene, displacing the most telomeric exon (exon 1) of F8 further towards the telomere and close to the C6.1A gene (BRCC3; <a href="/entry/300617">300617</a>). <a href="#21" class="mim-tip-reference" title="Brinke, A., Tagliavacca, L., Naylor, J., Green, P., Giangrande, P., Giannelli, F. <strong>Two chimaeric transcription units result from an inversion breaking intron 1 of the factor VIII gene and a region reportedly affected by reciprocal translocations in T-cell leukaemia.</strong> Hum. Molec. Genet. 5: 1945-1951, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968748</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968748">Brinke et al. (1996)</a> noted that this novel inversion creates 2 hybrid transcription units. One of these is formed by the promoter and first exon of F8 and widely expressed sequences that map telomeric to the C6.1A sequence. The other hybrid transcription unit contains the CpG island and all of the known sequence of C6.1A and the 3-prime section of most of the F8 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968748" 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>It is hypothesized that the inversion mutations occur almost exclusively in germ cells during meiotic cell division by an intrachromosomal recombination between a 9.6-kb sequence within intron 22 and 1 of 2 almost identical copies located about 300 kb distal to the F8 gene at the telomeric end of the X chromosome. Most inversion mutations originate in male germ cells, where the lack of bivalent formation may facilitate flipping of the telomeric end of the single X chromosome. <a href="#108" class="mim-tip-reference" title="Oldenburg, J., Rost, S., El-Maarri, O., Leuer, M., Olek, K., Muller, C. R., Schwaab, R. <strong>De novo factor VIII gene intron 22 inversion in a female carrier presents as a somatic mosaicism.</strong> Blood 96: 2905-2906, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11023529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11023529</a>]" pmid="11023529">Oldenburg et al. (2000)</a> reported the first instance of intron 22 inversion presenting as somatic mosaicism in a female, affecting only about 50% of lymphocyte and fibroblast cells of the proposita. Supposing a postzygotic de novo mutation as the usual cause of somatic mosaicism, the finding implies that the intron 22 inversion mutation is not restricted to meiotic cell divisions but can also occur during mitotic cell divisions, either in germ cell precursors or in somatic cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11023529" 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>Development of Factor VIII Inhibitors</em></strong></p><p>
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Approximately 10 to 20% of patients with severe hemophilia A develop antibodies, known as inhibitors, to factor VIII following treatment with exogenous factor VIII. Most of these patients have nonsense mutations or deletions in the F8 gene (<a href="#2" class="mim-tip-reference" title="Antonarakis, S. E., Kazazian, H. H., Tuddenham, G. D. <strong>Molecular etiology of factor VIII deficiency in hemophilia A.</strong> Hum. Mutat. 5: 1-22, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7728145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7728145</a>] [<a href="https://doi.org/10.1002/humu.1380050102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7728145">Antonarakis et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7728145" 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="#4" class="mim-tip-reference" title="Antonarakis, S. E., Waber, P. G., Kittur, S. D., Patel, A. S., Kazazian, H. H., Jr., Mellis, M. A., Counts, R. B., Stamatoyannopoulos, G., Bowie, E. J. W., Fass, D. N., Pittman, D. D., Wozney, J. M., Toole, J. J. <strong>Hemophilia A: detection of molecular defects and of carriers by DNA analysis.</strong> New Eng. J. Med. 313: 842-848, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2993888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2993888</a>] [<a href="https://doi.org/10.1056/NEJM198510033131402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2993888">Antonarakis et al. (1985)</a> identified several molecular defects in families with hemophilia A. One family had a deletion of about 80 kb in the F8 gene, whereas another had a single nucleotide change in the coding region of the gene, resulting in a nonsense codon and premature termination. In addition, they used 2 common polymorphic sites in the F8 gene to differentiate the normal gene from the defective gene in 4 of 6 obligate carriers from families with patients in whom inhibitors did not develop. In both the family with a large deletion and the family with premature termination, affected persons developed inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2993888" 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 variety of F8 gene mutations have been found in patients with hemophilia A due to inhibitors. Among 30 such cases, <a href="#2" class="mim-tip-reference" title="Antonarakis, S. E., Kazazian, H. H., Tuddenham, G. D. <strong>Molecular etiology of factor VIII deficiency in hemophilia A.</strong> Hum. Mutat. 5: 1-22, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7728145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7728145</a>] [<a href="https://doi.org/10.1002/humu.1380050102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7728145">Antonarakis et al. (1995)</a> found that 87% and 13% had different nonsense and missense mutations, respectively. F8 gene inversions do not seem to be a major predisposing factor for the development of inhibitors. Among severe hemophilia A cases, 16% of those without inversions and 20% of those with inversions developed inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7728145" 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="#130" class="mim-tip-reference" title="Schwaab, R., Brackmann, H.-H., Meyer, C., Seehafer, J., Kirchgesser, M., Haack, A., Olek, K., Tuddenham, E. G. D., Oldenburg, J. <strong>Haemophilia A: mutation type determines risk of inhibitor formation.</strong> Thromb. Haemost. 74: 1402-1406, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8772209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8772209</a>]" pmid="8772209">Schwaab et al. (1995)</a> found that the probability of developing factor VIII inhibitors is greater in patients with large deletions in the F8 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8772209" 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="#143" class="mim-tip-reference" title="Viel, K. R., Ameri, A., Abshire, T. C., Iyer, R. V., Watts, R. G., Lutcher, C., Channell, C., Cole, S. A., Fernstrom, K. M., Nakaya, S., Kasper, C. K., Thompson, A. R., Almasy, L., Howard, T. E. <strong>Inhibitors of factor VIII in black patients with hemophilia.</strong> New Eng. J. Med. 360: 1618-1627, 2009. Note: Erratum: New Eng. J. Med. 361: 544 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19369668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19369668</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19369668[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa075760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19369668">Viel et al. (2009)</a> sequenced the F8 gene in 78 black patients with hemophilia to identify the causative mutations and background haplotypes, which the authors designated H1 to H5. They found that 24% of the patients had an H3 or H4 haplotype, and that the prevalence of inhibitors was higher among patients with either of those haplotypes than among patients with haplotypes H1 or H2 (odds ratio, 3.6; p = 0.04), despite a similar spectrum of hemophilic mutations and degree of severity of illness in the 2 subgroups. Noting that Caucasians carry only the H1 or H2 haplotypes and that most blood donors are Caucasian, <a href="#143" class="mim-tip-reference" title="Viel, K. R., Ameri, A., Abshire, T. C., Iyer, R. V., Watts, R. G., Lutcher, C., Channell, C., Cole, S. A., Fernstrom, K. M., Nakaya, S., Kasper, C. K., Thompson, A. R., Almasy, L., Howard, T. E. <strong>Inhibitors of factor VIII in black patients with hemophilia.</strong> New Eng. J. Med. 360: 1618-1627, 2009. Note: Erratum: New Eng. J. Med. 361: 544 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19369668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19369668</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19369668[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa075760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19369668">Viel et al. (2009)</a> suggested that mismatched factor VIII replacement therapy might be a risk factor for the development of anti-factor VIII alloantibodies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19369668" 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 a Japanese family with mild to moderately severe hemophilia A, <a href="#149" class="mim-tip-reference" title="Young, M., Inaba, H., Hoyer, L. W., Higuchi, M., Kazazian, H. H., Jr., Antonarakis, S. E. <strong>Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene.</strong> Am. J. Hum. Genet. 60: 565-573, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9042915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9042915</a>]" pmid="9042915">Young et al. (1997)</a> found a deletion of a single nucleotide T within an A(8)TA(2) sequence of exon 14 of the F8 gene. The severity of the clinical phenotype did not correspond to that expected of a frameshift mutation. A small amount of functional factor VIII protein was detected in the patient's plasma. Analysis of DNA and RNA molecules from normal and affected individuals and in vitro transcription/translation suggested a partial correction of the molecular defect, because of the following: (i) DNA replication/RNA transcription errors resulted in restoration of the reading frame and/or (ii) 'ribosomal frameshifting' resulted in the production of normal factor VIII polypeptide and, thus, in a milder-than-expected hemophilia A. All of these mechanisms probably were promoted by the longer run of adenines, A(10) instead of A(8)TA(2), after the deleted T. <a href="#149" class="mim-tip-reference" title="Young, M., Inaba, H., Hoyer, L. W., Higuchi, M., Kazazian, H. H., Jr., Antonarakis, S. E. <strong>Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene.</strong> Am. J. Hum. Genet. 60: 565-573, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9042915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9042915</a>]" pmid="9042915">Young et al. (1997)</a> concluded that errors in the complex steps of gene expression therefore may partially correct a severe frameshift defect and ameliorate an expected severe phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9042915" 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="#31" class="mim-tip-reference" title="Cutler, J. A., Mitchell, M. J., Smith, M. P., Savidge, G. F. <strong>The identification and classification of 41 novel mutations in the factor VIII gene (F8C).</strong> Hum. Mutat. 19: 274-278, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11857744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11857744</a>] [<a href="https://doi.org/10.1002/humu.10056" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11857744">Cutler et al. (2002)</a> identified 81 mutations in the F8C gene in 96 unrelated patients, all of whom had previously typed negative for the common IVS22 inversion mutation (<a href="#0067">306700.0067</a>). Forty-one of these mutations were not recorded in F8C gene mutation databases. Analysis of these 41 mutations with regard to location, possible cross-species conservation, and type of substitution, in correlation with the clinical severity of the disease, supported the view that the phenotypic result of a mutation in the F8C gene correlates more with the position of the amino acid change within the 3-dimensional structure of the protein than with the actual nature of the alteration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11857744" 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>The mainstay of routine treatment for hemophilia A is infusion of factor VIII using amounts that are required to restore the factor VIII activity to therapeutic levels. Desmopressin (dDAVP), a synthetic analog of the neurohypophyseal nonapeptide arginine vasopressin (AVP; <a href="/entry/192340">192340</a>), has been approved for treatment of mild hemophilia A and von Willebrand disease. Following dDAVP in some cases concentrations of factor VIII and von Willebrand factor are transiently increased to levels that allow minor surgery (<a href="#122" class="mim-tip-reference" title="Richardson, D. W., Robinson, A. G. <strong>Desmopressin.</strong> Ann. Intern. Med. 103: 228-239, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3893256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3893256</a>] [<a href="https://doi.org/10.7326/0003-4819-103-2-228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3893256">Richardson and Robinson, 1985</a>; review by <a href="#60" class="mim-tip-reference" title="Hoyer, L. W. <strong>Hemophilia A.</strong> New Eng. J. Med. 330: 38-47, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8259143/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8259143</a>] [<a href="https://doi.org/10.1056/NEJM199401063300108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8259143">Hoyer, 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3893256+8259143" 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="#82" class="mim-tip-reference" title="Lewis, J. H., Bontempo, F. A., Spero, J. A., Ragni, M. V., Starzl, T. E. <strong>Liver transplantation in a hemophiliac.</strong> New Eng. J. Med. 312: 1189-1190, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3920523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3920523</a>] [<a href="https://doi.org/10.1056/NEJM198505023121812" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3920523">Lewis et al. (1985)</a> reported that a hemophiliac who received a liver transplant from a normal donor had nearly normal levels of factor VIII coagulant activity in the postoperative period. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3920523" 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="#100" class="mim-tip-reference" title="Nilsson, I. M., Berntorp, E., Zettervall, O. <strong>Induction of immune tolerance in patients with hemophilia and antibodies to factor VIII by combined treatment with intravenous IgG, cyclophosphamide, and factor VIII.</strong> New Eng. J. Med. 318: 947-950, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3127711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3127711</a>] [<a href="https://doi.org/10.1056/NEJM198804143181503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3127711">Nilsson et al. (1988)</a> used combined cyclophosphamide, intravenous IgG, and factor VIII therapy to induce immune tolerance to factor VIII infusions in patients with antibodies to factor VIII. Factor VIII coagulant antibodies disappeared in 9 of 11 patients so treated; the other 2 patients did not respond. Earlier treatment with either factor VIII and cyclophosphamide or factor VIII and IgG had been ineffective, suggesting that all 3 components of the protocol are necessary for the successful induction of tolerance. <a href="#113" class="mim-tip-reference" title="Pignone, A., Matucci-Cerinic, M., Morfini, M., Lombardi, A., Rossi Ferrini, P. L., Cagnoni, M. <strong>Suppression of autoantibodies to factor VIII and correction of factor VIII deficiency with a combined steroid-cyclophosphamide-porcine factor VIII treatment in a patient with rheumatoid arthritis.</strong> J. Intern. Med. 231: 617-619, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1619384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1619384</a>] [<a href="https://doi.org/10.1111/j.1365-2796.1992.tb01248.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1619384">Pignone et al. (1992)</a> had success within induction of immune tolerance in patients with hemophilia A and factor VIII inhibitors: combined treatment with gammaglobulin, cyclophosphamide, and factor VIII. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1619384+3127711" 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="#131" class="mim-tip-reference" title="Schwartz, R. S., Abildgaard, C. F., Aledort, L. M., Arkin, S., Bloom, A. L., Brackmann, H. H., Brettler, D. B., Fukui, H., Hilgartner, M. W., Inwood, M. J., Kasper, C. K., Kernoff, P. B. A., Levine, P. H., Lusher, J. M., Mannucci, P. M., Scharrer, I., MacKenzie, M. A., Pancham, N., Kuo, H. S., Allred, R. U., the Recombinant Factor VIII Study Group. <strong>Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A.</strong> New Eng. J. Med. 323: 1800-1805, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2123300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2123300</a>] [<a href="https://doi.org/10.1056/NEJM199012273232604" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2123300">Schwartz et al. (1990)</a> used antihemophilic factor produced by recombinant DNA methods in the successful treatment of hemophilia A in 107 subjects. The half-lives equaled or exceeded those of plasma-derived factor VIII, and immunogenicity appeared to be no greater. This represented a major advance because of the opportunity to avoid exposure to transfusion-associated viral diseases. F8 was one of the largest genes cloned to that time and, with the study of <a href="#131" class="mim-tip-reference" title="Schwartz, R. S., Abildgaard, C. F., Aledort, L. M., Arkin, S., Bloom, A. L., Brackmann, H. H., Brettler, D. B., Fukui, H., Hilgartner, M. W., Inwood, M. J., Kasper, C. K., Kernoff, P. B. A., Levine, P. H., Lusher, J. M., Mannucci, P. M., Scharrer, I., MacKenzie, M. A., Pancham, N., Kuo, H. S., Allred, R. U., the Recombinant Factor VIII Study Group. <strong>Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A.</strong> New Eng. J. Med. 323: 1800-1805, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2123300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2123300</a>] [<a href="https://doi.org/10.1056/NEJM199012273232604" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2123300">Schwartz et al. (1990)</a>, became the largest cloned protein to be used in clinical trials. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2123300" 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>Through a suppressive effect on premature termination codons, aminoglycoside antibiotics such as gentamicin have been used for therapeutic benefit in a number of conditions including cystic fibrosis (<a href="/entry/602421">602421</a>) and Duchenne muscular dystrophy (<a href="/entry/300377">300377</a>). <a href="#63" class="mim-tip-reference" title="James, P. D., Raut, S., Rivard, G. E., Poon, M.-C., Warner, M., McKenna, S., Leggo, J., Lillicrap, D. <strong>Aminoglycoside suppression of nonsense mutations in severe hemophilia.</strong> Blood 106: 3043-3048, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16051741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16051741</a>] [<a href="https://doi.org/10.1182/blood-2005-03-1307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16051741">James et al. (2005)</a> evaluated the effect of gentamicin on the factor VIII and factor IX levels of severe hemophiliacs with known nonsense mutations. They concluded that gentamicin was unlikely to be an effective treatment for severe hemophilia because of its potential toxicity and the minimal response observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16051741" 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 hemophilic SCID mice, <a href="#6" class="mim-tip-reference" title="Aronovich, A., Tchorsh, D., Katchman, H., Eventov-Friedman, S., Shezen, E., Martinowitz, U., Blazar, B. R., Cohen, S., Tal, O., Reisner, Y. <strong>Correction of hemophilia as a proof of concept for treatment of monogenic diseases by fetal spleen transplantation.</strong> Proc. Nat. Acad. Sci. 103: 19075-19080, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17148607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17148607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17148607[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0607012103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17148607">Aronovich et al. (2006)</a> reported successful treatment of hemophilia by transplantation of fetal pig spleen harvested at embryonic day 42 before the appearance of mature T cells. The transplanted tissue exhibited good growth and subsequent expression of factor VIII, leading to complete alleviation of hemophilia within 2 to 3 months after transplant. The results provided proof of principle that transplantation of fetal spleen can correct hemophilia while avoiding graft-versus-host disease (GVHD; see <a href="/entry/614395">614395</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17148607" 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>Development of Factor VIII Inhibitors</em></strong></p><p>
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An acquired disorder resembling hemophilia A can be caused by the development by autoantibodies against factor VIII (<a href="#104" class="mim-tip-reference" title="Nilsson, I. M., Lamme, S. <strong>On acquired hemophilia A: a survey of 11 cases.</strong> Acta Med. Scand. 208: 5-12, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6159777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6159777</a>]" pmid="6159777">Nilsson and Lamme, 1980</a>; <a href="#156" class="mim-tip-reference" title="Zimmerman, T. S., Ratnoff, O. D., Littell, A. S. <strong>Detection of carriers of classic hemophilia using an immunologic assay for antihemophilic factor (factor VIII).</strong> J. Clin. Invest. 50: 255-258, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5543880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5543880</a>] [<a href="https://doi.org/10.1172/JCI106481" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5543880">Zimmerman et al., 1971</a>). Approximately 10 to 20% of patients with severe hemophilia A develop antibodies, known as inhibitors, to factor VIII following treatment with exogenous factor VIII. Most of these patients have nonsense mutations or deletions in the F8 gene (<a href="#2" class="mim-tip-reference" title="Antonarakis, S. E., Kazazian, H. H., Tuddenham, G. D. <strong>Molecular etiology of factor VIII deficiency in hemophilia A.</strong> Hum. Mutat. 5: 1-22, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7728145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7728145</a>] [<a href="https://doi.org/10.1002/humu.1380050102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7728145">Antonarakis et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6159777+5543880+7728145" 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="Frommel, D., Muller, J. Y., Prou-Wartelle, O., Allain, J. P. <strong>Possible linkage between the major histocompatibility complex and the immune response to factor VIII in classic haemophilia.</strong> Vox Sang. 33: 270-272, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/919416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">919416</a>] [<a href="https://doi.org/10.1111/j.1423-0410.1977.tb04473.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="919416">Frommel et al. (1977)</a> studied 10 sibships of hemophilia A, each of which included 1 or 2 hemophilic brothers with antibody to factor VIII. Their results suggested linkage of the MHC (<a href="/entry/142800">142800</a>) and a gene responsible for an immune response to factor VIII. The development of factor VIII antibodies has been interpreted in terms of CRM-positivity versus CRM-negativity by others (<a href="#20" class="mim-tip-reference" title="Boyer, S. H., Siggers, D. C., Krueger, L. J. <strong>A caveat to protein replacement therapy for genetic disease. Immunologic implications of accurate molecular diagnosis.</strong> Lancet 302: 654-659, 1973. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4125628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4125628</a>] [<a href="https://doi.org/10.1016/s0140-6736(73)92489-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4125628">Boyer et al., 1973</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=919416+4125628" 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>Factor VIII inhibitors neutralize factor VIII procoagulant activity by sterically preventing the interaction of factor VIII with von Willebrand factor, phospholipids, activated factor IX, thrombin, and activated factor X. Another mechanism for inactivation of factor VIII is the proteolysis of factor VIII by anti-factor VIII antibodies. <a href="#130" class="mim-tip-reference" title="Schwaab, R., Brackmann, H.-H., Meyer, C., Seehafer, J., Kirchgesser, M., Haack, A., Olek, K., Tuddenham, E. G. D., Oldenburg, J. <strong>Haemophilia A: mutation type determines risk of inhibitor formation.</strong> Thromb. Haemost. 74: 1402-1406, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8772209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8772209</a>]" pmid="8772209">Schwaab et al. (1995)</a> found that the probability of developing factor VIII inhibitors is greater in patients with large deletions in the F8 gene (see MOLECULAR GENETICS). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8772209" 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="Lacroix-Desmazes, S., Bayry, J., Misra, N., Horn, M. P., Villard, S., Pashov, A., Stieltjes, N., d'Oiron, R., Saint-Remy, J.-M., Hoebeke, J., Kazatchkine, M. D., Kaveri, S. V. <strong>The prevalence of proteolytic antibodies against factor VIII in hemophilia A.</strong> New Eng. J. Med. 346: 662-667, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11870243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11870243</a>] [<a href="https://doi.org/10.1056/NEJMoa011979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11870243">Lacroix-Desmazes et al. (2002)</a> found significant proteolytic activity in IgG from 13 of 24 inhibitor-positive patients. No hydrolytic activity was detected in control antibodies of IgG from patients without inhibitors. The relationship between hydrolytic activity of IgG and factor VIII-neutralizing activity was not consistent. Antibodies from some patients caused hydrolysis of factor VIII at low rates, but the plasma had strong inhibitory activity; in other cases, the IgG caused hydrolysis of factor VIII at high rates, but the plasma had weak inhibitory activity; in yet other samples, there were high rates of both hydrolysis and inhibitory activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11870243" 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>
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Continuous delivery of factor VIII protein in hemophiliacs by gene therapy would represent a major clinical advance. Conceptually, retroviral vectors can permanently insert the F8 gene into DNA of the whole cell and, therefore, appear to be the most suitable vehicles for gene therapy. However, most retroviral vector systems have shown poor performance in the production of factor VIII from primary cells in vitro and in vivo. <a href="#34" class="mim-tip-reference" title="Dwarki, V. J., Belloni, P., Nijjar, T., Smith, J., Couto, L., Rabier, M., Clift, S., Berns, A., Cohen, L. K. <strong>Gene therapy for hemophilia A: production of therapeutic levels of human factor VIII in vivo in mice.</strong> Proc. Nat. Acad. Sci. 92: 1023-1027, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7862626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7862626</a>] [<a href="https://doi.org/10.1073/pnas.92.4.1023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7862626">Dwarki et al. (1995)</a> used the highly efficient MFG retroviral vector system to transfer F8 cDNA into murine and human cells (primary and established cell lines). The cDNA contained an open reading frame of 2,351 amino acids and lacked the B domain, which is not required for procoagulant activity in vitro or in vivo. In contrast to previous reports, <a href="#34" class="mim-tip-reference" title="Dwarki, V. J., Belloni, P., Nijjar, T., Smith, J., Couto, L., Rabier, M., Clift, S., Berns, A., Cohen, L. K. <strong>Gene therapy for hemophilia A: production of therapeutic levels of human factor VIII in vivo in mice.</strong> Proc. Nat. Acad. Sci. 92: 1023-1027, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7862626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7862626</a>] [<a href="https://doi.org/10.1073/pnas.92.4.1023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7862626">Dwarki et al. (1995)</a> demonstrated high transduction efficiency and a high rate of factor VIII production. They also demonstrated that factor VIII-secreting cells transplanted into immune-deficient mice gave rise to substantial levels of factor VIII in the plasma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7862626" 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="#141" class="mim-tip-reference" title="VandenDriessche, T., Vanslembrouck, V., Goovaerts, I., Zwinnen, H., Vanderhaeghen, M.-L., Collen, D., Chuah, M. K. L. <strong>Long-term expression of human coagulation factor VIII and correction of hemophilia A after in vivo retroviral gene transfer in factor VIII-deficient mice.</strong> Proc. Nat. Acad. Sci. 96: 10379-10384, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10468616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10468616</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10468616[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.18.10379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10468616">VandenDriessche et al. (1999)</a> demonstrated that hemophilia A could be corrected by in vivo gene therapy using retroviral vectors. Newborn F8-deficient mice were injected intravenously with retroviral vectors expressing high levels of human FVIII. High levels of functional human FVIII production could be detected in 6 of 13 animals, 4 of which expressed physiologic or higher levels. Five of the 6 expressors produced FVIII and survived an otherwise lethal tail clipping, demonstrating phenotypic correction of the bleeding disorder. F8 expression was sustained for more than 14 months. Gene transfer occurred into liver, spleen, and lungs, with predominant F8 mRNA expression in the liver. Six of the 7 animals with transient or no detectable human FVIII developed FVIII inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10468616" 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="#65" class="mim-tip-reference" title="Kay, M. A., High, K. <strong>Gene therapy for the hemophilias. (Commentary)</strong> Proc. Nat. Acad. Sci. 96: 9973-9975, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10468539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10468539</a>] [<a href="https://doi.org/10.1073/pnas.96.18.9973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10468539">Kay and High (1999)</a> discussed, in general terms, gene therapy for the hemophilias. They pointed out that gene therapy for factor VIII deficiency has been relatively more difficult than that for factor IX deficiency because of the large size of the F8 coding region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10468539" 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="#126" class="mim-tip-reference" title="Roth, D. A., Tawa, N. E., Jr., O'Brien, J. M., Treco, D. A., Selden, R. F. <strong>Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A.</strong> New Eng. J. Med. 344: 1735-1742, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11396439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11396439</a>] [<a href="https://doi.org/10.1056/NEJM200106073442301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11396439">Roth et al. (2001)</a> tested the safety of a nonviral somatic cell gene therapy system in patients with severe hemophilia A. Skin fibroblasts obtained by skin biopsy were transfected with a plasmid carrying sequences of the F8 gene. Cells that produced factor VIII were selected, cloned, and propagated in vitro. The cloned cells were then harvested and administered to the patients by laparoscopic injection into the omentum. Follow-up 12 months after implantation of the genetically altered cells showed no serious adverse reactions. No inhibitors of factor VIII were detected. In 4 of the 6 patients treated, plasma levels of factor VIII activity rose above the levels observed before the procedure. Coincident with the increase in factor VIII activity was a decrease in bleeding, a reduction in the use of exogenous factor VIII, or both. In the patient with the highest level of factor VIII activity, the clinical changes lasted approximately 10 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11396439" 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="Mannucci, P. M., Tuddenham, E. G. D. <strong>The hemophilias--from royal genes to gene therapy.</strong> New Eng. J. Med. 344: 1773-1779, 2001. Note: Erratum: New Eng. J. Med. 345: 384 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11396445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11396445</a>] [<a href="https://doi.org/10.1056/NEJM200106073442307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11396445">Mannucci and Tuddenham (2001)</a> reviewed the hemophilias. They stated that hemophilia is likely to be the first common severe genetic condition to be cured by gene therapy. Apart from the long-term consequences of viral infections transmitted by infected blood products, there seem to be only 2 remaining problems: first, the development of high titers of antibodies against factor VIII or factor IX, and second, the challenge to society that four-fifths of all patients with hemophilia, mainly those in developing countries, receive no treatment. They suggested that less expensive replacement therapy, such as large-scale production and purification of factor VIII and factor IX from the milk of transgenic farmyard animals, might be a solution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11396445" 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="#110" class="mim-tip-reference" title="Pasi, K. J. <strong>Gene therapy for haemophilia.</strong> Brit. J. Haemat. 115: 744-757, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11843805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11843805</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2001.03225.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11843805">Pasi (2001)</a> reviewed gene therapy for hemophilia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11843805" 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="#116" class="mim-tip-reference" title="Rangarajan, S., Walsh, L., Lester, W., Perry, D., Madan, B., Laffan, M., Yu, H., Vettermann, C., Pierce, G. F., Wong, W. Y., Pasi, K. J. <strong>AAV5-factor VIII gene transfer in severe hemophilia A.</strong> New Eng. J. Med. 377: 2519-2530, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29224506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29224506</a>] [<a href="https://doi.org/10.1056/NEJMoa1708483" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29224506">Rangarajan et al. (2017)</a> infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII in 9 men with severe hemophilia A. Participants were enrolled sequentially into 1 of 3 dose cohorts, low-dose (1 participant), intermediate-dose (1 participant), and high-dose (7 participants) and were followed through 52 weeks. Factor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all 7 participants, and the level in 6 participants increased to a normal value (greater than 50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase (ALT) level to 1.5 times the upper limit of normal or less. There was progression of preexisting chronic arthropathy in one participant. No neutralizing antibodies to factor VIII were detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29224506" 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="#41" class="mim-tip-reference" title="George, L. A., Monahan, P. E., Eyster, E., Sullivan, S. K., Ragni, M. V., Croteau, S. E., Rasko, J. E. J., Recht, M., Samelson-Jones, B. J., MacDougall, A., Jaworski, K., Noble, R., Curran, M., Kuranda, K., Mingozzi, F., Chang, T., Reape, K. Z., Anguela, X. M., High, K. A. <strong>Multiyear factor VIII expression after AAV gene transfer for hemophilia A.</strong> New Eng. J. Med. 385: 1961-1973, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34788507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34788507</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34788507[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa2104205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34788507">George et al. (2021)</a> reported results of a phase 1-2 clinical trial in 18 men with hemophilia A to evaluate the safety and efficacy of an adeno-associated viral vector with cDNA encoding a B-domain-deleted form of factor VIII on a liver-specific enhancer and promoter. The average observation period was 36.6 months. There were 4 dosing cohorts in the trial, ranging from 5 x 10(11) vector genomes to 2 x 10(12) vector genomes per kilogram of body weight. Some patients received glucocorticoid therapy and other immunosuppressive therapies to prevent or treat AAV capsid immune responses. Two patients lost all factor VIII expression due to an anti-AAV capsid cellular response that was not sensitive to immune suppression. Sustained and stable factor VIII expression was achieved in 16 of 18 patients, allowing for discontinuation of factor VIII prophylactic therapy and reduction in bleeding episodes to fewer than 1 per year. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34788507" 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="#109" class="mim-tip-reference" title="Ozelo, M. C., Mahlangu, J., Pasi, K. J., Giermasz, A., Leavitt, A. D., Laffan, M., Symington, E., Quon, D. V., Wang, J. D., Peerlinck, K., Pipe, S. W., Madan, B., and 11 others. <strong>Valoctocogene roxaparvovec gene therapy for hemophilia A.</strong> New Eng. J. Med. 386: 1013-1025, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35294811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35294811</a>] [<a href="https://doi.org/10.1056/NEJMoa2113708" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35294811">Ozelo et al. (2022)</a> reported results of an open-label, single-group, multicenter, phase 3 study to evaluate the safety and efficacy of a single infusion of valoctocogene roxaparvovec, an adeno-associated virus 5 (AAV5)-based gene therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter, among 134 men with severe hemophilia A. The infusion substantially increased factor VIII activity when measured at 49 to 52 weeks after dosing, with a median factor VIII activity level of 5 IU/dl or higher in 88.1% of participants. The gene therapy treatment also reduced the annualized rates of factor VIII concentrate use by 98.6% and of treated bleeding by 83.8% compared with factor VIII prophylaxis. Elevations in alanine aminotransferase levels occurred in 85.8% of those treated and were managed with glucocorticoids. Serious adverse events that were determined to be related to the study drug were seen in 3.7%; all serious adverse events resolved. No patients developed factor VIII inhibitors or thrombotic events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35294811" 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="Mahlangu, J., Kaczmarek, R., von Drygalski, A., Shapiro, S., Chou, S.-C., Ozelo, M. C., Kenet, G., Peyvandi, F., Wang, M., Madan, B., Key, N. S., Laffan, M., and 18 others. <strong>Two-year outcomes of valoctocogene roxaparvovec therapy for hemophilia A.</strong> New Eng. J. Med. 388: 694-705, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36812433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36812433</a>] [<a href="https://doi.org/10.1056/NEJMoa2211075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36812433">Mahlangu et al. (2023)</a> reported the 104-week follow-up results of the 134 participants in the valoctocogene roxaparvovec phase III gene therapy trial reported by <a href="#109" class="mim-tip-reference" title="Ozelo, M. C., Mahlangu, J., Pasi, K. J., Giermasz, A., Leavitt, A. D., Laffan, M., Symington, E., Quon, D. V., Wang, J. D., Peerlinck, K., Pipe, S. W., Madan, B., and 11 others. <strong>Valoctocogene roxaparvovec gene therapy for hemophilia A.</strong> New Eng. J. Med. 386: 1013-1025, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35294811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35294811</a>] [<a href="https://doi.org/10.1056/NEJMoa2113708" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35294811">Ozelo et al. (2022)</a>. The mean annualized treated bleeding rate decreased by 84.5% from baseline (p less than 0.001) among the treated participants. The risk of joint bleeding was estimated at 1.0 episodes per year. At 2 years postinfusion, no new safety signals or serious adverse events related to treatment were reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=36812433+35294811" 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>The incidence of hemophilia A, caused by a deficiency of factor VIII, is estimated at about 1 in 5,000 male live births. Hemophilia B, caused by a deficiency of factor IX, is estimated at about 1 in 30,000 male live births (<a href="#85" class="mim-tip-reference" title="Mannucci, P. M., Tuddenham, E. G. D. <strong>The hemophilias--from royal genes to gene therapy.</strong> New Eng. J. Med. 344: 1773-1779, 2001. Note: Erratum: New Eng. J. Med. 345: 384 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11396445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11396445</a>] [<a href="https://doi.org/10.1056/NEJM200106073442307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11396445">Mannucci and Tuddenham, 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11396445" 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="#135" class="mim-tip-reference" title="Soucie, J. M., Evatt, B., Jackson, D., Hemophilia Surveillance System Project Investigators. <strong>Occurrence of hemophilia in the United States.</strong> Am. J. Hemat. 59: 288-294, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9840909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9840909</a>] [<a href="https://doi.org/10.1002/(sici)1096-8652(199812)59:4<288::aid-ajh4>3.0.co;2-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9840909">Soucie et al. (1998)</a> studied the frequency of hemophilia A and hemophilia B in 6 U.S. states: Colorado, Georgia, Louisiana, Massachusetts, New York, and Oklahoma. A hemophilia case was defined as a person with physician-diagnosed hemophilia A or B and/or a measured baseline factor VIII or IX activity (FA) of 30% or less. Case-finding methods included patient reports from physicians, clinical laboratories, hospitals, and hemophilia treatment centers. Once identified, trained data abstractors collected clinical and outcome data retrospectively from medical records. Among cases identified in 1993 to 1995, 2,743 were residents of the 6 states in 1994, of whom 2,156 (79%) had hemophilia A. Of those with factor VIII measurements, 1,140 (43%) had severe (FA less than 1%), 684 (26%) had moderate (FA of 1-5%), and 848 (31%) had mild (FA of 6-30%) disease. The age-adjusted prevalence of hemophilia in all 6 states in 1994 was 13.4 cases per 100,000 males (10.5 hemophilia A and 2.9 hemophilia B). The prevalence by race/ethnicity was 13.2 cases per 100,000 white, 11.0% among African American, and 11.5% among Hispanic males. Application of age-specific prevalence rates from the 6 surveillance states to the U.S. population resulted in an estimated national population of 13,320 cases of hemophilia A and 3,640 cases of hemophilia B. For the 10-year period 1982 to 1991, the average incidence of hemophilia A and B in the 6 surveillance states was estimated to be 1 in 5,032 live male births. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9840909" 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>Earlier it was assumed that the hemophilia gene was lethal in homozygous females. That this was not the case was first demonstrated in the dog by <a href="#23" class="mim-tip-reference" title="Brinkhous, K. M., Graham, J. B. <strong>Hemophilia in the female dog.</strong> Science 111: 723-724, 1950.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15431070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15431070</a>] [<a href="https://doi.org/10.1126/science.111.2896.723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15431070">Brinkhous and Graham (1950)</a> who studied homozygous hemophilic female dogs. Splenic transplantation to dogs with hemophilia A corrects the coagulation defect (<a href="#106" class="mim-tip-reference" title="Norman, J. C., Covelli, V. H., Sise, H. S. <strong>Transplantation of the spleen. (Editorial)</strong> Ann. Intern. Med. 78: 700-704, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4868461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4868461</a>] [<a href="https://doi.org/10.7326/0003-4819-68-3-700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4868461">Norman et al., 1968</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15431070+4868461" 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="#83" class="mim-tip-reference" title="Lozier, J. N., Dutra, A., Pak, E., Zhou, N., Zheng, Z., Nichols, T. C., Bellinger, D. A., Read, M., Morgan, R. A. <strong>The Chapel Hill hemophilia A dog colony exhibits a factor VIII gene inversion.</strong> Proc. Nat. Acad. Sci. 99: 12991-12996, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12242334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12242334</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12242334[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.192219599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12242334">Lozier et al. (2002)</a> studied the nature of the molecular defect in the F8 gene in the Chapel Hill colony of factor VIII-deficient dogs started by <a href="#23" class="mim-tip-reference" title="Brinkhous, K. M., Graham, J. B. <strong>Hemophilia in the female dog.</strong> Science 111: 723-724, 1950.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15431070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15431070</a>] [<a href="https://doi.org/10.1126/science.111.2896.723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15431070">Brinkhous and Graham (1950)</a>. They found that the defect in these dogs replicates the F8 gene inversion (<a href="#0067">306700.0067</a>) commonly seen in humans with severe hemophilia A. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12242334+15431070" 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>Conventional gene therapy of hemophilia A relies on the transfer of F8 cDNA. <a href="#25" class="mim-tip-reference" title="Chao, H., Mansfield, S. G., Bartel, R. C., Hiriyanna, S., Mitchell, L. G., Garcia-Blanco, M. A., Walsh, C. E. <strong>Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing.</strong> Nature Med. 9: 1015-1019, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12847523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12847523</a>] [<a href="https://doi.org/10.1038/nm900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12847523">Chao et al. (2003)</a> adopted a different approach to the molecular treatment of hemophilia A in mice. They carried out spliceosome-mediated RNA trans-splicing (SMaRT) to repair mutant F8 mRNA. A pre-trans-splicing molecule (PTM) corrected endogenous F8 mRNA in F8 knockout mice with the hemophilia A phenotype, producing sufficient functional factor VIII to correct the hemophilia A phenotype. The results indicated the feasibility of using SMaRT to repair RNA for the treatment of genetic diseases. The use of mRNA repair may circumvent the problems associated with conventional methods of delivering full-length cDNA for gene therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12847523" 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>Early reports of hemophilia families emanated from this country beginning with a newspaper account in 1792 (<a href="#87" class="mim-tip-reference" title="McKusick, V. A. <strong>Hemophilia in early New England: a follow-up of four kindreds in which hemophilia occurred in pre-Revolutionary period.</strong> J. Hist. Med. 17: 342-365, 1962."None>McKusick, 1962</a>) and continuing with medical reports by Otto in 1803 and Hay in 1813 (<a href="#87" class="mim-tip-reference" title="McKusick, V. A. <strong>Hemophilia in early New England: a follow-up of four kindreds in which hemophilia occurred in pre-Revolutionary period.</strong> J. Hist. Med. 17: 342-365, 1962."None>McKusick, 1962</a>). <a href="#28" class="mim-tip-reference" title="Cone, T. E., Jr. <strong>A case of hereditary hemorrhagic tendency (hemophilia) reported in 1832 by a physician practicing in Simpsonville, Kentucky.</strong> Pediatrics 64: 291, 1979."None>Cone (1979)</a> called attention to an amazingly clear description of the genetics and rheumatic complications of hemophilia by Dr. James N. Hughes of Simpsonville, Kentucky, in 1832.</p><p>Although the type of hemophilia, hemophilia A or hemophilia B, is not known, the occurrence of hemophilia in the last Tsar of Russia and other descendants of Queen Victoria through the maternal lines is well documented (<a href="#90" class="mim-tip-reference" title="McKusick, V. A. <strong>The royal hemophilia.</strong> Sci. Am. 213(2): 88-95, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14319025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14319025</a>] [<a href="https://doi.org/10.1038/scientificamerican0865-88" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14319025">McKusick, 1965</a>). <a href="#43" class="mim-tip-reference" title="Gill, P., Ivanov, P. L., Kimpton, C., Piercy, R., Benson, N., Tully, G., Evett, I., Hagelberg, E., Sullivan, K. <strong>Identification of the remains of the Romanov family by DNA analysis.</strong> Nature Genet. 6: 130-135, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162066</a>] [<a href="https://doi.org/10.1038/ng0294-130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162066">Gill et al. (1994)</a> reported DNA studies on 9 skeletons found in a shallow grave in Ekaterinburg, Russia, in July 1991 and tentatively identified by Russian forensic authorities as the remains of the last Tsar, Tsarina, 3 of their 5 children, the Royal Physician and 3 servants. DNA-based sex testing and short-tandem repeat analysis confirmed that a family group was present in the grave. Analysis of mitochondrial DNA revealed an exact sequence match between the putative Tsarina and the 3 children and a living maternal relative. Amplified mtDNA extracted from the remains of the putative Tsar demonstrated heteroplasmy at a single base within the mtDNA control region. One of these sequences matched 2 living maternal relatives of the Tsar. The DNA data indicated that 1 of the princesses and Tsarevich Alexei were missing from the grave. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14319025+8162066" 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 paternal age effect may have been operative in the case of the 'royal hemophilia' in the descendants of Queen Victoria who was clearly a carrier. There were no earlier cases in the family and Victoria's father was 52 years old at the time of her birth (<a href="#90" class="mim-tip-reference" title="McKusick, V. A. <strong>The royal hemophilia.</strong> Sci. Am. 213(2): 88-95, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14319025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14319025</a>] [<a href="https://doi.org/10.1038/scientificamerican0865-88" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14319025">McKusick, 1965</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14319025" 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 identification of the remains of the Romanov family by DNA analysis (<a href="#43" class="mim-tip-reference" title="Gill, P., Ivanov, P. L., Kimpton, C., Piercy, R., Benson, N., Tully, G., Evett, I., Hagelberg, E., Sullivan, K. <strong>Identification of the remains of the Romanov family by DNA analysis.</strong> Nature Genet. 6: 130-135, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162066</a>] [<a href="https://doi.org/10.1038/ng0294-130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162066">Gill et al., 1994</a>; <a href="#62" class="mim-tip-reference" title="Ivanov, P. L., Wadhams, M. J., Roby, R. K., Holland, M. M., Weedn, V. W., Parsons, T. J. <strong>Mitochondrial DNA sequence heteroplasmy in the Grand Duke of Russia Georgij Romanov establishes the authenticity of the remains of Tsar Nicholas II.</strong> Nature Genet. 12: 417-420, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8630496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8630496</a>] [<a href="https://doi.org/10.1038/ng0496-417" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8630496">Ivanov et al., 1996</a>) and the laying to rest of the Romanov bones 80 years to the day after their assassination (17 July 1998) prompted <a href="#137" class="mim-tip-reference" title="Stevens, R. F. <strong>The history of haemophilia in the royal families of Europe.</strong> Brit. J. Haemat. 105: 25-32, 1999. Note: Erratum: Brit. J. Haemat. 107: 905 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10366244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10366244</a>]" pmid="10366244">Stevens (1999)</a> to review the history of hemophilia in the royal families of Europe, with a pedigree chart. In the studies reported by <a href="#43" class="mim-tip-reference" title="Gill, P., Ivanov, P. L., Kimpton, C., Piercy, R., Benson, N., Tully, G., Evett, I., Hagelberg, E., Sullivan, K. <strong>Identification of the remains of the Romanov family by DNA analysis.</strong> Nature Genet. 6: 130-135, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162066</a>] [<a href="https://doi.org/10.1038/ng0294-130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162066">Gill et al. (1994)</a> and <a href="#62" class="mim-tip-reference" title="Ivanov, P. L., Wadhams, M. J., Roby, R. K., Holland, M. M., Weedn, V. W., Parsons, T. J. <strong>Mitochondrial DNA sequence heteroplasmy in the Grand Duke of Russia Georgij Romanov establishes the authenticity of the remains of Tsar Nicholas II.</strong> Nature Genet. 12: 417-420, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8630496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8630496</a>] [<a href="https://doi.org/10.1038/ng0496-417" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8630496">Ivanov et al. (1996)</a>, 5 of the bodies were clearly related, and 3 were those of female sibs. Furthermore, a sample of maternally inherited mtDNA suspected of belonging to Tsarina Alexandra matched a sample generously donated by her grandnephew, Philip Duke of Edinburgh. Finding a reference sample for Nicholas proved more difficult. Two distant relatives with the same matrilineage agreed to help. The mtDNA sequences the Tsar's 2 relatives were identical to each other, but where the relatives had a T at nucleotide 16169, the bone mtDNA of Nicholas surprisingly had a C. <a href="#43" class="mim-tip-reference" title="Gill, P., Ivanov, P. L., Kimpton, C., Piercy, R., Benson, N., Tully, G., Evett, I., Hagelberg, E., Sullivan, K. <strong>Identification of the remains of the Romanov family by DNA analysis.</strong> Nature Genet. 6: 130-135, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162066</a>] [<a href="https://doi.org/10.1038/ng0294-130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162066">Gill et al. (1994)</a> concluded that this represented heteroplasmy with 2 populations of mitochondria within his cells that contained either a C or a T at this position. He estimated, furthermore, the probability of the remains belonging to the Tsar as being 98.5%. The Russian Orthodox Church demanded more evidence, leading to the exhumation of the Grand Duke Georgij Romanov, who had died before his brother of tuberculosis. Bone samples were studied at the Armed Forces Institute of Pathology DNA Identification Laboratory in Maryland. Analysis was carried out at the request of the Russian federal government. Results showed that the mtDNA of both Grand Duke Georgij and Tsar Nicholas had the same heteroplasmy. This was the first time that heteroplasmy had been applied in human identification. <a href="#62" class="mim-tip-reference" title="Ivanov, P. L., Wadhams, M. J., Roby, R. K., Holland, M. M., Weedn, V. W., Parsons, T. J. <strong>Mitochondrial DNA sequence heteroplasmy in the Grand Duke of Russia Georgij Romanov establishes the authenticity of the remains of Tsar Nicholas II.</strong> Nature Genet. 12: 417-420, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8630496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8630496</a>] [<a href="https://doi.org/10.1038/ng0496-417" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8630496">Ivanov et al. (1996)</a> calculated a likelihood ratio for the authenticity of the remains in excess of 100 million to 1, not including other anthropologic and forensic evidence. The events of 17 July 1998 emphasized the gap between church and science. The patriarch Alexksi II continued to insist that DNA tests were fallible; the Archbishop of St. Petersburg did not attend the burial service at the ancestral church of the Peter and Paul Fortress in St. Petersburg. The remains of Tsarevich Alexis and one of his sisters, possibly Maria, were not found. The most famous claimant to the title of Anastasia was Anna Anderson, who died in 1984 in the United States and was cremated, but 4 years previously had undergone emergency surgery for an ovarian tumor. DNA fingerprinting by several groups on the laparotomy material dismissed the posthumous claims of Anna Anderson (<a href="#44" class="mim-tip-reference" title="Gill, P., Kimpton, C., Aliston-Greiner, R., Sullivan, K., Stoneking, M., Melton, T., Nott, J., Barritt, S., Roby, R., Holland, M., Weedn, V. <strong>Establishing the identity of Anna Anderson Manahan. (Letter)</strong> Nature Genet. 9: 9-10, 1995. Note: Erratum: Nature Genet. 9: 218 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7704032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7704032</a>] [<a href="https://doi.org/10.1038/ng0195-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7704032">Gill et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8630496+10366244+7704032+8162066" 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="#137" class="mim-tip-reference" title="Stevens, R. F. <strong>The history of haemophilia in the royal families of Europe.</strong> Brit. J. Haemat. 105: 25-32, 1999. Note: Erratum: Brit. J. Haemat. 107: 905 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10366244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10366244</a>]" pmid="10366244">Stevens (1999)</a> also reviewed hemophilia in the Spanish royal family and the medical history of Victoria's hemophilic son, Leopold. His birth was a landmark for other reasons. Dr. John Snow (who later identified the water pump in Broad Street as the source of the London cholera outbreak) administered chloroform to Victoria in childbirth with Leopold and created a breakthrough in anesthesia. Leopold was a severe hemophiliac. Queen Victoria was obviously ashamed of Leopold and spoke of him disparagingly. Because of his incapacity and confinement to bed for protracted periods, he read widely and was undoubtedly the most intelligent and intellectual of Victoria's children. Leopold's letters recounted his problems with the arthropathy of hemophilia. At the age of 24, Leopold became one of his mother's private secretaries and had access to state papers. In 1881, Victoria created Leopold Duke of Albany and the following year he married Princess Helena of Waldeck, sister of the Dutch Queen. They had 2 children. Princess Alice was an obligate carrier and had a hemophilic son (Rupert, Viscount Trematon) who died in 1928 at the age of 21. Charles Edward Leopold was born posthumously, as his father had died at the age of 31 after a fall down a staircase in Cannes causing intracranial hemorrhage. Victoria's father did not have hemophilia but apparently did have porphyria, inherited from his father, George III. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10366244" 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="Mannucci, P. M., Tuddenham, E. G. D. <strong>The hemophilias--from royal genes to gene therapy.</strong> New Eng. J. Med. 344: 1773-1779, 2001. Note: Erratum: New Eng. J. Med. 345: 384 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11396445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11396445</a>] [<a href="https://doi.org/10.1056/NEJM200106073442307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11396445">Mannucci and Tuddenham (2001)</a> stated that none of the descendants of Queen Victoria who were known to be affected were alive; the last one, Waldemar, died in 1945. They stated, however, that Victoria's great-great-granddaughter Olympia, from the Spanish branch, had a son, Paul Alexander, who died in childhood of a 'blood' disorder, and she may therefore be the last surviving carrier, testing of whom might determine the nature of the type of hemophilia, A or B, and perhaps even the precise mutation in the royal family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11396445" 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="#119" class="mim-tip-reference" title="Ratnoff, O. D., Lewis, J. H. <strong>Heckathorn's disease: variable functional deficiency of antihemophilic factor (factor VIII).</strong> Blood 46: 161-173, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1139038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1139038</a>]" pmid="1139038">Ratnoff and Lewis (1975)</a> described a family with a bizarre X-linked bleeding disorder that probably represents a variant of hemophilia A. They called it Heckathorn disease after one of the affected persons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1139038" 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="#145" class="mim-tip-reference" title="Wacey, A. I., Kemball-Cook, G., Kazazian, H. H., Antonarakis, S. E., Schwaab, R., Lindley, P., Tuddenham, E. G. D. <strong>The haemophilia A mutation search test and resource site, home page of the factor VIII mutation database: HAMSTeRS.</strong> Nucleic Acids Res. 24: 100-102, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8594555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8594555</a>] [<a href="https://doi.org/10.1093/nar/24.1.100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8594555">Wacey et al. (1996)</a> described HAMSTeRS (the hemophilia A mutation search test and resource site), the homepage of the factor VIII mutation database maintained in the unit of EDG Tuddenham at Royal Postgraduate Medical School in London. The authors discussed how to access the database via the Internet. <a href="#67" class="mim-tip-reference" title="Kemball-Cook, G., Tuddenham, E. G. D. <strong>The factor VIII mutation database on the World Wide Web: the haemophilia A mutation, search, test and resource site. HAMSTeRS update (version 3.0).</strong> Nucleic Acids Res. 25: 128-132, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9016520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9016520</a>] [<a href="https://doi.org/10.1093/nar/25.1.128" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9016520">Kemball-Cook and Tuddenham (1997)</a> gave further information on the HAMSTeRS database which had been completely updated with easy submission for point mutations, deletions, and insertions via e-mail of custom-designed forms. A methods section devoted to mutation detection had been added, highlighting issues such as choice of technique and PCR primer sequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8594555+9016520" 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 href="#Antonarakis1987" class="mim-tip-reference" title="Antonarakis, S. E., Youssoufian, H., Kazazian, H. H. <strong>Molecular genetics of hemophilia-A in man (factor VIII deficiency).</strong> Molec. Biol. Med. 4: 81-95, 1987.">Antonarakis et al. (1987)</a>; <a href="#Arrants1962" class="mim-tip-reference" title="Arrants, J. E., Jordan, P. H., Jr., Newcomb, T. F. <strong>Von Willebrand's disease: a cause for massive postoperative bleeding--report of a case.</strong> Ann. Surg. 156: 845-851, 1962.">Arrants et al. (1962)</a>; <a href="#Bennett1974" class="mim-tip-reference" title="Bennett, B., Ratnoff, O. D. <strong>Deletion of the carrier state for classic hemophilia.</strong> New Eng. J. Med. 7: 342-345, 1974.">Bennett and Ratnoff
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(1974)</a>; <a href="#Bennett1970" class="mim-tip-reference" title="Bennett, E., Huehns, E. R. <strong>Immunological differentiation of three types of hemophilia and identification of some female carriers.</strong> Lancet 296: 956-958, 1970. Note: Originally Volume 2.">Bennett and Huehns (1970)</a>; <a href="#Bernardi1989" class="mim-tip-reference" title="Bernardi, F., Volinia, S., Patracchini, P., Gemmati, D., Boninsegna, S., Schwienbacher, C., Marchetti, G. <strong>A recurrent missense mutation (arg-to-gln) and a partial deletion in factor VIII gene causing severe haemophilia A.</strong> Brit. J. Haemat. 71: 271-276, 1989.">Bernardi et al. (1989)</a>; <a href="#Chediak1980" class="mim-tip-reference" title="Chediak, J., Telfer, M. C., Jaojaroenkul, T., Green, D. <strong>Lower factor VIII coagulant activity in daughters of subjects with hemophilia A compared to other obligate carriers.</strong> Blood 55: 552-558, 1980.">Chediak et
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al. (1980)</a>; <a href="#Edgell1978" class="mim-tip-reference" title="Edgell, C.-J. S., Kirkman, H. N., Clemons, E., Buchanan, P. D., Miller, C. H. <strong>Prenatal diagnosis by linkage: hemophilia A and polymorphic glucose-6-phosphate dehydrogenase.</strong> Am. J. Hum. Genet. 30: 80-84, 1978.">Edgell et al. (1978)</a>; <a href="#Firshein1979" class="mim-tip-reference" title="Firshein, S. I., Hoyer, L. W., Lazarchick, J., Forget, B. G., Hobbins, J. C., Clyne, L. P., Pitlick, F. A., Muir, W. A., Merkatz, I. R., Mahoney, M. J. <strong>Prenatal diagnosis of classic hemophilia.</strong> New Eng. J. Med. 300: 937-941, 1979.">Firshein et al. (1979)</a>; <a href="#Gitschier1985" class="mim-tip-reference" title="Gitschier, J., Wood, W. I., Tuddenham, E. G. D., Shuman, M. A., Goralka, T. M., Chen, E. Y., Lawn, R. M. <strong>Detection and sequence of mutations in the factor VIII gene of haemophiliacs.</strong> Nature 315: 427-430, 1985.">Gitschier
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et al. (1985)</a>; <a href="#Grozdea1969" class="mim-tip-reference" title="Grozdea, J., Colombies, P., Bierme, R., Ducos, J. <strong>Myeloperoxidases and genetics of haemophilia A. (Letter)</strong> Lancet 294: 220 only, 1969. Note: Originally Volume II.">Grozdea et al. (1969)</a>; <a href="#Hemker1980" class="mim-tip-reference" title="Hemker, H. C., Muller, A. D., Hermens, W. T., Zwaal, R. F. A. <strong>Oral treatment of hemophilia A by gastrointestinal absorption of factor VIII entrapped in liposomes.</strong> Lancet 315: 70-71, 1980. Note: Originally Volume I.">Hemker et al. (1980)</a>; <a href="#Kazazian1988" class="mim-tip-reference" title="Kazazian, H. H., Jr., Wong, C., Youssoufian, H., Scott, A. F., Phillips, D. G., Antonarakis, S. E. <strong>Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man.</strong> Nature 332: 164-166, 1988.">Kazazian
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et al. (1988)</a>; <a href="#Kitchens1980" class="mim-tip-reference" title="Kitchens, C. S. <strong>Occult hemophilia.</strong> Johns Hopkins Med. J. 146: 255-259, 1980.">Kitchens (1980)</a>; <a href="#Klein1977" class="mim-tip-reference" title="Klein, H. G., Aledort, L. M., Bouma, B. N., Hoyer, L. W., Zimmerman, T. S., De Mets, D. L. <strong>A co-operative study for the detection of the carrier state of classic hemophilia.</strong> New Eng. J. Med. 296: 959-962, 1977.">Klein et al. (1977)</a>; <a href="#Kogan1990" class="mim-tip-reference" title="Kogan, S., Gitschier, J. <strong>Mutations and a polymorphism in the factor VIII gene discovered by denaturing gradient gel electrophoresis.</strong> Proc. Nat. Acad. Sci. 87: 2092-2096, 1990.">Kogan and
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Gitschier (1990)</a>; <a href="#Krepelova1992" class="mim-tip-reference" title="Krepelova, A., Vorlova, Z., Zavadil, J., Brdicka, R. <strong>Factor VIII gene deletions in haemophilia A patients in Czechoslovakia.</strong> Brit. J. Haemat. 81: 271-276, 1992.">Krepelova et al. (1992)</a>; <a href="#Lavergne1992" class="mim-tip-reference" title="Lavergne, J. M., Bahnak, B. R., Vidaud, M., Laurian, Y., Meyer, D. <strong>A directed search for mutations in hemophilia A using restriction enzyme analysis and denaturing gradient gel electrophoresis: a study of seven exons in the factor VIII gene of 170 cases.</strong> Nouv. Rev. Fr. Hematol. 34: 85-91, 1992.">Lavergne et al. (1992)</a>; <a href="#Lawn1985" class="mim-tip-reference" title="Lawn, R. M. <strong>The molecular genetics of hemophilia: blood clotting factors VIII and IX.</strong> Cell 42: 405-406, 1985.">Lawn (1985)</a>; <a href="#Levinson1987" class="mim-tip-reference" title="Levinson, B., Janco, R., Phillips, J., III, Gitschier, J. <strong>A novel missense mutation in the factor VIII gene identified by analysis of amplified hemophilia DNA sequences.</strong> Nucleic Acids Res. 15: 9797-9805, 1987.">Levinson et al. (1987)</a>; <a href="#Levinson1990" class="mim-tip-reference" title="Levinson, B., Lehesjoki, A.-E., de la Chapelle, A., Gitschier, J. <strong>Molecular analysis of hemophilia A mutations in the Finnish population.</strong> Am. J. Hum. Genet. 46: 53-62, 1990.">Levinson et al. (1990)</a>; <a href="#Mazurier2002" class="mim-tip-reference" title="Mazurier, C., Parquet-Gernez, A., Gaucher, C., Lavergne, J.-M., Goudemand, J. <strong>Factor VIII deficiency not induced by FVIII gene mutation in a female first cousin of two brothers with haemophilia A.</strong> Brit. J. Haemat. 119: 390-392, 2002.">Mazurier
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et al. (2002)</a>; <a href="#McKusick1962" class="mim-tip-reference" title="McKusick, V. A. <strong>The earliest record of hemophilia in America?</strong> Blood 19: 243-244, 1962.">McKusick (1962)</a>; <a href="#Mibashan1980" class="mim-tip-reference" title="Mibashan, R. S., Peake, I. R., Rodeck, C. H., Thumpston, J. K., Furlong, R. A., Gorer, R., Bains, L., Bloom, A. L. <strong>Dual diagnosis of prenatal haemophilia A by measurement of fetal factor VIIIC and VIIIC antigen (VIIICAg).</strong> Lancet 316: 994-997, 1980. Note: Originally Volume II.">Mibashan et al. (1980)</a>; <a href="#Mori1979" class="mim-tip-reference" title="Mori, P. G., Pasino, M., Vadala, C. R., Bisogni, M. C., Tonini, G. P., Scarabicchi, S. <strong>Haemophilia 'A' in a 46,X,i(Xq) female.</strong> Brit. J. Haemat. 43: 143-147, 1979.">Mori et al.
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(1979)</a>; <a href="#Nilsson1962" class="mim-tip-reference" title="Nilsson, I. M., Blomback, M., Ramgren, O., Von Francken, I. <strong>Haemophilia in Sweden. II. Carriers of haemophilia A and B.</strong> Acta Med. Scand. 171: 223-235, 1962.">Nilsson et al. (1962)</a>; <a href="#Nilsson1966" class="mim-tip-reference" title="Nilsson, I. M., Blomback, M., Ramgren, O. <strong>Investigations on hemophilia A and B carriers.</strong> Bibl. Haemat. 26: 26-29, 1966.">Nilsson et al. (1966)</a>; <a href="#Patterson1989" class="mim-tip-reference" title="Patterson, M., Gitschier, J., Bloomfield, J., Bell, M., Dorkins, H., Froster-Iskenius, U., Sommer, S., Sobell, J., Schaid, D., Thibodeau, S., Davies, K. E. <strong>An intronic region within the human factor VIII gene is duplicated within Xq28 and is homologous to the polymorphic locus DXS115 (767).</strong> Am. J. Hum. Genet. 44: 679-685, 1989.">Patterson et
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al. (1989)</a>; <a href="#Reiner1992" class="mim-tip-reference" title="Reiner, A. P., Stray, S. M., Thompson, A. R. <strong>Three missense mutations in Arg codons of the factor VIII gene of mild to moderately severe hemophilia A patients.</strong> Thromb. Res. 66: 93-99, 1992.">Reiner et al. (1992)</a>; <a href="#Schiffman1966" class="mim-tip-reference" title="Schiffman, S., Rapaport, S. I. <strong>Increased factor VIII levels in suspected carriers of hemophilia A: taking contraceptives by mouth.</strong> New Eng. J. Med. 275: 599, 1966.">Schiffman and Rapaport (1966)</a>; <a href="#Seligsohn1979" class="mim-tip-reference" title="Seligsohn, U., Zivelin, A., Perez, C., Modan, M. A. <strong>Detection of hemophilia A carriers by replicate factor VIII activity and factor VIII antigenicity determinations.</strong> Brit. J. Haemat. 42: 433-439, 1979.">Seligsohn et al. (1979)</a>; <a href="#Sukarova2001" class="mim-tip-reference" title="Sukarova, E., Dimovski, A. J., Tchacarova, P., Petkov, G. H., Efremov, G. D. <strong>An Alu insert as the cause of a severe form of hemophilia A.</strong> Acta Haemat. 106: 126-129, 2001.">Sukarova et al. (2001)</a>; <a href="#Youssoufian1987" class="mim-tip-reference" title="Youssoufian, H., Antonarakis, S. E., Kasper, C. K., Phillips, D. G., Kazazian, H. H., Jr. <strong>The spectrum and origin of mutations in hemophilia A. (Abstract)</strong> Am. J. Hum. Genet. 41: A249 only, 1987.">Youssoufian et al.
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(1987)</a>; <a href="#Youssoufian1988" class="mim-tip-reference" title="Youssoufian, H., Wong, C., Aronis, S., Platokoukis, H., Kazazian, H. H., Jr., Antonarakis, S. E. <strong>Moderately severe hemophilia A resulting from glu-to-gly substitution in exon 7 of the factor VIII gene.</strong> Am. J. Hum. Genet. 42: 867-871, 1988.">Youssoufian et al. (1988)</a>; <a href="#Zimmerman1971" class="mim-tip-reference" title="Zimmerman, T. S., Ratnoff, O. D., Powell, A. E. <strong>Immunologic differentiation of classic hemophilia (factor VIII deficiency) and von Willebrand's disease, with observations on combined deficiencies of antihemophilic factor and proaccelerin (factor V) and on an acquired circulating anticoagulant against antihemophilic factor.</strong> J. Clin. Invest. 50: 244-245, 1971.">Zimmerman et al. (1971)</a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2888005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2888005</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2888005" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Aronovich, A., Tchorsh, D., Katchman, H., Eventov-Friedman, S., Shezen, E., Martinowitz, U., Blazar, B. R., Cohen, S., Tal, O., Reisner, Y.
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[<a href="https://doi.org/10.1016/s0140-6736(86)90672-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(70)92129-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00283618" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1365-2141.1989.tb04266.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5201386" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(76)92523-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM196202012660502" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(73)92489-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/5.12.1945" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.111.2896.723" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.28.10.672" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nm900" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00278187" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI107853" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(69)91464-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa2211075" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM200106073442307" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/scientificamerican0865-88" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(80)92155-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1993.1134" target="_blank">Full Text</a>]
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<strong>Haemophilia 'A' in a 46,X,i(Xq) female.</strong>
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[<a href="https://doi.org/10.1111/j.1365-2141.1979.tb03729.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0140-6736(91)92450-g" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0140-6736(92)93080-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/2.1.11" target="_blank">Full Text</a>]
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Naylor, J., Brinke, A., Hassock, S., Green, P. M., Giannelli, F.
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<strong>Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions.</strong>
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[<a href="https://doi.org/10.1093/hmg/2.11.1773" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2835904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2835904</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2835904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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<li>
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<a id="156" class="mim-anchor"></a>
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<a id="Zimmerman1971" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zimmerman, T. S., Ratnoff, O. D., Littell, A. S.
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<strong>Detection of carriers of classic hemophilia using an immunologic assay for antihemophilic factor (factor VIII).</strong>
|
|
J. Clin. Invest. 50: 255-258, 1971.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5543880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5543880</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5543880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI106481" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="157" class="mim-anchor"></a>
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<a id="Zimmerman1971" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zimmerman, T. S., Ratnoff, O. D., Powell, A. E.
|
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<strong>Immunologic differentiation of classic hemophilia (factor VIII deficiency) and von Willebrand's disease, with observations on combined deficiencies of antihemophilic factor and proaccelerin (factor V) and on an acquired circulating anticoagulant against antihemophilic factor.</strong>
|
|
J. Clin. Invest. 50: 244-245, 1971.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5543879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5543879</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5543879" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI106480" target="_blank">Full Text</a>]
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</p>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 03/08/2023
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</span>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Sonja A. Rasmussen - updated : 07/26/2022<br>Hilary J. Vernon - updated : 01/13/2022<br>Ada Hamosh - updated : 03/19/2018<br>Cassandra L. Kniffin - reorganized : 4/7/2011<br>Marla J. F. O'Neill - updated : 9/10/2009<br>Cassandra L. Kniffin - updated : 5/18/2009<br>Marla J. F. O'Neill - updated : 4/30/2009<br>Cassandra L. Kniffin - updated : 12/8/2008<br>Cassandra L. Kniffin - updated : 12/3/2008<br>Marla J. F. O'Neill - updated : 7/17/2008<br>Cassandra L. Kniffin - updated : 11/13/2007<br>Cassandra L. Kniffin - updated : 4/24/2007<br>Victor A. McKusick - updated : 9/29/2006<br>Victor A. McKusick - updated : 6/20/2006<br>Cassandra L. Kniffin - updated : 5/18/2005<br>Victor A. McKusick - updated : 1/30/2004<br>Victor A. McKusick - updated : 12/23/2003<br>Victor A. McKusick - updated : 9/8/2003<br>Victor A. McKusick - updated : 8/28/2003<br>Victor A. McKusick - updated : 7/7/2003<br>Victor A. McKusick - updated : 1/10/2003<br>Victor A. McKusick - updated : 11/15/2002<br>Victor A. McKusick - updated : 6/3/2002<br>Victor A. McKusick - updated : 4/4/2002<br>Victor A. McKusick - updated : 3/14/2002<br>Victor A. McKusick - updated : 8/15/2001<br>Victor A. McKusick - updated : 2/14/2001<br>Victor A. McKusick - updated : 1/5/2001<br>Ada Hamosh - updated : 12/15/1999<br>Victor A. McKusick - updated : 10/21/1999<br>Victor A. McKusick - updated : 6/3/1999<br>Victor A. McKusick - updated : 2/14/1999<br>Victor A. McKusick - updated : 3/12/1997<br>Moyra Smith - updated : 1/29/1997<br>Stylianos E. Antonarakis - updated : 7/18/1996
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</span>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 03/08/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/06/2023<br>carol : 07/26/2022<br>carol : 03/31/2022<br>carol : 03/11/2022<br>carol : 01/13/2022<br>carol : 09/29/2020<br>carol : 06/05/2018<br>carol : 03/20/2018<br>alopez : 03/19/2018<br>carol : 01/30/2016<br>terry : 3/14/2013<br>carol : 10/10/2012<br>terry : 9/14/2012<br>carol : 5/30/2012<br>terry : 4/12/2012<br>mgross : 12/16/2011<br>carol : 12/15/2011<br>ckniffin : 12/13/2011<br>carol : 7/21/2011<br>carol : 4/7/2011<br>carol : 4/7/2011<br>carol : 4/7/2011<br>ckniffin : 4/6/2011<br>wwang : 11/2/2010<br>ckniffin : 10/8/2010<br>carol : 10/5/2010<br>carol : 10/4/2010<br>terry : 12/17/2009<br>wwang : 9/23/2009<br>terry : 9/10/2009<br>wwang : 5/20/2009<br>ckniffin : 5/18/2009<br>wwang : 5/5/2009<br>terry : 4/30/2009<br>wwang : 4/29/2009<br>terry : 3/27/2009<br>ckniffin : 12/8/2008<br>wwang : 12/4/2008<br>ckniffin : 12/3/2008<br>carol : 10/21/2008<br>terry : 9/12/2008<br>terry : 7/30/2008<br>wwang : 7/21/2008<br>terry : 7/17/2008<br>wwang : 7/14/2008<br>terry : 7/11/2008<br>wwang : 11/20/2007<br>ckniffin : 11/13/2007<br>wwang : 5/1/2007<br>ckniffin : 4/24/2007<br>wwang : 10/16/2006<br>alopez : 10/13/2006<br>terry : 9/29/2006<br>wwang : 6/20/2006<br>terry : 6/20/2006<br>wwang : 6/8/2005<br>wwang : 6/6/2005<br>ckniffin : 5/18/2005<br>carol : 4/8/2005<br>wwang : 3/24/2005<br>terry : 6/3/2004<br>carol : 3/17/2004<br>carol : 3/4/2004<br>tkritzer : 1/30/2004<br>cwells : 12/24/2003<br>terry : 12/23/2003<br>joanna : 10/6/2003<br>terry : 9/8/2003<br>tkritzer : 9/2/2003<br>tkritzer : 8/29/2003<br>tkritzer : 8/28/2003<br>alopez : 7/10/2003<br>terry : 7/7/2003<br>tkritzer : 1/14/2003<br>terry : 1/10/2003<br>cwells : 11/19/2002<br>terry : 11/15/2002<br>terry : 6/27/2002<br>cwells : 6/17/2002<br>terry : 6/3/2002<br>cwells : 4/15/2002<br>cwells : 4/10/2002<br>terry : 4/4/2002<br>alopez : 3/15/2002<br>terry : 3/14/2002<br>alopez : 1/3/2002<br>cwells : 9/7/2001<br>cwells : 8/24/2001<br>terry : 8/15/2001<br>mcapotos : 7/3/2001<br>mcapotos : 6/28/2001<br>terry : 6/26/2001<br>cwells : 2/20/2001<br>terry : 2/14/2001<br>mcapotos : 1/17/2001<br>mcapotos : 1/10/2001<br>terry : 1/5/2001<br>mcapotos : 7/25/2000<br>carol : 1/10/2000<br>alopez : 12/20/1999<br>terry : 12/15/1999<br>mgross : 10/28/1999<br>terry : 10/21/1999<br>kayiaros : 7/12/1999<br>kayiaros : 7/8/1999<br>jlewis : 6/15/1999<br>jlewis : 6/15/1999<br>jlewis : 6/15/1999<br>terry : 6/3/1999<br>terry : 5/20/1999<br>carol : 4/16/1999<br>carol : 2/14/1999<br>terry : 6/23/1998<br>terry : 6/18/1998<br>alopez : 5/21/1998<br>alopez : 8/4/1997<br>alopez : 7/10/1997<br>alopez : 7/10/1997<br>joanna : 7/9/1997<br>alopez : 7/3/1997<br>alopez : 7/3/1997<br>alopez : 6/27/1997<br>alopez : 6/26/1997<br>alopez : 6/11/1997<br>mark : 5/29/1997<br>jenny : 5/28/1997<br>mark : 5/28/1997<br>mark : 5/28/1997<br>mark : 5/28/1997<br>terry : 5/10/1997<br>terry : 4/29/1997<br>terry : 3/21/1997<br>terry : 3/17/1997<br>terry : 3/12/1997<br>terry : 3/10/1997<br>jamie : 2/4/1997<br>mark : 1/29/1997<br>terry : 1/29/1997<br>terry : 1/28/1997<br>mark : 1/27/1997<br>terry : 9/20/1996<br>terry : 7/24/1996<br>mark : 7/18/1996<br>mark : 7/18/1996<br>terry : 7/16/1996<br>mark : 6/25/1996<br>mark : 4/26/1996<br>terry : 4/22/1996<br>mark : 3/31/1996<br>mark : 3/30/1996<br>terry : 3/12/1996<br>pfoster : 11/14/1995<br>mark : 11/13/1995<br>terry : 11/2/1995<br>phil : 5/3/1995<br>carol : 3/3/1995<br>warfield : 4/20/1994
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</span>
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 306700
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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HEMOPHILIA A; HEMA
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</span>
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</h3>
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</div>
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<div>
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<br />
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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HEMOPHILIA, CLASSIC
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 28293008;
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<strong>ICD10CM:</strong> D66;
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<strong>ICD9CM:</strong> 286.0;
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<strong>ORPHA:</strong> 169802, 169805, 169808, 177926, 98878;
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<strong>DO:</strong> 12134;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
|
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Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
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</th>
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<th>
|
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
|
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
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Xq28
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Hemophilia A
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</span>
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</td>
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<td>
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<span class="mim-font">
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306700
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
X-linked recessive
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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3
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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F8
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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300841
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because classic hemophilia, or hemophilia A (HEMA), is caused by mutation in the gene encoding coagulation factor VIII (F8; 300841) on chromosome Xq28.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hemophilia A (HEMA) is an X-linked recessive bleeding disorder caused by a deficiency in the activity of coagulation factor VIII. The disorder is clinically heterogeneous with variable severity, depending on the plasma levels of coagulation factor VIII: mild, with levels 6 to 30% of normal; moderate, with levels 2 to 5% of normal; and severe, with levels less than 1% of normal. Patients with mild hemophilia usually bleed excessively only after trauma or surgery, whereas those with severe hemophilia have an annual average of 20 to 30 episodes of spontaneous or excessive bleeding after minor trauma, particularly into joints and muscles. These symptoms differ substantially from those of bleeding disorders due to platelet defects or von Willebrand disease (193400), in which mucosal bleeding predominates (review by Mannucci and Tuddenham, 2001). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Nomenclature</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The term 'hemophilia' is used in reference to hemophilia A (factor VIII deficiency); hemophilia B or Christmas disease (factor IX deficiency; 306900) and von Willebrand disease (von Willebrand factor deficiency; 193400). Hemophilia A and B are X-linked recessive disorders; von Willebrand disease has an autosomal dominant, or in some cases an autosomal recessive mode of inheritance (review by Mannucci and Tuddenham, 2001). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Clinical Features</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The severity and frequency of bleeding in hemophilia A is inversely related to the amount of residual factor VIII in the plasma: less than 1% factor VIII results in severe bleeding, 2 to 6% results in moderate bleeding, and 6 to 30% results in mild bleeding. The proportion of cases that are severe, moderate, and mild are about 50, 10, and 40%, respectively, The joints are frequently affected, causing swelling, pain, decreased function, and degenerative arthritis. Similarly, muscle hemorrhage can cause necrosis, contractures, and neuropathy by entrapment. Hematuria occurs occasionally and is usually painless. Intracranial hemorrhage, while uncommon, can occur after even mild head trauma and lead to severe complications. Bleeding from tongue or lip lacerations is often persistent (review by Antonarakis et al., 1995). </p><p>The clinical hallmarks of hemophilia A are joint and muscle hemorrhages, easy bruising, and prolonged hemorrhage after surgery or trauma, but no excessive bleeding after minor cuts or abrasions. Affected individuals may have little bleeding during the first year of life, but develop hemarthroses when beginning to walk. The most frequently affected joints are the knees, elbows, ankles, shoulders, and hips. Hemophilic arthropathy can be a progressive inflammatory condition which may result in limitation of motion and permanent disability (review by Hoyer, 1994). </p><p><strong><em>Female Carriers</em></strong></p><p>
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Rapaport et al. (1960) demonstrated a partial deficiency of factor VIII in heterozygous female carriers. </p><p>Most heterozygous female carriers of hemophilia A or hemophilia B (306900) have concentrations of clotting factor VIII or IX (F9; 300746) of about 50% of normal, respectively, and in most cases have mildly decreased coagulability without clinical signs. Sramek et al. (2003) followed up a cohort of 1,012 mothers of all known people with hemophilia in the Netherlands from birth to death, or the end-of-study date (41,984 person years of follow-up). Overall mortality was decreased by 22%. Deaths from ischemic heart disease were reduced by 36%. No decrease in mortality was observed for cerebral stroke (ischemic and hemorrhagic combined). Women in the cohort had an increased risk of deaths from extra cranial hemorrhage; however, the number of deaths from this cause was much lower than that for ischemic heart disease. The results were interpreted as showing that a mild decrease in coagulability has a protective effect against fatal ischemic heart disease. </p><p>In a population-based survey in the Netherlands, Plug et al. (2006) found that female carriers of hemophilia A and B bled more frequently than noncarrier women, especially after medical procedures, such as tooth extraction or tonsillectomy. Reduced clotting factor levels correlated with a mild hemophilia phenotype. Variation in clotting levels was attributed to lyonization. </p>
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<strong>Other Features</strong>
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<p>Rosendaal et al. (1990) presented evidence supporting their earlier findings that mortality due to ischemic heart disease is lower in hemophilia patients than in the general male population. </p><p>Chronic synovitis occurs in about 10% of Indian patients with severe hemophilia. Ghosh et al. (2003) reported an association between the development of chronic synovitis in patients with hemophilia and the HLA-B27 allele (142830.0001). Twenty-one (64%) of 33 patients with both disorders had HLA-B27, compared to 23 (5%) of 440 with severe hemophilia without synovitis (odds ratio of 31.6). There were 3 sib pairs with hemophilia in whom only 1 sib had synovitis; all the affected sibs had the HLA-B27 allele, whereas the unaffected sibs did not. Chronic synovitis presented as swelling of the joint with heat and redness and absence of response to treatment with factor concentrate. Ghosh et al. (2003) suggested that patients with HLA-B27 may not be able to easily downregulate inflammatory mediators after bleeding in the joints, leading to chronic synovitis. </p>
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<strong>Biochemical Features</strong>
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<p>Alexander and Goldstein (1953) first noted low levels of factor VIII in cases of von Willebrand disease (see 193400). This was confirmed by other workers including Nilsson et al. (1957), who studied von Willebrand's original family in the Aland Islands. Since von Willebrand disease is an autosomal disorder, these findings indicated that an autosomal locus can also cause low factor VIII levels. This overlap in phenotype between hemophilia A and von Willebrand disease is seen in families such as that of Graham et al. (1953) and Bond et al. (1962) in which the carrier females showed depression of factor VIII levels, but not as low as in hemizygous affected males and sometimes clinical hemophilia. Cooper and Wagner (1974) presented evidence that the factor VIII carrier molecule, von Willebrand factor, is normally present in the plasma of hemophilia A patients. </p><p>Using F8 antibodies, Denson (1968) and Feinstein et al. (1969) demonstrated that patients with hemophilia A have heterogeneous F8 molecules: plasma from some patients can be neutralized by the antibody, whereas plasma from other patients is not neutralized by the antibody. Denson et al. (1969) postulated that there are 2 subtypes of hemophilia A: one without any immunologically demonstrable protein and one with immunologically normal, but hemostatically defective protein. Hoyer and Breckenridge (1968) also found heterogeneity of the F8 protein in hemophilia A. </p><p>Stites et al. (1971) were able to detect F8 immunologically in all of 14 patients with hemophilia A they studied, whereas little or no F8 was identified in patients with von Willebrand disease. Zimmerman et al. (1971) found immunoreactive material in all of 22 patients with hemophilia A. </p>
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<strong>Inheritance</strong>
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<p>Hemophilia A is an X-linked recessive disorder and usually occurs in males. In familial cases, the affected boy has inherited the mutant gene from his carrier mother, but about 30% of cases arise from a spontaneous mutation (review by Mannucci and Tuddenham, 2001). </p><p>Using improved methods of carrier detection, Biggs and Rizza (1976) studied 41 mothers of presumably sporadic cases of hemophilia A and found that 39 were carriers. </p><p>Hermann (1966) reported an age effect on the mutation rate in hemophilia, but Barrai et al. (1968) concluded that there was no effect of maternal age or maternal grandfather's age. </p><p>Vogel (1977) concluded that the mutation rate causing hemophilia A is higher in males than in females; however Barrai et al. (1979) did not. Based on carrier detection tests of 21 mothers of isolated cases of severe hemophilia A, Winter et al. (1983) derived a maximum likelihood estimate of 9.6 (95% confidence limits 2.2-41.5) for the ratio of male to female mutation. Bernardi et al. (1987) found data consistent with a higher mutation rate in males than in females by using RFLP analysis in families with sporadic hemophilia A, </p><p>Rosendaal et al. (1990) collected information by mail on 462 Dutch patients with severe or moderately severe hemophilia A. Pedigree analysis on 189 of these patients who were the first hemophiliacs in their family showed, by the maximum likelihood method, that the ratio of mutation frequencies in males and females was 2.1, with a 95% confidence interval of 0.7-6.7. Rosendaal et al. (1990) performed a meta-analysis of all published studies on the sex ratio of mutation frequencies. From pooling of 6 studies, they estimated that mutations originate 3.1 times more often in males than in females (95% confidence interval 1.9-4.9). This implies that 80% of mothers of an isolated patient are expected to be hemophilia carriers. This estimate of prior risk is required for the application of Bayes theorem to probability calculations in carriership testing. </p><p>Brocker-Vriends et al. (1991) estimated that the mutation rate in males is 5.2 times that in females (95% confidence interval 1.8 to 15.1) suggesting that the probability of carriership for mothers of an isolated case amounts to 86%. Although this would imply that 14% of the mothers are not carriers in the classical sense, they may be mosaic for the mutation and, therefore, at risk of transmitting the mutation more than once. </p><p>Leuer et al. (2001) explored the hypothesis that a significant proportion of de novo mutations causing hemophilia A can be attributed to a germline or somatic mosaic originating from a mutation during early embryogenesis. They used allele-specific PCR to analyze 61 families that included members who had sporadic severe hemophilia A and known F8 gene defects. The presence of somatic mosaicism of varying degrees (0.2 to 25%) could be shown in 8 (13%) of the 61 families and was confirmed by a mutation-enrichment procedure. All mosaics were found in families with point mutations (8 of 32 families). In a subgroup of 8 families with CpG transitions, the percentage with mosaicism increased to 50% (4 of 8 families). In contrast, no mosaics were observed in 13 families with small deletions or insertions or in 16 families with intron 22 inversions. These data suggested that mosaicism may represent a fairly common event in hemophilia A. As a consequence, risk assessment in genetic counseling should include consideration of the possibility of somatic mosaicism in families with apparently de novo mutations, especially families with this subtype of point mutations. </p><p><strong><em>Unusual Inheritance Patterns</em></strong></p><p>
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Hemophilia A can also occur in females because of inheritance of defective F8 genes from both parents or on the basis of an autosome translocation disrupting the structure of the gene (e.g., Migeon et al., 1989). Pola and Svojitka (1957) reported a homozygous affected female who was the daughter of a hemophilic man married to a double first cousin. Sie et al. (1985) reported a homozygous female. In these cases, the homozygous female was not more severely affected than the hemizygous male. Theoretically, a female can be homozygous on the basis of uniparental isodisomy. It is also possible, in some cases diagnosed as hemophilia A, that actually von Willebrand disease (see 193400) is producing the hemorrhagic diathesis with very low levels of factor VIII. </p><p>Howard et al. (1988) showed that the mother of a hemophilic boy carried a mutation in the X chromosome she received from her nonhemophilic father rather than in the X chromosome received from her mother. Thus, the father was a gonadal mosaic. </p><p>In studies of a sporadic case of hemophilia, Gitschier (1988) found that the mother had partial duplication of the F8 gene. Among her 7 children, in addition to the hemophilic male who had partial deletion of factor VIII, there were some who inherited her normal X chromosome and others who inherited her duplicated X chromosome. Possibly the duplication in the mother predisposed to deletion. </p><p>Vidaud et al. (1989) presented evidence that a case of apparent transmission of hemophilia from father to son was due to uniparental disomy. Gamete complementation, involving fertilization of a nullisomic oocyte by a disomic sperm carrying both an X and a Y, was thought to have occurred. More than 15 X-linked DNA markers indicated that the son's X chromosome was inherited from his father.</p><p>Nisen and Waber (1989) studied X-chromosome inactivation patterns, as indicated by DNA methylation, in 3 families with hemophilic daughters. One was a case of severe hemophilia B in a girl referred to in 306900. The other 2 were cases of hemophilia A. The maternal and paternal X chromosomes were distinguished by RFLPs, and then patterns of methylation of selected genes on the X-chromosome were determined using methylation-sensitive restriction endonucleases. Of the 6 X-chromosome probes tested, only the PGK (311800) and HPRT (308000) clones were informative. After digestion with HpaII or HhaI, the hybridization intensity of the RFLPs of all 3 mothers and an unaffected sister were diminished by 50%, consistent with random X-chromosome inactivation. The methylation patterns of the X chromosomes of the affected females, however, were clearly nonrandom. Depending on the probe and the patient, HPRT and PGK sequences were either completely methylated or unmethylated. Thus, nonrandom X-chromosome inactivation was the basis for severe hemophilia in these females. </p><p>Coleman et al. (1993) reported another unusual mechanism for full-blown hemophilia A in a female, namely, biased X inactivation. A female infant born to a mother with incontinentia pigmenti (IP; 308300) and a father with hemophilia A manifested both disorders. Methylation studies of peripheral blood DNA from the infant, her mother, and 2 female relatives with IP showed a highly skewed pattern of X inactivation. Random patterns were observed in the infant's 2 sisters, who did not have IP and had the usual carrier activity of factor VIII. Coleman et al. (1993) postulated that the usual negative selection against cells with the IP-bearing X chromosome as the active one had unmasked the factor VIII mutation on the infant's other X chromosome. Thus, the infant was functionally hemizygous for the F8 mutation inherited from the father. </p><p>Windsor et al. (1995) described another mechanism for severe hemophilia A in a female: the presence of 2 de novo F8 mutations, an X chromosome deletion, and a paternal F8 inversion mutation. Neither parent showed evidence of the mutation in somatic DNA. </p><p>Valleix et al. (2002) described monozygotic twin females who were heterozygous for a tyr16-to-cys mutation in the F8 gene (Y16C; 306700.0269) which most probably arose in the paternal germline. Both twins showed skewing of X inactivation toward the maternally derived normal X chromosome, the most severely affected twin exhibiting a higher percentage of inactivation of the normal X chromosome. The degree of skewing of X inactivation closely correlated with both the coagulation parameters and the clinical phenotype of the twins. Monozygotic twins may be monochorionic or dichorionic, depending on whether they develop in a single or 2 distinct chorionic sacs. Dichorionic twinning occurs prior to or around the onset of X inactivation and monochorionic twinning occurs later. A discordant X-inactivation pattern might therefore be expected to be seen more frequently in dichorionic twins. As these twins were monochorionic, Valleix et al. (2002) suggested that the twinning event in this case may have been after the onset of X inactivation. </p><p>Bicocchi et al. (2005) reported a 3-generation family in which 3 females were affected with classic hemophilia A due to a heterozygous missense mutation in the F8 gene. All 3 women showed completely skewed X inactivation with expression only of the mutant gene in all tissues analyzed, including leukocytes, skin fibroblasts, uroepithelium, and buccal mucosa. Although no mutations were identified in the XIST gene (314670), Bicocchi et al. (2005) determined that all 3 women had the same XIST allele, and suggested that an alteration within the X-inactivation center on the chromosome carrying the F8C mutation prevented it from being inactivated. </p><p>Renault et al. (2007) described a 3-generation family segregating 2 distinct phenotypes, hemophilia A and dramatically skewed X chromosome inactivation, the convergence of which led to the expression of hemophilia A in 3 heterozygous females. All affected males and females had a proximal (type II) IVS22 inversion of the F8 gene. No female carried more than 1 inverted allele. The 3 affected females had skewed X inactivation in favor of the mutant X; 3 unaffected females also had skewed X inactivation, 2 in favor of the normal X, and the third did not carry the mutation. Renault et al. (2007) stated that known causes of skewing were not consistent with their findings in this family, suggesting that the X-chromosome inactivation ratios were genetically influenced (SXI2; 300179). </p>
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<strong>Diagnosis</strong>
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<p>Hemophilia A should be suspected whenever unusual bleeding is encountered in a male patient. Laboratory tests show normal platelet count and prothrombin time (PT), but a prolonged activated partial thromboplastin time (aPTT). Since hemophilia A and B are clinically similar, specific assays of factor VIII and factor IX (F9; 300746) must be performed. Patients with von Willebrand disease (VWD; 193400) also have factor VIII deficiency secondary to a deficiency of von Willebrand factor (VWF; 613160).</p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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Baty et al. (1986) demonstrated how DNA diagnosis can be helpful in obstetrical decisions and early care of hemophilia even though the family does not make use of the information for elective abortion. Specifically, Cesarean section was performed and the parents were psychologically prepared. </p><p>Pecorara et al. (1987) reported a relatively large experience with carrier detection and prenatal diagnosis by means of RFLP analysis. </p><p>Kogan et al. (1987) modified the procedure of PCR to use a heat-stable DNA polymerase which allowed the repeated rounds of DNA synthesis to proceed at 63 degrees C. The high sequence specificity of PCR at this temperature enabled detection of restriction-site polymorphisms, contained in PCR products derived from clinical samples to be analyzed by visual inspection of their digestion products on polyacrylamide gels. Kogan et al. (1987) used the improved method to detect carriers of hemophilia A and to diagnose hemophilia prenatally. Erlich et al. (1988) improved the PCR method using thermostable DNA polymerase from Thermus aquaticus. </p><p>Lavery (2008) described strategies for preimplantation genetic diagnosis of hemophilia, including embryo sexing, specific mutation analysis, coamplification of polymorphic markers, direct sequencing of F8, and haplotyping after multiple displacement amplification, and discussed the ethical challenges. </p>
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<strong>Mapping</strong>
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<p>Linkage studies in the early 1960s indicated that hemophilia A and B (306900) are not allelic (McKusick, 1964). The independence of the 2 loci was confirmed when Robertson and Trueman (1964) found a family in which both hemophilia A and hemophilia B were segregating; one male was deficient in both factor VIII and factor IX. From study of another family in which both hemophilia A and hemophilia B were segregating, Woodliff and Jackson (1966) concluded that the 2 loci are far apart. Direct studies of linkage between hemophilias A and B in the dog indicated that the 2 loci are at least 50 map units apart (Brinkhous et al., 1973). </p><p>Haldane and Smith (1947) concluded that there is 5-20% recombination between the color blindness (CBD; 303800) and hemophilia loci with the most probable value about 10%. However, Smith (1968) subsequently concluded that the data on which that estimate was based were heterogeneous, with some families (presumably hemophilia A) showing very close linkage and others (presumably hemophilia B) showing no linkage. </p><p>Samama et al. (1977) confirmed assignment of the hemophilia A locus to the long arm of the X chromosome by demonstration of hemophilia in a girl whose mother was a carrier and one of whose X chromosomes had partial deletion of the long arm. </p><p>In families of African descent, Boyer and Graham (1965) demonstrated close linkage of hemophilia A and the A/B polymorphism of G6PD (305900). Filippi et al. (1984) stated that 58 scorable sibs, all nonrecombinant for the linkage of HEMA and G6PD, were known by that time. From this, they inferred that the 90% upper limit of meiotic recombination between the 2 loci is less than 4%. </p><p>Harper et al. (1984) did linkage studies with the DNA probe DX13, which had been localized to band Xq28. When DNA is digested with the restriction enzyme BglII, the probe recognizes an RFLP for which 50% of females are heterozygous. No recombination was observed between the HEMA and DX13 loci. The workers concluded that the marker is useful for carrier detection and prenatal diagnosis. About 30% recombination was found between the factor VIII and IX loci. </p><p>Oberle et al. (1985) observed very close linkage of a polymorphic anonymous DNA probe called St14 (from Strasbourg, France). No recombination (theta=0) was found in 12 families (lod score 9.65). The probe was informative in more than 90% of families, and the authors suggested that it could be used in conjunction with assays of factor VIII to identify carriers with 96% confidence or better. St14 could be used for prenatal diagnosis of disorders such as hemophilia A and adrenoleukodystrophy because of close linkage (Oberle et al., 1985). Janco et al. (1987) used the more accurate intragenic F8 RFLPs to detect hemophilia A carriers. </p><p>In a 9-year-old Malaysian female with de novo hemophilia A as well as a complex de novo translocation involving one X chromosome and one chromosome 17 (Muneer et al., 1986), Migeon et al. (1993) identified a breakpoint within Xq28 with deletion of the 5-prime end of the factor VIII gene, leaving the more proximal G6PD locus intact on the derivative chromosome 17. As the deleted segment included the 5-prime half of F8C as well as the subtelomeric DXYS64 locus, they concluded that F8 is oriented on the chromosome with its 5-prime region closest to the telomere. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>Ratnoff and Bennett (1973) reviewed the genetics of hereditary disorders of blood coagulation. </p><p>Gitschier et al. (1985) identified truncating mutations in the F8 gene (see, e.g., 300841.0001-300841.0003) as the basis for hemophilia A. A severe hemophiliac with no detectable factor VIIIC activity had an R2307X mutation (300841.0001). Gitschier et al. (1986) found that the same codon was converted to glutamine (R2307Q; 300841.0042) in a mild hemophiliac with 10% of normal activity. A diminished level of factor VIII Ag in the latter patient coincided with the level of clotting activity, suggesting that the abnormal factor VIII was relatively unstable. </p><p>In a study of 83 patients with hemophilia A, Youssoufian et al. (1986) identified 2 different point mutations, one in exon 18 and one in exon 22, that recurred independently in unrelated families. Each mutation produced a nonsense codon by a change of CG to TG. In the opinion of Youssoufian et al. (1986), these observations indicated that CpG dinucleotides are mutation hotspots. It had been postulated that methylated cytosines may be mutation hotspots because 5-methylcytosine can spontaneously deaminate to thymine, resulting in a C-to-T transition in DNA. </p><p>Youssoufian et al. (1987) characterized 5 different partial deletions of the F8 gene in 83 patients with hemophilia. None had developed circulating inhibitors. One of the deletions occurred de novo in a germ cell of the maternal grandmother, while a second deletion occurred in a germ cell of a maternal grandfather. The findings indicated that de novo deletions of X-linked genes can occur in either male or female gametes. Youssoufian et al. (1988) reported 6 other partial F8 gene deletions in severe hemophilia A, bringing to 12 the number of deletions among 240 patients. No association was observed between the size or location of deletions and the presence of inhibitors to factor VIII. Furthermore, no 'hotspots' for deletion breakpoints were identified. </p><p>Youssoufian et al. (1988) screened 240 patients with hemophilia A and found CG to TG transitions in an exon in 9. They identified novel missense mutations leading to severe hemophilia A and estimated that the extent of hypermutability of CpG dinucleotides is 10 to 20 times greater than the average mutation rate for hemophilia A. </p><p>Cooper and Youssoufian (1988) collated reports of single basepair mutations within gene coding regions causing human genetic disease. They found that 35% of mutations occurred within CpG dinucleotides. Over 90% of these mutations were C-to-T or G-to-A transitions, which thus occur within coding regions at a frequency 42-times higher than that predicted from random mutation. Cooper and Youssoufian (1988) believed these findings were consistent with methylation-induced deamination of 5-methylcytosine and suggested that methylation of DNA within coding regions may contribute significantly to the incidence of human genetic disease. </p><p>Higuchi et al. (1988) found deletion of about 2,000 bases spanning exon 3 and part of IVS3 of the F8 gene in a patient with severe hemophilia A. The mother was judged to be somatic mosaic because the defective gene could be identified in only a portion of the leukocytes and cultured fibroblasts. </p><p>In a review, Antonarakis et al. (1995) collected the findings of more than 1,000 hemophilia subjects examined for F8 gene mutations. These include point mutations, inversions, deletions, and unidentified mutations which constitute 46%, 42%, 8%, 4%, and 91%, 0%, 0%, and 9%, respectively, of those with severe versus mild to moderate disease, respectively, in selected studies. The 266 point mutations described as of April, 1994 comprised missense (53%), CpG-to-TpG (16%), small deletions (12%), nonsense (9%), small inversions and splicing (3% each), and missense polymorphisms and silent mutations in exons (2% each). In addition to these point mutations 100 different larger deletions and 9 insertion mutations had been reported. </p><p>In a study of 147 sporadic cases of severe hemophilia A, Becker et al. (1996) were able to identify the causative defect in the F8 gene in 126 patients (85.7%). An inversion of the gene was found in 55 patients (37.4%), a point mutation in 47 (32%), a small deletion in 14 (9.5%), a large deletion in 8 (5.4%), and a small insertion in 2 (1.4%). In 4 (2.7%), mutations were localized but not yet sequenced. No mutation was identified in 17 patients (11.6%). The identified mutations occurred in the B domain in 16 (10.9%); 4 of these were located in an adenosine nucleotide stretch at codon 1192, indicating a mutation hotspot. Somatic mosaicism was detected in 3 (3.9%) of 76 patients' mothers, comprising 3 of 16 de novo mutations in the patients' mothers. Investigation of family relatives allowed detection of a de novo mutation in 16 of 76 2-generation and 28 of 34 3-generation families. On the basis of these data, Becker et al. (1996) estimated the male:female ratio of mutation frequencies (k) to be 3.6. By use of the quotients of mutation origin in maternal grandfather to patients' mother or to maternal grandmother, k values were directly estimated as 15 and 7.5, respectively. Considering each mutation type separately, they found a mutation type-specific sex ratio of mutation frequencies. Point mutations showed a 5-to-10-fold-higher and inversions a more than 10-fold-higher mutation rate in male germ cells, whereas deletions showed a more than 5-fold-higher mutation rate in female germ cells. Consequently, and in accordance with the data of other disorders such as Duchenne muscular dystrophy, the results indicated to Becker et al. (1996) that at least for X-chromosomal disorders the male:female mutation rate is determined by its proportion of the different mutation types. </p><p>The molecular diagnosis of hemophilia A is challenging because of the high number of different causative mutations that are distributed through the large F8 gene. The putative role of the novel mutations, especially missense mutations, may be difficult to interpret as causing hemophilia A. Guillet et al. (2006) identified 95 novel mutations out of 180 different mutations found among 515 patients with hemophilia A from 406 unrelated families followed up at a single hemophilia treatment center in a Paris hospital. The 95 novel mutations comprised 55 missense mutations, 12 nonsense mutations, 11 splice site mutations, and 17 small insertions/deletions. They used a strategy in interpreting the causality of novel F8 mutations based on a combination of the familial segregation of the mutation, the resulting biologic and clinical hemophilia A phenotype, and the molecular consequences of the amino acid substitution. For the latter, they studied the putative biochemical modifications: its conservation status with cross-species factor VIII and homologous proteins, its putative location in known factor VIII functional regions, and its spatial position in the available factor VIII 3D structures. </p><p>Among 1,410 Italian patients with hemophilia A, Santacroce et al. (2008) identified 382 different mutations in the F8 gene, 217 (57%) of which had not previously been reported. Mutations leading to a null allele accounted for 82%, 15%, and less than 1% of severe, moderate, or mild hemophilia, respectively. Missense mutations were identified in 16%, 68%, and 81% of severe, moderate, or mild hemophilia, respectively, yielding a good genotype/phenotype correlation useful for treatment and genetic counseling. </p><p>In order to establish a national database of F8 mutations, Green et al. (2008) identified and cataloged multiple mutations in approximately one-third of the U.K. hemophilia A population. The risk of developing inhibitors for patients with nonsense mutations was greater when the stop codon was in the 3-prime half of the mRNA. The most common change was the intron 22 inversion (306700.0067), which accounted for 16.6% of all mutations and for 38% of those causing severe disease. </p><p><strong><em>Inversion Mutations in Intron 22 of the F8 Gene</em></strong></p><p>
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Intron 22 of the human F8 gene is hypomethylated on the active X and methylated on the inactive X. Inaba et al. (1990) described an MspI RFLP in intron 22 of the F8 gene. Japanese showed 45% heterozygosity and Asian Indians showed 13%; polymorphism was not found in American blacks or Caucasians. </p><p>Naylor et al. (1992) found an unusual cluster of mutations involving regions of intron 22 not examined earlier and leading to defective joining of exons 22 and 23 in the mRNA (300841.0067) as the cause of hemophilia A in 10 of 24 severely affected UK patients. These results confirmed predictions about the efficacy of the mRNA-based method suggested by Naylor et al. (1991), and also excluded hypotheses proposing that mutations outside the F8 gene are responsible for a large proportion of severe hemophilia A. </p><p>Of the 28 patients reported by Naylor et al. (1993), 5 had mild or moderate disease and all had a missense mutation. The other 23 patients were severely affected; unexpectedly, intron 22 seemed to be the target of approximately 40% of the mutations causing severe hemophilia A. Naylor et al. (1993) found that the basis of the unique F8 mRNA defect that prevented PCR amplification across the boundary between exons 22 and 23 was an abnormality in the internal regions of intron 22. They showed that exons 1-22 of the F8 mRNA had become part of a hybrid message containing new multi-exonic sequences expressed in normal cells. The novel sequences were not located in a YAC containing the whole F8 gene. Southern blots from patients probed by novel sequences and clones covering intron 22 showed no obvious abnormalities. Naylor et al. (1993) also suggested that inversions involving intron 22 repeated sequences are the basis of the mRNA defect. These mutations in severely affected patients occur at the surprising rate of approximately 4 x 10(-6) per gene per gamete per generation. Furthermore, it has been shown that these de novo inversions occur more frequently in males than females with a ratio of 302:1 estimated in male:female germ cells. </p><p>The F8A gene (305423) is contained entirely within intron 22 of the F8 gene and is transcript in the reverse orientation from the F8 gene (Levinson et al., 1990). Lakich et al. (1993) proposed that many of the previously unidentified mutations resulting in severe hemophilia A are based on recombination between the homologous F8A sequences within intron 22 and upstream of the F8 gene. Such a recombination would lead to an inversion of all intervening DNA and a disruption of the gene. Lakich et al. (1993) presented evidence to support this model and described a Southern blot assay that detects the inversion. They suggested that this assay should permit genetic prediction of hemophilia A in approximately 45% of families with severe disease. </p><p>Inversion mutations resulting from recombinations between DNA sequences in the A gene in intron 22 of the F8 gene and 1 of 2 other A genes upstream to F8 have been shown to cause a large portion of cases. From data on more than 2,000 samples, Antonarakis et al. (1995) concluded that the common inversion mutations are found in 42% of all severe hemophilia A subjects. Whereas 98% of the mothers of those with inversions were carriers of the inversion, only about 1 de novo inversion was found in maternal cells for every 25 mothers of sporadic cases. When the maternal grandparental origin of inversions was examined the ratio of de novo occurrences in male:female germ cells was 69:1. </p><p>Brinke et al. (1996) reported the presence of a novel inversion in 2 hemophilic monozygotic twins. These patients showed an inversion that affects the first intron of the F8 gene, displacing the most telomeric exon (exon 1) of F8 further towards the telomere and close to the C6.1A gene (BRCC3; 300617). Brinke et al. (1996) noted that this novel inversion creates 2 hybrid transcription units. One of these is formed by the promoter and first exon of F8 and widely expressed sequences that map telomeric to the C6.1A sequence. The other hybrid transcription unit contains the CpG island and all of the known sequence of C6.1A and the 3-prime section of most of the F8 gene. </p><p>It is hypothesized that the inversion mutations occur almost exclusively in germ cells during meiotic cell division by an intrachromosomal recombination between a 9.6-kb sequence within intron 22 and 1 of 2 almost identical copies located about 300 kb distal to the F8 gene at the telomeric end of the X chromosome. Most inversion mutations originate in male germ cells, where the lack of bivalent formation may facilitate flipping of the telomeric end of the single X chromosome. Oldenburg et al. (2000) reported the first instance of intron 22 inversion presenting as somatic mosaicism in a female, affecting only about 50% of lymphocyte and fibroblast cells of the proposita. Supposing a postzygotic de novo mutation as the usual cause of somatic mosaicism, the finding implies that the intron 22 inversion mutation is not restricted to meiotic cell divisions but can also occur during mitotic cell divisions, either in germ cell precursors or in somatic cells. </p><p><strong><em>Development of Factor VIII Inhibitors</em></strong></p><p>
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Approximately 10 to 20% of patients with severe hemophilia A develop antibodies, known as inhibitors, to factor VIII following treatment with exogenous factor VIII. Most of these patients have nonsense mutations or deletions in the F8 gene (Antonarakis et al., 1995). </p><p>Antonarakis et al. (1985) identified several molecular defects in families with hemophilia A. One family had a deletion of about 80 kb in the F8 gene, whereas another had a single nucleotide change in the coding region of the gene, resulting in a nonsense codon and premature termination. In addition, they used 2 common polymorphic sites in the F8 gene to differentiate the normal gene from the defective gene in 4 of 6 obligate carriers from families with patients in whom inhibitors did not develop. In both the family with a large deletion and the family with premature termination, affected persons developed inhibitors. </p><p>A variety of F8 gene mutations have been found in patients with hemophilia A due to inhibitors. Among 30 such cases, Antonarakis et al. (1995) found that 87% and 13% had different nonsense and missense mutations, respectively. F8 gene inversions do not seem to be a major predisposing factor for the development of inhibitors. Among severe hemophilia A cases, 16% of those without inversions and 20% of those with inversions developed inhibitors. </p><p>Schwaab et al. (1995) found that the probability of developing factor VIII inhibitors is greater in patients with large deletions in the F8 gene. </p><p>Viel et al. (2009) sequenced the F8 gene in 78 black patients with hemophilia to identify the causative mutations and background haplotypes, which the authors designated H1 to H5. They found that 24% of the patients had an H3 or H4 haplotype, and that the prevalence of inhibitors was higher among patients with either of those haplotypes than among patients with haplotypes H1 or H2 (odds ratio, 3.6; p = 0.04), despite a similar spectrum of hemophilic mutations and degree of severity of illness in the 2 subgroups. Noting that Caucasians carry only the H1 or H2 haplotypes and that most blood donors are Caucasian, Viel et al. (2009) suggested that mismatched factor VIII replacement therapy might be a risk factor for the development of anti-factor VIII alloantibodies. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>In a Japanese family with mild to moderately severe hemophilia A, Young et al. (1997) found a deletion of a single nucleotide T within an A(8)TA(2) sequence of exon 14 of the F8 gene. The severity of the clinical phenotype did not correspond to that expected of a frameshift mutation. A small amount of functional factor VIII protein was detected in the patient's plasma. Analysis of DNA and RNA molecules from normal and affected individuals and in vitro transcription/translation suggested a partial correction of the molecular defect, because of the following: (i) DNA replication/RNA transcription errors resulted in restoration of the reading frame and/or (ii) 'ribosomal frameshifting' resulted in the production of normal factor VIII polypeptide and, thus, in a milder-than-expected hemophilia A. All of these mechanisms probably were promoted by the longer run of adenines, A(10) instead of A(8)TA(2), after the deleted T. Young et al. (1997) concluded that errors in the complex steps of gene expression therefore may partially correct a severe frameshift defect and ameliorate an expected severe phenotype. </p><p>Cutler et al. (2002) identified 81 mutations in the F8C gene in 96 unrelated patients, all of whom had previously typed negative for the common IVS22 inversion mutation (306700.0067). Forty-one of these mutations were not recorded in F8C gene mutation databases. Analysis of these 41 mutations with regard to location, possible cross-species conservation, and type of substitution, in correlation with the clinical severity of the disease, supported the view that the phenotypic result of a mutation in the F8C gene correlates more with the position of the amino acid change within the 3-dimensional structure of the protein than with the actual nature of the alteration. </p>
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<strong>Clinical Management</strong>
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<p>The mainstay of routine treatment for hemophilia A is infusion of factor VIII using amounts that are required to restore the factor VIII activity to therapeutic levels. Desmopressin (dDAVP), a synthetic analog of the neurohypophyseal nonapeptide arginine vasopressin (AVP; 192340), has been approved for treatment of mild hemophilia A and von Willebrand disease. Following dDAVP in some cases concentrations of factor VIII and von Willebrand factor are transiently increased to levels that allow minor surgery (Richardson and Robinson, 1985; review by Hoyer, 1994). </p><p>Lewis et al. (1985) reported that a hemophiliac who received a liver transplant from a normal donor had nearly normal levels of factor VIII coagulant activity in the postoperative period. </p><p>Nilsson et al. (1988) used combined cyclophosphamide, intravenous IgG, and factor VIII therapy to induce immune tolerance to factor VIII infusions in patients with antibodies to factor VIII. Factor VIII coagulant antibodies disappeared in 9 of 11 patients so treated; the other 2 patients did not respond. Earlier treatment with either factor VIII and cyclophosphamide or factor VIII and IgG had been ineffective, suggesting that all 3 components of the protocol are necessary for the successful induction of tolerance. Pignone et al. (1992) had success within induction of immune tolerance in patients with hemophilia A and factor VIII inhibitors: combined treatment with gammaglobulin, cyclophosphamide, and factor VIII. </p><p>Schwartz et al. (1990) used antihemophilic factor produced by recombinant DNA methods in the successful treatment of hemophilia A in 107 subjects. The half-lives equaled or exceeded those of plasma-derived factor VIII, and immunogenicity appeared to be no greater. This represented a major advance because of the opportunity to avoid exposure to transfusion-associated viral diseases. F8 was one of the largest genes cloned to that time and, with the study of Schwartz et al. (1990), became the largest cloned protein to be used in clinical trials. </p><p>Through a suppressive effect on premature termination codons, aminoglycoside antibiotics such as gentamicin have been used for therapeutic benefit in a number of conditions including cystic fibrosis (602421) and Duchenne muscular dystrophy (300377). James et al. (2005) evaluated the effect of gentamicin on the factor VIII and factor IX levels of severe hemophiliacs with known nonsense mutations. They concluded that gentamicin was unlikely to be an effective treatment for severe hemophilia because of its potential toxicity and the minimal response observed. </p><p>In hemophilic SCID mice, Aronovich et al. (2006) reported successful treatment of hemophilia by transplantation of fetal pig spleen harvested at embryonic day 42 before the appearance of mature T cells. The transplanted tissue exhibited good growth and subsequent expression of factor VIII, leading to complete alleviation of hemophilia within 2 to 3 months after transplant. The results provided proof of principle that transplantation of fetal spleen can correct hemophilia while avoiding graft-versus-host disease (GVHD; see 614395). </p><p><strong><em>Development of Factor VIII Inhibitors</em></strong></p><p>
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An acquired disorder resembling hemophilia A can be caused by the development by autoantibodies against factor VIII (Nilsson and Lamme, 1980; Zimmerman et al., 1971). Approximately 10 to 20% of patients with severe hemophilia A develop antibodies, known as inhibitors, to factor VIII following treatment with exogenous factor VIII. Most of these patients have nonsense mutations or deletions in the F8 gene (Antonarakis et al., 1995). </p><p>Frommel et al. (1977) studied 10 sibships of hemophilia A, each of which included 1 or 2 hemophilic brothers with antibody to factor VIII. Their results suggested linkage of the MHC (142800) and a gene responsible for an immune response to factor VIII. The development of factor VIII antibodies has been interpreted in terms of CRM-positivity versus CRM-negativity by others (Boyer et al., 1973). </p><p>Factor VIII inhibitors neutralize factor VIII procoagulant activity by sterically preventing the interaction of factor VIII with von Willebrand factor, phospholipids, activated factor IX, thrombin, and activated factor X. Another mechanism for inactivation of factor VIII is the proteolysis of factor VIII by anti-factor VIII antibodies. Schwaab et al. (1995) found that the probability of developing factor VIII inhibitors is greater in patients with large deletions in the F8 gene (see MOLECULAR GENETICS). </p><p>Lacroix-Desmazes et al. (2002) found significant proteolytic activity in IgG from 13 of 24 inhibitor-positive patients. No hydrolytic activity was detected in control antibodies of IgG from patients without inhibitors. The relationship between hydrolytic activity of IgG and factor VIII-neutralizing activity was not consistent. Antibodies from some patients caused hydrolysis of factor VIII at low rates, but the plasma had strong inhibitory activity; in other cases, the IgG caused hydrolysis of factor VIII at high rates, but the plasma had weak inhibitory activity; in yet other samples, there were high rates of both hydrolysis and inhibitory activity. </p><p><strong><em>Gene Therapy</em></strong></p><p>
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Continuous delivery of factor VIII protein in hemophiliacs by gene therapy would represent a major clinical advance. Conceptually, retroviral vectors can permanently insert the F8 gene into DNA of the whole cell and, therefore, appear to be the most suitable vehicles for gene therapy. However, most retroviral vector systems have shown poor performance in the production of factor VIII from primary cells in vitro and in vivo. Dwarki et al. (1995) used the highly efficient MFG retroviral vector system to transfer F8 cDNA into murine and human cells (primary and established cell lines). The cDNA contained an open reading frame of 2,351 amino acids and lacked the B domain, which is not required for procoagulant activity in vitro or in vivo. In contrast to previous reports, Dwarki et al. (1995) demonstrated high transduction efficiency and a high rate of factor VIII production. They also demonstrated that factor VIII-secreting cells transplanted into immune-deficient mice gave rise to substantial levels of factor VIII in the plasma. </p><p>VandenDriessche et al. (1999) demonstrated that hemophilia A could be corrected by in vivo gene therapy using retroviral vectors. Newborn F8-deficient mice were injected intravenously with retroviral vectors expressing high levels of human FVIII. High levels of functional human FVIII production could be detected in 6 of 13 animals, 4 of which expressed physiologic or higher levels. Five of the 6 expressors produced FVIII and survived an otherwise lethal tail clipping, demonstrating phenotypic correction of the bleeding disorder. F8 expression was sustained for more than 14 months. Gene transfer occurred into liver, spleen, and lungs, with predominant F8 mRNA expression in the liver. Six of the 7 animals with transient or no detectable human FVIII developed FVIII inhibitors. </p><p>Kay and High (1999) discussed, in general terms, gene therapy for the hemophilias. They pointed out that gene therapy for factor VIII deficiency has been relatively more difficult than that for factor IX deficiency because of the large size of the F8 coding region. </p><p>Roth et al. (2001) tested the safety of a nonviral somatic cell gene therapy system in patients with severe hemophilia A. Skin fibroblasts obtained by skin biopsy were transfected with a plasmid carrying sequences of the F8 gene. Cells that produced factor VIII were selected, cloned, and propagated in vitro. The cloned cells were then harvested and administered to the patients by laparoscopic injection into the omentum. Follow-up 12 months after implantation of the genetically altered cells showed no serious adverse reactions. No inhibitors of factor VIII were detected. In 4 of the 6 patients treated, plasma levels of factor VIII activity rose above the levels observed before the procedure. Coincident with the increase in factor VIII activity was a decrease in bleeding, a reduction in the use of exogenous factor VIII, or both. In the patient with the highest level of factor VIII activity, the clinical changes lasted approximately 10 months. </p><p>Mannucci and Tuddenham (2001) reviewed the hemophilias. They stated that hemophilia is likely to be the first common severe genetic condition to be cured by gene therapy. Apart from the long-term consequences of viral infections transmitted by infected blood products, there seem to be only 2 remaining problems: first, the development of high titers of antibodies against factor VIII or factor IX, and second, the challenge to society that four-fifths of all patients with hemophilia, mainly those in developing countries, receive no treatment. They suggested that less expensive replacement therapy, such as large-scale production and purification of factor VIII and factor IX from the milk of transgenic farmyard animals, might be a solution. </p><p>Pasi (2001) reviewed gene therapy for hemophilia. </p><p>Rangarajan et al. (2017) infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII in 9 men with severe hemophilia A. Participants were enrolled sequentially into 1 of 3 dose cohorts, low-dose (1 participant), intermediate-dose (1 participant), and high-dose (7 participants) and were followed through 52 weeks. Factor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all 7 participants, and the level in 6 participants increased to a normal value (greater than 50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase (ALT) level to 1.5 times the upper limit of normal or less. There was progression of preexisting chronic arthropathy in one participant. No neutralizing antibodies to factor VIII were detected. </p><p>George et al. (2021) reported results of a phase 1-2 clinical trial in 18 men with hemophilia A to evaluate the safety and efficacy of an adeno-associated viral vector with cDNA encoding a B-domain-deleted form of factor VIII on a liver-specific enhancer and promoter. The average observation period was 36.6 months. There were 4 dosing cohorts in the trial, ranging from 5 x 10(11) vector genomes to 2 x 10(12) vector genomes per kilogram of body weight. Some patients received glucocorticoid therapy and other immunosuppressive therapies to prevent or treat AAV capsid immune responses. Two patients lost all factor VIII expression due to an anti-AAV capsid cellular response that was not sensitive to immune suppression. Sustained and stable factor VIII expression was achieved in 16 of 18 patients, allowing for discontinuation of factor VIII prophylactic therapy and reduction in bleeding episodes to fewer than 1 per year. </p><p>Ozelo et al. (2022) reported results of an open-label, single-group, multicenter, phase 3 study to evaluate the safety and efficacy of a single infusion of valoctocogene roxaparvovec, an adeno-associated virus 5 (AAV5)-based gene therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter, among 134 men with severe hemophilia A. The infusion substantially increased factor VIII activity when measured at 49 to 52 weeks after dosing, with a median factor VIII activity level of 5 IU/dl or higher in 88.1% of participants. The gene therapy treatment also reduced the annualized rates of factor VIII concentrate use by 98.6% and of treated bleeding by 83.8% compared with factor VIII prophylaxis. Elevations in alanine aminotransferase levels occurred in 85.8% of those treated and were managed with glucocorticoids. Serious adverse events that were determined to be related to the study drug were seen in 3.7%; all serious adverse events resolved. No patients developed factor VIII inhibitors or thrombotic events. </p><p>Mahlangu et al. (2023) reported the 104-week follow-up results of the 134 participants in the valoctocogene roxaparvovec phase III gene therapy trial reported by Ozelo et al. (2022). The mean annualized treated bleeding rate decreased by 84.5% from baseline (p less than 0.001) among the treated participants. The risk of joint bleeding was estimated at 1.0 episodes per year. At 2 years postinfusion, no new safety signals or serious adverse events related to treatment were reported. </p>
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<strong>Population Genetics</strong>
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<p>The incidence of hemophilia A, caused by a deficiency of factor VIII, is estimated at about 1 in 5,000 male live births. Hemophilia B, caused by a deficiency of factor IX, is estimated at about 1 in 30,000 male live births (Mannucci and Tuddenham, 2001). </p><p>Soucie et al. (1998) studied the frequency of hemophilia A and hemophilia B in 6 U.S. states: Colorado, Georgia, Louisiana, Massachusetts, New York, and Oklahoma. A hemophilia case was defined as a person with physician-diagnosed hemophilia A or B and/or a measured baseline factor VIII or IX activity (FA) of 30% or less. Case-finding methods included patient reports from physicians, clinical laboratories, hospitals, and hemophilia treatment centers. Once identified, trained data abstractors collected clinical and outcome data retrospectively from medical records. Among cases identified in 1993 to 1995, 2,743 were residents of the 6 states in 1994, of whom 2,156 (79%) had hemophilia A. Of those with factor VIII measurements, 1,140 (43%) had severe (FA less than 1%), 684 (26%) had moderate (FA of 1-5%), and 848 (31%) had mild (FA of 6-30%) disease. The age-adjusted prevalence of hemophilia in all 6 states in 1994 was 13.4 cases per 100,000 males (10.5 hemophilia A and 2.9 hemophilia B). The prevalence by race/ethnicity was 13.2 cases per 100,000 white, 11.0% among African American, and 11.5% among Hispanic males. Application of age-specific prevalence rates from the 6 surveillance states to the U.S. population resulted in an estimated national population of 13,320 cases of hemophilia A and 3,640 cases of hemophilia B. For the 10-year period 1982 to 1991, the average incidence of hemophilia A and B in the 6 surveillance states was estimated to be 1 in 5,032 live male births. </p>
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<p>Earlier it was assumed that the hemophilia gene was lethal in homozygous females. That this was not the case was first demonstrated in the dog by Brinkhous and Graham (1950) who studied homozygous hemophilic female dogs. Splenic transplantation to dogs with hemophilia A corrects the coagulation defect (Norman et al., 1968). </p><p>Lozier et al. (2002) studied the nature of the molecular defect in the F8 gene in the Chapel Hill colony of factor VIII-deficient dogs started by Brinkhous and Graham (1950). They found that the defect in these dogs replicates the F8 gene inversion (306700.0067) commonly seen in humans with severe hemophilia A. </p><p>Conventional gene therapy of hemophilia A relies on the transfer of F8 cDNA. Chao et al. (2003) adopted a different approach to the molecular treatment of hemophilia A in mice. They carried out spliceosome-mediated RNA trans-splicing (SMaRT) to repair mutant F8 mRNA. A pre-trans-splicing molecule (PTM) corrected endogenous F8 mRNA in F8 knockout mice with the hemophilia A phenotype, producing sufficient functional factor VIII to correct the hemophilia A phenotype. The results indicated the feasibility of using SMaRT to repair RNA for the treatment of genetic diseases. The use of mRNA repair may circumvent the problems associated with conventional methods of delivering full-length cDNA for gene therapy. </p>
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<strong>History</strong>
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<p>Early reports of hemophilia families emanated from this country beginning with a newspaper account in 1792 (McKusick, 1962) and continuing with medical reports by Otto in 1803 and Hay in 1813 (McKusick, 1962). Cone (1979) called attention to an amazingly clear description of the genetics and rheumatic complications of hemophilia by Dr. James N. Hughes of Simpsonville, Kentucky, in 1832.</p><p>Although the type of hemophilia, hemophilia A or hemophilia B, is not known, the occurrence of hemophilia in the last Tsar of Russia and other descendants of Queen Victoria through the maternal lines is well documented (McKusick, 1965). Gill et al. (1994) reported DNA studies on 9 skeletons found in a shallow grave in Ekaterinburg, Russia, in July 1991 and tentatively identified by Russian forensic authorities as the remains of the last Tsar, Tsarina, 3 of their 5 children, the Royal Physician and 3 servants. DNA-based sex testing and short-tandem repeat analysis confirmed that a family group was present in the grave. Analysis of mitochondrial DNA revealed an exact sequence match between the putative Tsarina and the 3 children and a living maternal relative. Amplified mtDNA extracted from the remains of the putative Tsar demonstrated heteroplasmy at a single base within the mtDNA control region. One of these sequences matched 2 living maternal relatives of the Tsar. The DNA data indicated that 1 of the princesses and Tsarevich Alexei were missing from the grave. </p><p>A paternal age effect may have been operative in the case of the 'royal hemophilia' in the descendants of Queen Victoria who was clearly a carrier. There were no earlier cases in the family and Victoria's father was 52 years old at the time of her birth (McKusick, 1965). </p><p>The identification of the remains of the Romanov family by DNA analysis (Gill et al., 1994; Ivanov et al., 1996) and the laying to rest of the Romanov bones 80 years to the day after their assassination (17 July 1998) prompted Stevens (1999) to review the history of hemophilia in the royal families of Europe, with a pedigree chart. In the studies reported by Gill et al. (1994) and Ivanov et al. (1996), 5 of the bodies were clearly related, and 3 were those of female sibs. Furthermore, a sample of maternally inherited mtDNA suspected of belonging to Tsarina Alexandra matched a sample generously donated by her grandnephew, Philip Duke of Edinburgh. Finding a reference sample for Nicholas proved more difficult. Two distant relatives with the same matrilineage agreed to help. The mtDNA sequences the Tsar's 2 relatives were identical to each other, but where the relatives had a T at nucleotide 16169, the bone mtDNA of Nicholas surprisingly had a C. Gill et al. (1994) concluded that this represented heteroplasmy with 2 populations of mitochondria within his cells that contained either a C or a T at this position. He estimated, furthermore, the probability of the remains belonging to the Tsar as being 98.5%. The Russian Orthodox Church demanded more evidence, leading to the exhumation of the Grand Duke Georgij Romanov, who had died before his brother of tuberculosis. Bone samples were studied at the Armed Forces Institute of Pathology DNA Identification Laboratory in Maryland. Analysis was carried out at the request of the Russian federal government. Results showed that the mtDNA of both Grand Duke Georgij and Tsar Nicholas had the same heteroplasmy. This was the first time that heteroplasmy had been applied in human identification. Ivanov et al. (1996) calculated a likelihood ratio for the authenticity of the remains in excess of 100 million to 1, not including other anthropologic and forensic evidence. The events of 17 July 1998 emphasized the gap between church and science. The patriarch Alexksi II continued to insist that DNA tests were fallible; the Archbishop of St. Petersburg did not attend the burial service at the ancestral church of the Peter and Paul Fortress in St. Petersburg. The remains of Tsarevich Alexis and one of his sisters, possibly Maria, were not found. The most famous claimant to the title of Anastasia was Anna Anderson, who died in 1984 in the United States and was cremated, but 4 years previously had undergone emergency surgery for an ovarian tumor. DNA fingerprinting by several groups on the laparotomy material dismissed the posthumous claims of Anna Anderson (Gill et al., 1995). </p><p>Stevens (1999) also reviewed hemophilia in the Spanish royal family and the medical history of Victoria's hemophilic son, Leopold. His birth was a landmark for other reasons. Dr. John Snow (who later identified the water pump in Broad Street as the source of the London cholera outbreak) administered chloroform to Victoria in childbirth with Leopold and created a breakthrough in anesthesia. Leopold was a severe hemophiliac. Queen Victoria was obviously ashamed of Leopold and spoke of him disparagingly. Because of his incapacity and confinement to bed for protracted periods, he read widely and was undoubtedly the most intelligent and intellectual of Victoria's children. Leopold's letters recounted his problems with the arthropathy of hemophilia. At the age of 24, Leopold became one of his mother's private secretaries and had access to state papers. In 1881, Victoria created Leopold Duke of Albany and the following year he married Princess Helena of Waldeck, sister of the Dutch Queen. They had 2 children. Princess Alice was an obligate carrier and had a hemophilic son (Rupert, Viscount Trematon) who died in 1928 at the age of 21. Charles Edward Leopold was born posthumously, as his father had died at the age of 31 after a fall down a staircase in Cannes causing intracranial hemorrhage. Victoria's father did not have hemophilia but apparently did have porphyria, inherited from his father, George III. </p><p>Mannucci and Tuddenham (2001) stated that none of the descendants of Queen Victoria who were known to be affected were alive; the last one, Waldemar, died in 1945. They stated, however, that Victoria's great-great-granddaughter Olympia, from the Spanish branch, had a son, Paul Alexander, who died in childhood of a 'blood' disorder, and she may therefore be the last surviving carrier, testing of whom might determine the nature of the type of hemophilia, A or B, and perhaps even the precise mutation in the royal family. </p><p>Ratnoff and Lewis (1975) described a family with a bizarre X-linked bleeding disorder that probably represents a variant of hemophilia A. They called it Heckathorn disease after one of the affected persons. </p><p>Wacey et al. (1996) described HAMSTeRS (the hemophilia A mutation search test and resource site), the homepage of the factor VIII mutation database maintained in the unit of EDG Tuddenham at Royal Postgraduate Medical School in London. The authors discussed how to access the database via the Internet. Kemball-Cook and Tuddenham (1997) gave further information on the HAMSTeRS database which had been completely updated with easy submission for point mutations, deletions, and insertions via e-mail of custom-designed forms. A methods section devoted to mutation detection had been added, highlighting issues such as choice of technique and PCR primer sequences. </p>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
|
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Antonarakis et al. (1987); Arrants et al. (1962); Bennett and Ratnoff
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(1974); Bennett and Huehns (1970); Bernardi et al. (1989); Chediak et
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al. (1980); Edgell et al. (1978); Firshein et al. (1979); Gitschier
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et al. (1985); Grozdea et al. (1969); Hemker et al. (1980); Kazazian
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et al. (1988); Kitchens (1980); Klein et al. (1977); Kogan and
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Gitschier (1990); Krepelova et al. (1992); Lavergne et al. (1992);
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Lawn (1985); Levinson et al. (1987); Levinson et al. (1990); Mazurier
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et al. (2002); McKusick (1962); Mibashan et al. (1980); Mori et al.
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(1979); Nilsson et al. (1962); Nilsson et al. (1966); Patterson et
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al. (1989); Reiner et al. (1992); Schiffman and Rapaport (1966);
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Seligsohn et al. (1979); Sukarova et al. (2001); Youssoufian et al.
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(1987); Youssoufian et al. (1988); Zimmerman et al. (1971)
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</span>
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<br />
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Vogel, F.
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Wacey, A. I., Kemball-Cook, G., Kazazian, H. H., Antonarakis, S. E., Schwaab, R., Lindley, P., Tuddenham, E. G. D.
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Young, M., Inaba, H., Hoyer, L. W., Higuchi, M., Kazazian, H. H., Jr., Antonarakis, S. E.
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Youssoufian, H., Antonarakis, S. E., Bell, W., Griffin, A. M., Kazazian, H. H., Jr.
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<strong>Nonsense and missense mutations in hemophilia A: estimate of the relative mutation rate at CG dinucleotides.</strong>
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Youssoufian, H., Antonarakis, S. E., Kasper, C. K., Phillips, D. G., Kazazian, H. H., Jr.
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<strong>The spectrum and origin of mutations in hemophilia A. (Abstract)</strong>
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Youssoufian, H., Kasper, C. K., Phillips, D. G., Kazazian, H. H., Jr., Antonarakis, S. E.
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<strong>Restriction endonuclease mapping of six novel deletions of the factor VIII gene in hemophilia A.</strong>
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Youssoufian, H., Kazazian, H. H., Jr., Phillips, D. G., Aronis, S., Tsiftis, G., Brown, V. A., Antonarakis, S. E.
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Youssoufian, H., Wong, C., Aronis, S., Platokoukis, H., Kazazian, H. H., Jr., Antonarakis, S. E.
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<strong>Moderately severe hemophilia A resulting from glu-to-gly substitution in exon 7 of the factor VIII gene.</strong>
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Zimmerman, T. S., Ratnoff, O. D., Littell, A. S.
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Zimmerman, T. S., Ratnoff, O. D., Powell, A. E.
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<strong>Immunologic differentiation of classic hemophilia (factor VIII deficiency) and von Willebrand's disease, with observations on combined deficiencies of antihemophilic factor and proaccelerin (factor V) and on an acquired circulating anticoagulant against antihemophilic factor.</strong>
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Ada Hamosh - updated : 03/08/2023<br>Sonja A. Rasmussen - updated : 07/26/2022<br>Hilary J. Vernon - updated : 01/13/2022<br>Ada Hamosh - updated : 03/19/2018<br>Cassandra L. Kniffin - reorganized : 4/7/2011<br>Marla J. F. O'Neill - updated : 9/10/2009<br>Cassandra L. Kniffin - updated : 5/18/2009<br>Marla J. F. O'Neill - updated : 4/30/2009<br>Cassandra L. Kniffin - updated : 12/8/2008<br>Cassandra L. Kniffin - updated : 12/3/2008<br>Marla J. F. O'Neill - updated : 7/17/2008<br>Cassandra L. Kniffin - updated : 11/13/2007<br>Cassandra L. Kniffin - updated : 4/24/2007<br>Victor A. McKusick - updated : 9/29/2006<br>Victor A. McKusick - updated : 6/20/2006<br>Cassandra L. Kniffin - updated : 5/18/2005<br>Victor A. McKusick - updated : 1/30/2004<br>Victor A. McKusick - updated : 12/23/2003<br>Victor A. McKusick - updated : 9/8/2003<br>Victor A. McKusick - updated : 8/28/2003<br>Victor A. McKusick - updated : 7/7/2003<br>Victor A. McKusick - updated : 1/10/2003<br>Victor A. McKusick - updated : 11/15/2002<br>Victor A. McKusick - updated : 6/3/2002<br>Victor A. McKusick - updated : 4/4/2002<br>Victor A. McKusick - updated : 3/14/2002<br>Victor A. McKusick - updated : 8/15/2001<br>Victor A. McKusick - updated : 2/14/2001<br>Victor A. McKusick - updated : 1/5/2001<br>Ada Hamosh - updated : 12/15/1999<br>Victor A. McKusick - updated : 10/21/1999<br>Victor A. McKusick - updated : 6/3/1999<br>Victor A. McKusick - updated : 2/14/1999<br>Victor A. McKusick - updated : 3/12/1997<br>Moyra Smith - updated : 1/29/1997<br>Stylianos E. Antonarakis - updated : 7/18/1996
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Victor A. McKusick : 6/4/1986
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Scientific Director, OMIM <br />
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