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Entry
- #166200 - OSTEOGENESIS IMPERFECTA, TYPE I; OI1
- OMIM
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<span class="h4">#166200</span>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/166200"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS166200"> <strong>Phenotypic Series</strong> </a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#otherFeatures">Other Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</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="#diagnosis">Diagnosis</a>
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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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<div><a href="https://clinicaltrials.gov/search?cond=OSTEOGENESIS IMPERFECTA, TYPE I" 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 style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=18791&Typ=Pat" title="Osteogenesis imperfecta type 1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Osteogenesis imperfecta ty…&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=654&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Osteogenesis imperfecta&nbsp;</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1295/" 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 style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=216796" title="Osteogenesis imperfecta type 1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Osteogenesis imperfecta ty…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Osteogenesis imperfecta</a></div>
</div>
<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/936828cc-cb7e-4ecc-9f1d-8ff86815f8ec/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
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</a>
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</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0110334" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/166200" 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 class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
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</a>
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</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:166200" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
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</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
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</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 385482004<br />
<strong>ORPHA:</strong> 216796, 666<br />
<strong>DO:</strong> 0110334<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
166200
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
OSTEOGENESIS IMPERFECTA, TYPE I; OI1
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
OI, TYPE I<br />
OSTEOGENESIS IMPERFECTA TARDA<br />
OSTEOGENESIS IMPERFECTA WITH BLUE SCLERAE
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/735?start=-3&limit=10&highlight=735">
17q21.33
</a>
</span>
</td>
<td>
<span class="mim-font">
Osteogenesis imperfecta, type I
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/166200"> 166200 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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">
COL1A1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120150"> 120150 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/166200" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS166200" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
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&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/166200" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/166200" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GROWTH </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Height </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Normal to near normal stature <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833774&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833774</a>]</span><br /> -
Height often shorter than unaffected family members <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833775&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833775</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Ears </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hearing loss, progressive conductive and/or sensorineural, during adulthood <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277249&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277249</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/103276001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">103276001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/343087000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">343087000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15188001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15188001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H91.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H91.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span><br /> -
Otosclerosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11543004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11543004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H80" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H80</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H80.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H80.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H80.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H80.90</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/387.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">387.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/387" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">387</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029899&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029899</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000362" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000362</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000362" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000362</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Blue sclerae <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/204164000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">204164000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q13.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q13.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0542514&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0542514</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000592" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000592</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000592" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000592</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Teeth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Normal teeth (in most patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/162005007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">162005007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0426482&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0426482</a>]</span><br /> -
Dentinogenesis imperfecta (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/196286005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">196286005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K00.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K00.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011436&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011436</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000703" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000703</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000703" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000703</a>]</span><br /> -
Opalescent teeth (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843673&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843673</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Mitral valve prolapse <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/409712001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">409712001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8074002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8074002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026267&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026267</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001634" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001634</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001634" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001634</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Mild osteopenia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849057&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849057</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/312894000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">312894000</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000938" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000938</a>]</span><br /> -
Varying degree of multiple fractures <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833752&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833752</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002757" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002757</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002757" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002757</a>]</span><br />
</span>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Skull </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Wormian bones <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/113194005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">113194005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3553900&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3553900</a>, <a href="https://bioportal.bioontology.org/search?q=C0222716&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0222716</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002645" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002645</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002645" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002645</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Spine </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Biconcave flattened vertebrae <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833753&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833753</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003321" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003321</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003321" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003321</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Limbs </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Occasional femoral bowing <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833777&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833777</a>]</span><br /> -
Mild joint hypermobility <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833778&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833778</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/788453008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">788453008</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001382" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001382</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">
- Thin skin <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/277797007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">277797007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423757&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423757</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000963" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000963</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000963" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000963</a>]</span><br /> -
Easy bruisability <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/425075004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">425075004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/424131007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">424131007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423798&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423798</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000978" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000978</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000978" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000978</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Onset of fracture usually when child begins to walk<br /> -
Fracture frequency constant through childhood, decreases after puberty<br /> -
Fractures often heal without deformity<br /> -
Fracture frequency increases after menopause and in men ages 60-80<br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the collagen I, alpha-1 polypeptide gene (COL1A1, <a href="/entry/120150#0024">120150.0024</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Osteogenesis imperfecta
- <a href="/phenotypicSeries/PS166200">PS166200</a>
- 26 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/510?start=-3&limit=10&highlight=510"> 1p34.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610915"> Osteogenesis imperfecta, type VIII </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610915"> 610915 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610339"> P3H1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610339"> 610339 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/150?start=-3&limit=10&highlight=150"> 3p22.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610682"> Osteogenesis imperfecta, type VII </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610682"> 610682 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605497"> CRTAP </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605497"> 605497 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/5/688?start=-3&limit=10&highlight=688"> 5q33.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616507"> Osteogenesis imperfecta, type XVII </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616507"> 616507 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/182120"> SPARC </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/182120"> 182120 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/670?start=-3&limit=10&highlight=670"> 6q14.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617952"> Osteogenesis imperfecta, type XVIII </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617952"> 617952 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611357"> TENT5A </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611357"> 611357 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/59?start=-3&limit=10&highlight=59"> 7p22.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619131"> Osteogenesis imperfecta, type XXI </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619131"> 619131 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609024"> KDELR2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609024"> 609024 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/423?start=-3&limit=10&highlight=423"> 7q21.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/166210"> Osteogenesis imperfecta, type II </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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">
<a href="/entry/166210"> 166210 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120160"> COL1A2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120160"> 120160 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/423?start=-3&limit=10&highlight=423"> 7q21.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/259420"> Osteogenesis imperfecta, type III </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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">
<a href="/entry/259420"> 259420 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120160"> COL1A2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120160"> 120160 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/423?start=-3&limit=10&highlight=423"> 7q21.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/166220"> Osteogenesis imperfecta, type IV </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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">
<a href="/entry/166220"> 166220 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120160"> COL1A2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120160"> 120160 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/108?start=-3&limit=10&highlight=108"> 8p21.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614856"> Osteogenesis imperfecta, type XIII </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614856"> 614856 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/112264"> BMP1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/112264"> 112264 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/391?start=-3&limit=10&highlight=391"> 9q31.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615066"> Osteogenesis imperfecta, type XIV </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615066"> 615066 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611236"> TMEM38B </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611236"> 611236 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/18?start=-3&limit=10&highlight=18"> 11p15.5 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610967"> Osteogenesis imperfecta, type V </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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">
<a href="/entry/610967"> 610967 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614757"> IFITM5 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614757"> 614757 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/342?start=-3&limit=10&highlight=342"> 11p11.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616229"> Osteogenesis imperfecta, type XVI </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616229"> 616229 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616215"> CREB3L1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616215"> 616215 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/761?start=-3&limit=10&highlight=761"> 11q13.5 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613848"> Osteogenesis imperfecta, type X </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613848"> 613848 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600943"> SERPINH1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600943"> 600943 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/991?start=-3&limit=10&highlight=991"> 11q23.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620639"> Osteogenesis imperfecta, type XXIII </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620639"> 620639 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612834"> PHLDB1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612834"> 612834 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/344?start=-3&limit=10&highlight=344"> 12q13.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615220"> Osteogenesis imperfecta, type XV </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615220"> 615220 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164820"> WNT1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164820"> 164820 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/438?start=-3&limit=10&highlight=438"> 12q13.13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613849"> Osteogenesis imperfecta, type XII </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613849"> 613849 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606633"> SP7 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606633"> 606633 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/281?start=-3&limit=10&highlight=281"> 15q22.31 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/259440"> Osteogenesis imperfecta, type IX </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/259440"> 259440 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/123841"> PPIB </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/123841"> 123841 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/446?start=-3&limit=10&highlight=446"> 15q25.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618644"> Osteogenesis imperfecta, type XX </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618644"> 618644 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607783"> MESD </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607783"> 607783 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/36?start=-3&limit=10&highlight=36"> 17p13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613982"> Osteogenesis imperfecta, type VI </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613982"> 613982 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/172860"> SERPINF1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/172860"> 172860 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/557?start=-3&limit=10&highlight=557"> 17q21.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610968"> Osteogenesis imperfecta, type XI </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610968"> 610968 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607063"> FKBP10 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607063"> 607063 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/735?start=-3&limit=10&highlight=735"> 17q21.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/259420"> Osteogenesis imperfecta, type III </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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">
<a href="/entry/259420"> 259420 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120150"> COL1A1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120150"> 120150 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/735?start=-3&limit=10&highlight=735"> 17q21.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/166210"> Osteogenesis imperfecta, type II </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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">
<a href="/entry/166210"> 166210 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120150"> COL1A1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120150"> 120150 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/735?start=-3&limit=10&highlight=735"> 17q21.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/166220"> Osteogenesis imperfecta, type IV </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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">
<a href="/entry/166220"> 166220 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120150"> COL1A1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120150"> 120150 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/735?start=-3&limit=10&highlight=735"> 17q21.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/166200"> Osteogenesis imperfecta, type I </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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">
<a href="/entry/166200"> 166200 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120150"> COL1A1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/120150"> 120150 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/22/331?start=-3&limit=10&highlight=331"> 22q13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619795"> Osteogenesis imperfecta, type XXII </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619795"> 619795 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618788"> CCDC134 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618788"> 618788 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/X/112?start=-3&limit=10&highlight=112"> Xp22.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/301014"> Osteogenesis imperfecta, type XIX </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">
<a href="/entry/301014"> 301014 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300294"> MBTPS2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300294"> 300294 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
<div class="text-right small">
<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="text" class="mim-anchor"></a>
<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon &lt;span class='glyphicon glyphicon-plus-sign'&gt;&lt;/span&gt at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
<strong>TEXT</strong>
</span>
</span>
</h4>
<div id="mimTextFold" class="collapse in ">
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because OI type I (OI1) is caused by heterozygous mutation in the COL1A1 gene (<a href="/entry/120150">120150</a>) or the COL1A2 gene (<a href="/entry/120160">120160</a>).</p>
</span>
<div>
<br />
</div>
</div>
<div>
<a id="description" class="mim-anchor"></a>
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
</div>
<div id="mimDescriptionFold" class="collapse in ">
<span class="mim-text-font">
<p>Osteogenesis imperfecta type I (OI1) is a dominantly inherited, generalized connective tissue disorder characterized mainly by bone fragility and blue sclerae. In most cases, 'functional null' alleles of COL1A1 on chromosome 17 or COL1A2 on chromosome 7 lead to reduced amounts of normal collagen I.</p>
</span>
<div>
<br />
</div>
</div>
<div>
<a id="clinicalFeatures" class="mim-anchor"></a>
<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<strong>Clinical Features</strong>
</span>
</h4>
</div>
<div id="mimClinicalFeaturesFold" class="collapse in mimTextToggleFold">
<span class="mim-text-font">
<p>Osteogenesis imperfecta (see <a href="#19" class="mim-tip-reference" title="Byers, P. H. &lt;strong&gt;Osteogenesis imperfecta. In: Royce, P. M.; Steinmann, B.: Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects.&lt;/strong&gt; New York: Wiley-Liss (pub.) 1993. Pp. 317-350."None>Byers, 1993</a>) is characterized chiefly by multiple bone fractures, usually resulting from minimal trauma. Affected individuals have blue sclerae, normal teeth, and normal or near-normal stature (for growth curves, see <a href="#108" class="mim-tip-reference" title="Vetter, U., Pontz, B., Zauner, E., Brenner, R. E., Spranger, J. &lt;strong&gt;Osteogenesis imperfecta: a clinical study of the first ten years of life.&lt;/strong&gt; Calcif. Tissue Int. 50: 36-41, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1739868/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1739868&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00297295&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1739868">Vetter et al., 1992</a>). Fractures are rare in the neonatal period; fracture tendency is constant from childhood to puberty, decreases thereafter, and often increases following menopause in women and after the sixth decade in men. Fractures heal rapidly with evidence of a good callus formation, and, with good orthopedic care, without deformity. Hearing loss of conductive or mixed type occurs in about 50% of families, beginning in the late teens and leading, gradually, to profound deafness, tinnitus, and vertigo by the end of the fourth to fifth decade. Additional clinical findings may be thin, easily bruised skin, moderate joint hypermobility and kyphoscoliosis, hernias, and arcus senilis. Mitral valve prolapse, aortic valvular insufficiency, and a slightly larger than normal aortic root diameter have been identified in some individuals (<a href="#43" class="mim-tip-reference" title="Hortop, J., Tsipouras, P., Hanley, J. A., Maron, B. J., Shapiro, J. R. &lt;strong&gt;Cardiovascular involvement in osteogenesis imperfecta.&lt;/strong&gt; Circulation 73: 54-61, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3940669/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3940669&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/01.cir.73.1.54&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3940669">Hortop et al., 1986</a>), but it is not clear that these disorders are significantly more frequent than in the general population. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3940669+1739868" 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>Radiologically, wormian bones are common but bone morphology is generally normal at birth, although mild osteopenia and femoral bowing may be present. Vertebral body morphology in the adult is normal initially, but often develops the classic 'cod-fish' appearance (<a href="#97" class="mim-tip-reference" title="Steinmann, B., Superti-Furga, A., Giedion, A. &lt;strong&gt;Osteogenesis imperfecta. In: Dihlmann, W.; Frommhold, W. (eds.): Radiologische Diagnostik in Klinik und Praxis/Schinz. Vol. 6. Part 2.&lt;/strong&gt; Stuttgart: Georg Thieme (pub.) 1991. Pp. 728-745."None>Steinmann et al., 1991</a>).</p><p><strong><em>EYES</em></strong></p><p>
Individuals with OI type I have distinctly blue sclerae which remain intensely blue throughout life, in contrast to the sclerae in OI type III and OI type IV which may also be blue at birth and during infancy. The intensity of the blue fades with time such that these individuals may have sclerae of normal hue by adolescence and adult life (<a href="#89" class="mim-tip-reference" title="Sillence, D., Butler, B., Latham, M., Barlow, K. &lt;strong&gt;Natural history of blue sclerae in osteogenesis imperfecta.&lt;/strong&gt; Am. J. Med. Genet. 45: 183-186, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8456800/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8456800&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320450207&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8456800">Sillence et al., 1993</a>). In a likely heterogeneous group of 16 patients with OI syndromes, <a href="#45" class="mim-tip-reference" title="Kaiser-Kupfer, M. I., McCain, L., Shapiro, J. R., Podgor, M. J., Kupfer, C., Rowe, D. &lt;strong&gt;Low ocular rigidity in patients with osteogenesis imperfecta.&lt;/strong&gt; Invest. Ophthal. Vis. Sci. 20: 807-809, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7239850/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7239850&lt;/a&gt;]" pmid="7239850">Kaiser-Kupfer et al. (1981)</a> found low ocular rigidity and small corneal diameter and globe length; no correlation was found between rigidity of the eyeball and blueness of the sclera. The central corneal thickness was found to be significantly lower in 53 patients with OI than that in 35 patients with otosclerosis and in 35 control subjects (<a href="#68" class="mim-tip-reference" title="Pedersen, U., Bramsen, T. &lt;strong&gt;Central corneal thickness in osteogenesis imperfecta and otosclerosis.&lt;/strong&gt; ORL J. Otorhinolaryngol. Relat. Spec. 46: 38-41, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6700954/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6700954&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000275682&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6700954">Pedersen and Bramsen, 1984</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8456800+6700954+7239850" 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="Hartikka, H., Kuurila, K., Korkko, J., Kaitila, I., Grenman, R., Pynnonen, S., Hyland, J. C., Ala-Kokko, L. &lt;strong&gt;Lack of correlation between the type of COL1A1 or COL1A2 mutation and hearing loss in osteogenesis imperfecta patients.&lt;/strong&gt; Hum. Mutat. 24: 147-154, 2004. Note: Erratum: Hum. Mutat. 24: 437 only, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15241796/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15241796&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20071&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15241796">Hartikka et al. (2004)</a> found that patients with COL1A1 mutations more frequently had blue sclerae than those with COL1A2 mutations. In addition, patients with COL1A2 mutations tended to be shorter than those with COL1A1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15241796" 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>CARDIOVASCULAR SYSTEM</em></strong></p><p>
The prevalence and severity of cardiovascular involvement in OI type I was determined in a prospective study of patients of all ages (<a href="#74" class="mim-tip-reference" title="Pyeritz, R. E., Levin, L. S. &lt;strong&gt;Aortic root dilatation and valvular dysfunction in osteogenesis imperfecta. (Abstract)&lt;/strong&gt; Circulation 64: IV-311 only, 1981."None>Pyeritz and Levin, 1981</a>). Mitral valve prolapse occurred in 18% (3 times the prevalence in unaffected relatives) and rarely progressed to mitral regurgitation. Mean aortic root diameter was slightly but significantly increased and was associated with aortic regurgitation in 1 to 2%. No patient had suffered a dissection. Later, <a href="#43" class="mim-tip-reference" title="Hortop, J., Tsipouras, P., Hanley, J. A., Maron, B. J., Shapiro, J. R. &lt;strong&gt;Cardiovascular involvement in osteogenesis imperfecta.&lt;/strong&gt; Circulation 73: 54-61, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3940669/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3940669&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/01.cir.73.1.54&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3940669">Hortop et al. (1986)</a> studied 109 persons with nonlethal OI from 66 families. They could demonstrate no definite increase in the frequency of mitral valve prolapse over that to be expected in any group of persons. Aortic root dilatation was found by echocardiogram to be present in 8 of 66 persons with OI syndrome; dilatation was mild and unrelated to age of the patient but was strikingly aggregated in families. Of 109 persons surveyed, valvular disease was evident clinically in only 4 persons (aortic regurgitation in 2, aortic stenosis in one, and mitral valve prolapse in one). <a href="#43" class="mim-tip-reference" title="Hortop, J., Tsipouras, P., Hanley, J. A., Maron, B. J., Shapiro, J. R. &lt;strong&gt;Cardiovascular involvement in osteogenesis imperfecta.&lt;/strong&gt; Circulation 73: 54-61, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3940669/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3940669&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/01.cir.73.1.54&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3940669">Hortop et al. (1986)</a> stated that aortic root dilatation was seen in each of the different OI syndromes but strikingly segregated within certain families. They concluded that the mild and apparently nonprogressive nature of this lesion in OI argues against the use of beta-adrenergic blockade in affected individuals in the absence of systemic arterial hypertension. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3940669" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#62" class="mim-tip-reference" title="Mayer, S. A., Rubin, B. S., Starman, B. J., Byers, P. H. &lt;strong&gt;Spontaneous multivessel cervical artery dissection in a patient with a substitution of alanine for glycine (G13A) in the alpha-1(I) chain of type I collagen.&lt;/strong&gt; Neurology 47: 552-556, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8757037/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8757037&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.47.2.552&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8757037">Mayer et al. (1996)</a> reported a 35-year-old woman with a mild form of OI1 who presented with spontaneous dissection of the right internal carotid artery and the right vertebral artery after scuba diving. She had no obvious head or neck trauma. Other than a history of easy bruising and bluish sclerae, she had no evidence of a connective tissue disorder. There had been no bone fractures or dental problems nor was there family history of vasculopathy. Genetic analysis identified a heterozygous mutation in the COL1A1 gene (G13A; <a href="/entry/120150#0052">120150.0052</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8757037" 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>EARS</em></strong></p><p>
In likely heterogeneous groups of patients with OI, about half of affected individuals have hearing loss that begins during the second decade as a conductive loss; older individuals have sensorineural losses (<a href="#79" class="mim-tip-reference" title="Riedner, E. D., Levin, L. S., Holliday, M. J. &lt;strong&gt;Hearing patterns in dominant osteogenesis imperfecta.&lt;/strong&gt; Arch. Otolaryng. 106: 737-740, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7436848/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7436848&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archotol.1980.00790360015006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7436848">Riedner et al., 1980</a>; <a href="#69" class="mim-tip-reference" title="Pedersen, U. &lt;strong&gt;Hearing loss in patients with osteogenesis imperfecta. A clinical and audiological study of 201 patients.&lt;/strong&gt; Scand. Audiol. 13: 67-74, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6463554/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6463554&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.3109/01050398409043042&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6463554">Pedersen, 1984</a>). In only 1 major study was a majority of patients with sensorineural pattern observed (<a href="#85" class="mim-tip-reference" title="Shapiro, J. R., Pikus, A., Weiss, G., Rowe, D. W. &lt;strong&gt;Hearing and middle ear function in osteogenesis imperfecta.&lt;/strong&gt; JAMA 247: 2120-2126, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7062527/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7062527&lt;/a&gt;]" pmid="7062527">Shapiro et al., 1982</a>). A female-to-male preponderance of 2:1 has been reported (<a href="#88" class="mim-tip-reference" title="Shea, J. J., Postma, D. S. &lt;strong&gt;Findings and long-term surgical results in the hearing loss of osteogenesis imperfecta.&lt;/strong&gt; Arch. Otolaryng. 108: 467-470, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7103822/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7103822&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archotol.1982.00790560005002&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7103822">Shea and Postma, 1982</a>). Hearing loss is different from otosclerosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7062527+7103822+6463554+7436848" 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>Vertigo is frequently associated with otosclerosis in which the hearing loss clinically resembles that in OI. Vertigo is also common in basilar impression found in up to 25% of adult OI patients. To evaluate the cause, frequency, and characteristics of vertigo in OI, <a href="#47" class="mim-tip-reference" title="Kuurila, K., Kentala, E., Karjalainen, S., Pynnonen, S., Kovero, O., Kaitila, I., Grenman, R., Waltimo, J. &lt;strong&gt;Vestibular dysfunction in adult patients with osteogenesis imperfecta.&lt;/strong&gt; Am. J. Med. Genet. 120A: 350-358, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12838554/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12838554&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.20088&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12838554">Kuurila et al. (2003)</a> studied 42 patients by interview, clinical examination, and audiologic examination supplemented with electronystagmography (ENG) and lateral skull radiography. Audiometry showed hearing loss in 25 patients (59.5%). In 9 patients (21%), abnormal skull base anatomy was found in the forms of basilar impression, basilar invagination, or both. Vertigo, mostly of floating or rotational sensation of short duration, was reported by 22 patients (52.4%). Patients with hearing loss tended to have more vertigo than patients with normal hearing. Vertigo was not correlated with type of hearing loss or auditory brainstem response pathology. ENG was abnormal in 14 patients (33.3%). <a href="#47" class="mim-tip-reference" title="Kuurila, K., Kentala, E., Karjalainen, S., Pynnonen, S., Kovero, O., Kaitila, I., Grenman, R., Waltimo, J. &lt;strong&gt;Vestibular dysfunction in adult patients with osteogenesis imperfecta.&lt;/strong&gt; Am. J. Med. Genet. 120A: 350-358, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12838554/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12838554&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.20088&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12838554">Kuurila et al. (2003)</a> concluded that vertigo is common in patients with OI and that in most cases, it is secondary to inner ear pathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12838554" 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="Hartikka, H., Kuurila, K., Korkko, J., Kaitila, I., Grenman, R., Pynnonen, S., Hyland, J. C., Ala-Kokko, L. &lt;strong&gt;Lack of correlation between the type of COL1A1 or COL1A2 mutation and hearing loss in osteogenesis imperfecta patients.&lt;/strong&gt; Hum. Mutat. 24: 147-154, 2004. Note: Erratum: Hum. Mutat. 24: 437 only, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15241796/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15241796&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20071&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15241796">Hartikka et al. (2004)</a> reported a correlative analysis between types of mutation in the COL1A1 and COL1A2 genes and OI-associated hearing loss. A total of 54 Finnish OI patients with previously diagnosed hearing loss or age 35 or more years were analyzed for mutations in COL1A1 or COL1A2. Altogether 49 mutations were identified, of which 41 were novel. No correlation was found between the mutated gene or mutation type and hearing pattern. The authors interpreted this to mean that the basis of hearing loss in OI is complex, and that it is a result of multifactorial, still unknown genetic effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15241796" 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>SKIN</em></strong></p><p>
Using a suction-cup technique, <a href="#40" class="mim-tip-reference" title="Hansen, B., Jemec, G. B. E. &lt;strong&gt;The mechanical properties of skin in osteogenesis imperfecta.&lt;/strong&gt; Arch. Derm. 138: 909-911, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12071818/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12071818&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archderm.138.7.909&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12071818">Hansen and Jemec (2002)</a> performed quantitative studies of skin mechanics (elasticity, distensibility, and hysteresis) in 10 patients with OI, 8 with type I and 2 with type III (<a href="/entry/259420">259420</a>), and 24 age-matched controls. Skin elasticity, distensibility, and hysteresis were significantly decreased in patients versus controls. OI type I patients had decreased distensibility and hysteresis but increased elasticity in comparison to the type III patients. The authors concluded that the skin of patients with OI is more stiff and less elastic than normal skin. These changes differ from age-related changes, which have been described as increased distensibility and viscosity (similar to hysteresis). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12071818" 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>CRANIOFACIAL AND DENTAL FEATURES</em></strong></p><p>
To obtain baseline information on craniofacial development in OI patients who had not received bisphosphonate treatment, <a href="#110" class="mim-tip-reference" title="Waltimo-Siren, J., Kolkka, M., Pynnonen, S., Kuurila, K., Kaitila, I., Kovero, O. &lt;strong&gt;Craniofacial features in osteogenesis imperfecta: a cephalometric study.&lt;/strong&gt; Am. J. Med. Genet. 133A: 142-150, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15666304/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15666304&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30523&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15666304">Waltimo-Siren et al. (2005)</a> used lateral radiographs to analyze the size and form of the bony structures in heads of 59 consecutive patients with OI types I, III, or IV (Sillence classification). In OI type I they found linear measurements that were smaller than normal, indicating a general growth deficiency, but no remarkable craniofacial deformity. In OI types III and IV, the growth impairment was pronounced and the craniofacial form was altered as a result of differential growth deficiency and bending of the skeletal head structures. They found strong support both for an abnormally ventral position of the sella region due to bending of the cranial base and for a closing mandibular growth rotation. Vertical underdevelopment of the dentoalveolar structures and the condylar process were identified as the main reasons for the relative mandibular prognathism in OI. <a href="#110" class="mim-tip-reference" title="Waltimo-Siren, J., Kolkka, M., Pynnonen, S., Kuurila, K., Kaitila, I., Kovero, O. &lt;strong&gt;Craniofacial features in osteogenesis imperfecta: a cephalometric study.&lt;/strong&gt; Am. J. Med. Genet. 133A: 142-150, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15666304/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15666304&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30523&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15666304">Waltimo-Siren et al. (2005)</a> concluded that facial growth impairment would probably remain characteristic for many OI patients despite the widespread intervention with bisphosphonates and that orthodontic treatment should be further developed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15666304" 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>CLINICAL VARIABILITY</em></strong></p><p>
The disorder may exhibit considerable interfamilial and intrafamilial variability in the number of fractures and degree of disability. <a href="#81" class="mim-tip-reference" title="Rowe, D. W., Shapiro, J. R., Schlesinger, S. &lt;strong&gt;Diminished type I collagen synthesis and reduced alpha 1(I) collagen messenger RNA in cultured fibroblasts from patients with dominantly inherited (type I) osteogenesis imperfecta.&lt;/strong&gt; J. Clin. Invest. 76: 604-611, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4031065/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4031065&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI112012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4031065">Rowe et al. (1985)</a> reported a spectrum of disease severity within a 5-generation family. Those most severely affected exhibited more severe short stature and a mild degree of scoliosis relative to those who were less severely affected. Most striking were identical twins, the offspring of a mildly affected mother. Twin B was born small for gestational age, had had 12 fractures and was 150 cm tall (3rd centile) at 11 years of age. Her twin was born appropriate for gestational age and had had only 2 fractures at age 8 and 9 secondary to strenuous exercise; her current height was 162 cm (50th centile). This family study suggested that the severity of the disease is roughly correlated with the reduction in collagen I synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4031065" 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="Willing, M. C., Cohn, D. H., Byers, P. H. &lt;strong&gt;Frameshift mutation near the 3-prime end of the COL1A1 gene of type I collagen predicts an elongated pro-alpha-1(I) chain and results in osteogenesis imperfecta type I.&lt;/strong&gt; J. Clin. Invest. 85: 282-290, 1990. Note: Erratum: J. Clin. Invest. 85: following 1338, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2295701/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2295701&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI114424&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2295701">Willing et al. (1990)</a> described 5 affected individuals of a 3-generation family with marked clinical variability. They wondered if there might be subtle biochemical differences between the family members with respect to the amount of the abnormal pro-alpha-1(I) chains produced or their intracellular fate, but no differences were observed. They noticed that the more severely affected family members had children with both mild and severe phenotypes, while the mildly affected individual had an offspring with a mild phenotype. This suggested to them that there might be some other, not identified, factor segregating independently in this family that acts to modulate the final phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2295701" 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>CLASSIFICATION</em></strong></p><p>
Using clinical, radiographic, and genetic criteria, <a href="#90" class="mim-tip-reference" title="Sillence, D. O., Senn, A., Danks, D. M. &lt;strong&gt;Genetic heterogeneity in osteogenesis imperfecta.&lt;/strong&gt; J. Med. Genet. 16: 101-116, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/458828/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;458828&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.16.2.101&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="458828">Sillence et al. (1979)</a> developed the classification currently in use into types I to IV: a dominant form with blue sclerae, type I; a dominant form with normal sclerae, type IV (<a href="/entry/166220">166220</a>); a perinatally lethal OI syndrome, type II (<a href="/entry/166210">166210</a>); and a progressively deforming form with normal sclerae, type III. The biochemical and linkage studies support the broad validity of the classification but confirm that it is incomplete. Although biochemical and genetic studies will provide the basis of the most rational classification, even such a detailed scheme probably will never predict correctly the evolution of OI in every affected individual, because of the still unexplained variability of expression seen in many families (<a href="#19" class="mim-tip-reference" title="Byers, P. H. &lt;strong&gt;Osteogenesis imperfecta. In: Royce, P. M.; Steinmann, B.: Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects.&lt;/strong&gt; New York: Wiley-Liss (pub.) 1993. Pp. 317-350."None>Byers, 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=458828" 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="#5" class="mim-tip-reference" title="Bauze, R. J., Smith, R., Francis, M. J. O. &lt;strong&gt;A new look at osteogenesis imperfecta: a clinical, radiological and biochemical study of forty-two patients.&lt;/strong&gt; J. Bone Joint Surg. Br. 57: 2-12, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1117018/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1117018&lt;/a&gt;]" pmid="1117018">Bauze et al. (1975)</a> divided their 42 patients with OI into mild, moderate, and severe groups according to deformity of long bones. None of the 17 patients in the mild group had scoliosis or white sclerae. The terms 'congenita' and 'tarda' now have limited usefulness, since they do not specify the mode of inheritance or basic biochemical defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1117018" 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="#51" class="mim-tip-reference" title="Levin, L. S., Brady, J. M., Melnick, M. &lt;strong&gt;Scanning electron microscopy of teeth in dominant osteogenesis imperfecta.&lt;/strong&gt; Am. J. Med. Genet. 5: 189-199, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7395911/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7395911&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320050213&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7395911">Levin et al. (1980)</a> concluded that dominant type I OI separates clearly into families in which affected persons have opalescent teeth and those in which dentinogenesis imperfecta (DGI) is absent. In 5 families, all members whose teeth were studied radiographically and by scanning electron microscopy had opalescent teeth. In 2 families the teeth of all affected persons were normal. Some members of both classes of families had blue sclerae and others did not. These 2 forms of OI were designated type IA and IB, depending on the presence or absence, respectively, of DGI. <a href="#67" class="mim-tip-reference" title="Paterson, C. R., McAllion, S., Miller, R. &lt;strong&gt;Heterogeneity of osteogenesis imperfecta type I.&lt;/strong&gt; J. Med. Genet. 20: 203-205, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6876111/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6876111&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.20.3.203&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6876111">Paterson et al. (1983)</a> found that patients with associated DGI (type IA) have more severe disease, with a greater fracture rate and greater likelihood of growth impairment, than do type IB patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7395911+6876111" 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="Superti-Furga, A., Unger, S., the Nosology Group of the International Skeletal Dysplasia Society. &lt;strong&gt;Nosology and classification of genetic skeletal disorders: 2006 revision.&lt;/strong&gt; Am. J. Med. Genet. 143A: 1-18, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17120245/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17120245&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31483&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17120245">Superti-Furga et al. (2007)</a> discussed the 2006 revisions to the Nosology of Constitutional Disorders of Bone by the Nosology Group of the International Skeletal Dysplasia Society and provided a comprehensive table of the new classification scheme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17120245" 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="#19" class="mim-tip-reference" title="Byers, P. H. &lt;strong&gt;Osteogenesis imperfecta. In: Royce, P. M.; Steinmann, B.: Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects.&lt;/strong&gt; New York: Wiley-Liss (pub.) 1993. Pp. 317-350."None>Byers (1993)</a> summarized that 'functional null' alleles, i.e., silent alleles or mutations leading to excluded proteins, are the most common biochemical and genetic features of OI type I, although structural mutations in COL1A1 and COL1A2 leading to the synthesis of abnormal procollagen I can occasionally produce the OI type I phenotype.</p><p>Assessing reports of biochemical findings in the OI syndromes is difficult because the phenotype and genetics generally are not specified. Most studies deal, no doubt, with heterogeneous groups of patients. Several forms of OI were among the earliest of the inherited disorders of collagen biosynthesis and structure to be studied using cultured dermal fibroblasts from affected individuals (<a href="#61" class="mim-tip-reference" title="Martin, G. R., Layman, D. L., Narayanan, A. S., Nigra, T. P., Siegel, R. C. &lt;strong&gt;Collagen synthesis by cultured human fibroblasts. (Abstract)&lt;/strong&gt; Isr. J. Med. Sci. 7: 455-456, 1971."None>Martin et al., 1971</a>; <a href="#70" class="mim-tip-reference" title="Penttinen, R. P., Lichtenstein, J. R., Martin, G. R., McKusick, V. A. &lt;strong&gt;Abnormal collagen metabolism in cultured cells in osteogenesis imperfecta.&lt;/strong&gt; Proc. Nat. Acad. Sci. 72: 586-589, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1054840/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1054840&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.72.2.586&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1054840">Penttinen et al., 1975</a>). Cells cultured from patients who, in retrospect, would be considered to have OI type I, synthesized less procollagen I than did controls, but the mechanism by which production was decreased was not determined. These studies were extended from culture to tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1054840" 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="Francis, M. J. O., Smith, R., Bauze, R. J. &lt;strong&gt;Instability of polymeric skin collagen in osteogenesis imperfecta.&lt;/strong&gt; Brit. Med. J. 1: 421-424, 1974.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4816854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4816854&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/bmj.1.5905.421&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4816854">Francis et al. (1974)</a> concluded that patients with OI and blue sclerae tend to have a reduced amount of collagen that has normal stability, as measured by resistance to depolymerization by pronase, heat, or cold alkali, whereas those with white sclerae have a normal amount of collagen with reduced stability; they suggested that a defect in cross-linking of collagen is present in the severe form of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4816854" 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="#101" class="mim-tip-reference" title="Sykes, B., Francis, M. J. O., Phil, F. D., Smith, R. &lt;strong&gt;Altered relation of two collagen types in osteogenesis imperfecta.&lt;/strong&gt; New Eng. J. Med. 296: 1200-1203, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/857159/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;857159&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197705262962104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="857159">Sykes et al. (1977)</a> and, in a slightly extended study, <a href="#33" class="mim-tip-reference" title="Francis, M. J. O., Williams, K. J., Sykes, B. C., Smith, R. &lt;strong&gt;The relative amounts of the collagen chains alpha-1(I), alpha-2 and alpha-1(III) in the skin of 31 patients with osteogenesis imperfecta.&lt;/strong&gt; Clin. Sci. (Lond.) 60: 617-623, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6788428/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6788428&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1042/cs0600617&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6788428">Francis et al. (1981)</a>, found an increased ratio of collagen III to I in dermis and interpreted this as indicating a deficiency of collagen I. In studies of 44 patients with OI, <a href="#22" class="mim-tip-reference" title="Cetta, G., de Luca, G., Tenni, R., Zanaboni, G., Lenzi, L., Castellani, A. A. &lt;strong&gt;Biochemical investigations of different forms of osteogenesis imperfecta: evaluation of 44 cases.&lt;/strong&gt; Connect. Tissue Res. 11: 103-111, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6224635/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6224635&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.3109/03008208309004847&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6224635">Cetta et al. (1983)</a> found in the largest category, the mild form, also an increased ratio of collagens III to I in skin and, in addition, an increased ratio of hydroxylysine diglycoside to monoglycoside in skin collagen. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6224635+6788428+857159" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#80" class="mim-tip-reference" title="Rowe, D. W., Poirier, M., Shapiro, J. R. &lt;strong&gt;Type I collagen in osteogenesis imperfecta: a genetic probe to study type I collagen biosynthesis. In: Veis, A.: The Chemistry and Biology of Mineralized Connective Tissues.&lt;/strong&gt; New York: Elsevier/North Holland (pub.) 1981. Pp. 155-162."None>Rowe et al. (1981)</a> proposed that an additional criterion for OI type I is the production of a reduced quantity of collagen I. Among the cases of osteogenesis imperfecta with reduced synthesis of pro-alpha-1 chains, considerable heterogeneity is likely to emerge at the level of gene structure, as in the case of the globin genes in the thalassemias. <a href="#4" class="mim-tip-reference" title="Barsh, G. S., David, K. E., Byers, P. H. &lt;strong&gt;Type I osteogenesis imperfecta: a nonfunctional allele for pro-alpha-1(I) chains of type I procollagen.&lt;/strong&gt; Proc. Nat. Acad. Sci. 79: 3838-3842, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6954526/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6954526&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.79.12.3838&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6954526">Barsh et al. (1982)</a> found that cultured skin fibroblasts from 3 patients produced half-normal levels of procollagen type I. Furthermore, the OI cells contained equimolar amounts of pro-alpha-1(I) and pro-alpha-2(I) chains, which suggested that trimer assembly and secretion were limited by the level of pro-alpha-1(I) chain synthesis. The 'extra' pro-alpha-2(I) chain in the OI cells was in a non-disulfide bonded configuration and apparently contributed to an increased level of intracellular degradation. The results of <a href="#4" class="mim-tip-reference" title="Barsh, G. S., David, K. E., Byers, P. H. &lt;strong&gt;Type I osteogenesis imperfecta: a nonfunctional allele for pro-alpha-1(I) chains of type I procollagen.&lt;/strong&gt; Proc. Nat. Acad. Sci. 79: 3838-3842, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6954526/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6954526&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.79.12.3838&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6954526">Barsh et al. (1982)</a> suggested that the stoichiometry of the pro-alpha chains in procollagen I is determined by the conformation of the chains rather than by the ratio in which they are synthesized, that molecules containing more than a single pro-alpha-2(I) chain are not assembled, and that the production of collagen I can be regulated by controlling synthesis of only one of its subunits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6954526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#81" class="mim-tip-reference" title="Rowe, D. W., Shapiro, J. R., Schlesinger, S. &lt;strong&gt;Diminished type I collagen synthesis and reduced alpha 1(I) collagen messenger RNA in cultured fibroblasts from patients with dominantly inherited (type I) osteogenesis imperfecta.&lt;/strong&gt; J. Clin. Invest. 76: 604-611, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4031065/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4031065&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI112012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4031065">Rowe et al. (1985)</a> demonstrated that reductions in collagen I production and in the ratio of alpha-1(I) to alpha-2(I) mRNA are clearly segregated with affected individuals within the 5 generation family. <a href="#81" class="mim-tip-reference" title="Rowe, D. W., Shapiro, J. R., Schlesinger, S. &lt;strong&gt;Diminished type I collagen synthesis and reduced alpha 1(I) collagen messenger RNA in cultured fibroblasts from patients with dominantly inherited (type I) osteogenesis imperfecta.&lt;/strong&gt; J. Clin. Invest. 76: 604-611, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4031065/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4031065&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI112012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4031065">Rowe et al. (1985)</a> further suggested that the severity of the disorder is roughly correlated with the reduction in collagen I synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4031065" 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="#111" class="mim-tip-reference" title="Wenstrup, R. J., Willing, M. C., Starman, B. J., Byers, P. H. &lt;strong&gt;Distinct biochemical phenotypes predict clinical severity in nonlethal variants of osteogenesis imperfecta.&lt;/strong&gt; Am. J. Hum. Genet. 46: 975-982, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2339695/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2339695&lt;/a&gt;]" pmid="2339695">Wenstrup et al. (1990)</a> correlated clinical severity in nonlethal variants of OI with the nature of the alteration in the alpha chains of procollagen I secreted by cultured fibroblasts. Cells from 40 probands secreted about half the normal amount of normal procollagen I and no identifiable abnormal molecules; these patients were generally of normal stature, rarely had bone deformity or dentinogenesis imperfecta, and had blue sclerae. Cells from 74 other probands produced and secreted normal and abnormal procollagen I molecules; these patients were usually short and had bone deformity and dentinogenesis imperfecta, and many had gray or blue-gray sclerae. In cells from yet another 18 probands, <a href="#111" class="mim-tip-reference" title="Wenstrup, R. J., Willing, M. C., Starman, B. J., Byers, P. H. &lt;strong&gt;Distinct biochemical phenotypes predict clinical severity in nonlethal variants of osteogenesis imperfecta.&lt;/strong&gt; Am. J. Hum. Genet. 46: 975-982, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2339695/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2339695&lt;/a&gt;]" pmid="2339695">Wenstrup et al. (1990)</a> were unable to identify altered procollagen I synthesis or structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2339695" 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="#35" class="mim-tip-reference" title="Gauba, V., Hartgerink, J. D. &lt;strong&gt;Synthetic collagen heterotrimers: structural mimics of wild-type and mutant collagen type I.&lt;/strong&gt; J. Am. Chem. Soc. 130: 7509-7515, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18481852/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18481852&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1021/ja801670v&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18481852">Gauba and Hartgerink (2008)</a> reported the design of a novel model system based upon collagen-like heterotrimers that can mimic the glycine mutations present in either the alpha-1 or alpha-2 chains of type I collagen. The design utilized an electrostatic recognition motif in 3 chains that can force the interaction of any 3 peptides, including AAA (all same), AAB (2 same and 1 different), or ABC (all different) triple helices. Therefore, the component peptides could be designed in such a way that glycine mutations were present in zero, 1, 2, or all 3 chains of the triple helix. They reported collagen mutants containing 1 or 2 glycine substitutions with structures relevant to native forms of OI. <a href="#35" class="mim-tip-reference" title="Gauba, V., Hartgerink, J. D. &lt;strong&gt;Synthetic collagen heterotrimers: structural mimics of wild-type and mutant collagen type I.&lt;/strong&gt; J. Am. Chem. Soc. 130: 7509-7515, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18481852/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18481852&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1021/ja801670v&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18481852">Gauba and Hartgerink (2008)</a> demonstrated the difference in thermal stability and refolding half-life times between triple helices that vary only in the frequency of glycine mutations at a particular position. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18481852" 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>By differential scanning calorimetry and circular dichroism, <a href="#59" class="mim-tip-reference" title="Makareeva, E., Mertz, E. L., Kuznetsova, N. V., Sutter, M. B., DeRidder, A. M., Cabral, W. A., Barnes, A. M., McBride, D. J., Marini, J. C., Leikin, S. &lt;strong&gt;Structural heterogeneity of type I collagen triple helix and its role in osteogenesis imperfecta.&lt;/strong&gt; J. Biol. Chem. 283: 4787-4798, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18073209/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18073209&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M705773200&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18073209">Makareeva et al. (2008)</a> measured and mapped changes in the collagen melting temperature (delta-T(m)) for 41 different glycine substitutions from 47 OI patients. In contrast to peptides, they found no correlation of delta-T(m) with the identity of the substituting residue but instead observed regular variations in delta-T(m) with the substitution location on different triple helix regions. To relate the delta-T(m) map to peptide-based stability predictions, the authors extracted the activation energy of local helix unfolding from the reported peptide data and constructed the local helix unfolding map and tested it by measuring the hydrogen-deuterium exchange rate for glycine NH residues involved in interchain hydrogen bonds. <a href="#59" class="mim-tip-reference" title="Makareeva, E., Mertz, E. L., Kuznetsova, N. V., Sutter, M. B., DeRidder, A. M., Cabral, W. A., Barnes, A. M., McBride, D. J., Marini, J. C., Leikin, S. &lt;strong&gt;Structural heterogeneity of type I collagen triple helix and its role in osteogenesis imperfecta.&lt;/strong&gt; J. Biol. Chem. 283: 4787-4798, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18073209/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18073209&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M705773200&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18073209">Makareeva et al. (2008)</a> delineated regional variations in the collagen triple helix stability. Two large, flexible regions deduced from the delta-T(m) map aligned with the regions important for collagen fibril assembly and ligand binding. One of these regions also aligned with a lethal region for Gly substitutions in the alpha-1(I) chain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18073209" 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="#29" class="mim-tip-reference" title="Dickson, I. R., Millar, E. A., Veis, A. &lt;strong&gt;Evidence for abnormality of bone-matrix proteins in osteogenesis imperfecta.&lt;/strong&gt; Lancet 306: 586-587, 1975. Note: Originally Volume II.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/51410/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;51410&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(75)90173-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="51410">Dickson et al. (1975)</a> reported a quantitative and qualitative abnormality of noncollagenous proteins of bone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=51410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#49" class="mim-tip-reference" title="Lancaster, G., Goldman, H., Scriver, C. R., Gold, R. J. M., Wong, I. &lt;strong&gt;Dominantly inherited osteogenesis imperfecta in man: an examination of collagen biosynthesis.&lt;/strong&gt; Pediat. Res. 9: 83-88, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1118195/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1118195&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-197502000-00005&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1118195">Lancaster et al. (1975)</a> found a consistent morphologic abnormality of cultured skin fibroblasts: irregular packing of aggregated cells and an irregular tessellated appearance of individual fibroblasts. <a href="#12" class="mim-tip-reference" title="Boright, A. P., Lancaster, G. A., Scriver, C. R. &lt;strong&gt;Osteogenesis imperfecta: a heterogeneous morphologic phenotype in cultured dermal fibroblasts.&lt;/strong&gt; Hum. Genet. 67: 29-33, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6745923/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6745923&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00270554&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6745923">Boright et al. (1984)</a> showed that dermal fibroblasts derived from individuals with OI type I take longer than control cells to reach confluency, have a lower cell density at stationary phase and have an abnormal cell shape as judged by the increased ratio of width to length. An increase in population doubling time of fibroblasts derived from individuals with the milder form of OI was also observed by <a href="#82" class="mim-tip-reference" title="Rowe, D. W., Shapiro, J. R. &lt;strong&gt;Biochemical features of cultured skin fibroblasts from patients with osteogenesis imperfecta. In: Akeson, W. H.; Bornstein, P.; Glimcher, M. J.: Symposium on Heritable Disorders of Connective Tissue.&lt;/strong&gt; St. Louis: C. V. Mosby (pub.) 1982. Pp. 269-282."None>Rowe and Shapiro (1982)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6745923+1118195" 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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<div>
<a id="inheritance" class="mim-anchor"></a>
<h4 href="#mimInheritanceFold" id="mimInheritanceToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Inheritance</strong>
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<p>The mode of inheritance is autosomal dominant. Penetrance of blue sclerae is 100 percent, while penetrance of hearing loss is clearly age-dependent (<a href="#34" class="mim-tip-reference" title="Garretsen, T. J. T. M., Cremers, C. W. R. J. &lt;strong&gt;Clinical and genetic aspects in autosomal dominant inherited osteogenesis imperfecta type I.&lt;/strong&gt; Ann. N.Y. Acad. Sci. 630: 240-248, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1952595/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1952595&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1749-6632.1991.tb19594.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1952595">Garretsen and Cremers, 1991</a>). Paternal age effect for increased risk of new mutations has been documented although it appears to be considerably lower than, for example, in achondroplasia (<a href="/entry/100800">100800</a>). In 10 cases with OI type I presumed to have arisen by new mutation, the mean paternal age was increased by 2.1 years (<a href="#90" class="mim-tip-reference" title="Sillence, D. O., Senn, A., Danks, D. M. &lt;strong&gt;Genetic heterogeneity in osteogenesis imperfecta.&lt;/strong&gt; J. Med. Genet. 16: 101-116, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/458828/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;458828&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.16.2.101&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="458828">Sillence et al., 1979</a>), whereas in 38 other cases it was significantly increased by 2.9 years (<a href="#20" class="mim-tip-reference" title="Carothers, A. D., McAllion, S. J., Paterson, C. R. &lt;strong&gt;Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta.&lt;/strong&gt; J. Med. Genet. 23: 227-230, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3723550/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3723550&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.23.3.227&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3723550">Carothers et al., 1986</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3723550+1952595+458828" 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="#10" class="mim-tip-reference" title="Blumsohn, A., McAllion, S. J., Paterson, C. R. &lt;strong&gt;Excess paternal age in apparently sporadic osteogenesis imperfecta.&lt;/strong&gt; Am. J. Med. Genet. 100: 280-286, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11343319/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11343319&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1269&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11343319">Blumsohn et al. (2001)</a> confirmed the presence of a small paternal age effect in apparently sporadic OI. The study evaluated patients born in England, Wales, and Scotland between 1961 and 1998. For 357 apparently sporadic cases among 730 eligible cases, the mean age of fathers at the birth of their children was 0.87 years greater than expected (p = 0.01). The relative risk was 1.62 for fathers in the highest quintile of paternal age compared with fathers in the lowest quintile. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11343319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="mapping" class="mim-anchor"></a>
<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Mapping</strong>
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<p>In all but 1 of 11 families with OI tarda, <a href="#102" class="mim-tip-reference" title="Sykes, B., Ogilvie, D., Wordsworth, P., Anderson, J., Jones, N. &lt;strong&gt;Osteogenesis imperfecta is linked to both type I collagen structural genes.&lt;/strong&gt; Lancet 328: 69-72, 1986. Note: Originally Volume II.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2873381/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2873381&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(86)91609-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2873381">Sykes et al. (1986)</a> found that the disorder segregated with either the COL1A1 locus or the COL1A2 locus. In 1 small family, segregation occurred with both genes, but this disorder clearly cannot be linked to both; had further meioses been available, the OI gene would probably have segregated independently of at least 1 of the 2 loci. <a href="#106" class="mim-tip-reference" title="Tsipouras, P. &lt;strong&gt;Genetic heterogeneity of mild osteogenesis imperfecta (OI types I and IV): linkage to COL1A1, COL1A2 and possibly other loci. (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 46: 706 only, 1987."None>Tsipouras (1987)</a>, also, concluded that mild OI is genetically heterogeneous and that 1 or more loci other than COL1A1 and COL1A2 may be involved in the causation of phenotypically indistinguishable autosomal dominant OI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2873381" 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="#103" class="mim-tip-reference" title="Sykes, B., Ogilvie, D., Wordsworth, P., Wallis, G., Mathew, C., Beighton, P., Nicholls, A., Pope, F. M., Thompson, E., Tsipouras, P., Schwartz, R., Jensson, O., Arnason, A., Borresen, A.-L., Heiberg, A., Frey, D., Steinmann, B. &lt;strong&gt;Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2.&lt;/strong&gt; Am. J. Hum. Genet. 46: 293-307, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1967900/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1967900&lt;/a&gt;]" pmid="1967900">Sykes et al. (1990)</a> studied segregation of the COL1A1 and COL1A2 genes in 38 dominant osteogenesis imperfecta pedigrees. None of the 38 pedigrees showed recombination between the OI gene and both collagen loci. All 8 pedigrees with OI type IV (<a href="/entry/166220">166220</a>) segregated with COL1A2. On the other hand, 17 type I pedigrees segregated with COL1A1 and 7 with COL1A2. The concordant locus was uncertain in the remaining 6 OI type I pedigrees. The presence or absence of presenile hearing loss was the best predictor of the mutant locus in OI type I families, with 13 of the 17 COL1A1 segregants and none of the 7 COL1A2 segregants showing this feature. By linkage analysis in 7 autosomal dominant osteogenesis imperfecta families in Italy, <a href="#63" class="mim-tip-reference" title="Mottes, M., Cugola, L., Cappello, N., Pignatti, P. F. &lt;strong&gt;Segregation analysis of dominant osteogenesis imperfecta in Italy.&lt;/strong&gt; J. Med. Genet. 27: 367-370, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1972760/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1972760&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.27.6.367&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1972760">Mottes et al. (1990)</a> showed that the COL1A1 gene was implicated in 2 families and the COL1A2 gene in 1 family with OI type I. The COL1A2 gene was implicated in 2 families with OI type IV. In 2 OI type I families, the molecular genetic data were insufficient for exclusion of one gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1972760+1967900" 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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<div>
<a id="molecularGenetics" class="mim-anchor"></a>
<h4 href="#mimMolecularGeneticsFold" id="mimMolecularGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Molecular Genetics</strong>
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<div id="mimMolecularGeneticsFold" class="collapse in mimTextToggleFold">
<span class="mim-text-font">
<p><a href="#19" class="mim-tip-reference" title="Byers, P. H. &lt;strong&gt;Osteogenesis imperfecta. In: Royce, P. M.; Steinmann, B.: Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects.&lt;/strong&gt; New York: Wiley-Liss (pub.) 1993. Pp. 317-350."None>Byers (1993)</a> summarized that 'functional null' alleles are the most common genetic features of OI type I. The mechanism by which the synthesis of pro-alpha-1(I) chains is decreased remains a difficult problem to solve. A variety of mutations, such as deletion of an allele, promoter and enhancer mutations, splicing mutations, premature termination, as well as other mutations that result in the inability of pro-alpha-1(I) chains to assemble into molecules, would presumably result in the same biochemical picture and the same phenotype.</p><p>In some individuals, the decreased production of pro-alpha-1(I) chains by fibroblasts results from about half-normal steady-state levels of the mRNA (<a href="#81" class="mim-tip-reference" title="Rowe, D. W., Shapiro, J. R., Schlesinger, S. &lt;strong&gt;Diminished type I collagen synthesis and reduced alpha 1(I) collagen messenger RNA in cultured fibroblasts from patients with dominantly inherited (type I) osteogenesis imperfecta.&lt;/strong&gt; J. Clin. Invest. 76: 604-611, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4031065/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4031065&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI112012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4031065">Rowe et al., 1985</a>). Later studies on these cells indicated that there is a defect in splicing of the pre-mRNA of COL1A1 that prohibits transport of the product of the mutant allele to the cytoplasm; the ratio of pro-alpha-1(I) to pro-alpha-2(I) mRNA was 1:1 in the cytoplasm instead of the normal 2:1, whereas the ratio was 4:1 in the nucleus instead of the normal 2:1 (<a href="#37" class="mim-tip-reference" title="Genovese, C., Rowe, D. &lt;strong&gt;Analysis of cytoplasmatic and nuclear messenger RNA in fibroblasts from patients with type I osteogenesis imperfecta.&lt;/strong&gt; Methods Enzymol. 145: 223-235, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3474490/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3474490&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0076-6879(87)45012-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3474490">Genovese and Rowe, 1987</a>). Furthermore, a novel species of alpha-1(I) mRNA present in the nuclear compartment was not collinear with a cDNA probe (<a href="#36" class="mim-tip-reference" title="Genovese, C., Brufsky, A., Shapiro, J., Rowe, D. &lt;strong&gt;Detection of mutations in human type I collagen mRNA in osteogenesis imperfecta by indirect RNase protection.&lt;/strong&gt; J. Biol. Chem. 264: 9632-9637, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2542316/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2542316&lt;/a&gt;]" pmid="2542316">Genovese et al., 1989</a>). In another individual with OI type I, <a href="#99" class="mim-tip-reference" title="Stover, M. L., Primorac, D., McKinstry, M. B., Rowe, D. W. &lt;strong&gt;Defective splicing of mRNA from one COL1A1 allele of type I collagen in nondeforming (type I) osteogenesis imperfecta.&lt;/strong&gt; J. Clin. Invest. 92: 1994-2002, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8408653/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8408653&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI116794&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8408653">Stover et al. (1993)</a> demonstrated a G-A transition in the first position of the splice donor site of intron 26 which resulted in inclusion of the entire succeeding intron in the mature mRNA that accumulated in the nuclear compartment; apparently because no abnormal pro-alpha-1(I) chains were synthesized from the mutant allele, the clinical phenotype of this individual was mild. In a large study, <a href="#113" class="mim-tip-reference" title="Willing, M. C., Pruchno, C. J., Atkinson, M., Byers, P. H. &lt;strong&gt;Osteogenesis imperfecta type I is commonly due to a COL1A1 null allele of type I collagen.&lt;/strong&gt; Am. J. Hum. Genet. 51: 508-515, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1353940/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1353940&lt;/a&gt;]" pmid="1353940">Willing et al. (1992)</a> showed that among 70 individuals with OI type I 23 from 21 families were heterozygous at the COL1A1 polymorphic MnlI site. As shown by primer extension with nucleotide-specific chain termination, there was in each case marked diminution in steady-state mRNA levels from one COL1A1 allele. Loss of an allele through deletion or rearrangement was not the cause of the diminished COL1A1 mRNA levels. Only in one family has the causative mutation been identified; an A-G transition in the obligatory acceptor splice site of intron 16 resulted in skipping of exon 17 in the mRNA which represented only 10% of the total COL1A1 mRNA. Further, linkage studies in 38 additional families have demonstrated no evidence of deletion of those regions of the COL1A1 gene used for linkage analysis (Sykes et al. (<a href="#102" class="mim-tip-reference" title="Sykes, B., Ogilvie, D., Wordsworth, P., Anderson, J., Jones, N. &lt;strong&gt;Osteogenesis imperfecta is linked to both type I collagen structural genes.&lt;/strong&gt; Lancet 328: 69-72, 1986. Note: Originally Volume II.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2873381/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2873381&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(86)91609-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2873381">1986</a>, <a href="#103" class="mim-tip-reference" title="Sykes, B., Ogilvie, D., Wordsworth, P., Wallis, G., Mathew, C., Beighton, P., Nicholls, A., Pope, F. M., Thompson, E., Tsipouras, P., Schwartz, R., Jensson, O., Arnason, A., Borresen, A.-L., Heiberg, A., Frey, D., Steinmann, B. &lt;strong&gt;Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2.&lt;/strong&gt; Am. J. Hum. Genet. 46: 293-307, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1967900/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1967900&lt;/a&gt;]" pmid="1967900">1990</a>)) and confirmed that most individuals with the OI type I phenotype have mutations linked to the COL1A1 gene. In some families, a similar phenotype is thought to result from mutations in the COL1A2 gene (Sykes et al. (<a href="#102" class="mim-tip-reference" title="Sykes, B., Ogilvie, D., Wordsworth, P., Anderson, J., Jones, N. &lt;strong&gt;Osteogenesis imperfecta is linked to both type I collagen structural genes.&lt;/strong&gt; Lancet 328: 69-72, 1986. Note: Originally Volume II.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2873381/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2873381&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(86)91609-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2873381">1986</a>, <a href="#103" class="mim-tip-reference" title="Sykes, B., Ogilvie, D., Wordsworth, P., Wallis, G., Mathew, C., Beighton, P., Nicholls, A., Pope, F. M., Thompson, E., Tsipouras, P., Schwartz, R., Jensson, O., Arnason, A., Borresen, A.-L., Heiberg, A., Frey, D., Steinmann, B. &lt;strong&gt;Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2.&lt;/strong&gt; Am. J. Hum. Genet. 46: 293-307, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1967900/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1967900&lt;/a&gt;]" pmid="1967900">1990</a>); <a href="#109" class="mim-tip-reference" title="Wallis, G., Beighton, P., Boyd, C., Mathew, C. G. &lt;strong&gt;Mutations linked to the pro alpha2(I) collagen gene are responsible for several cases of osteogenesis imperfecta type I.&lt;/strong&gt; J. Med. Genet. 23: 411-416, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3023615/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3023615&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.23.5.411&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3023615">Wallis et al., 1986</a>), but the clinical criteria by which the diagnosis of OI type I is made are not always clear. <a href="#112" class="mim-tip-reference" title="Willing, M. C., Cohn, D. H., Byers, P. H. &lt;strong&gt;Frameshift mutation near the 3-prime end of the COL1A1 gene of type I collagen predicts an elongated pro-alpha-1(I) chain and results in osteogenesis imperfecta type I.&lt;/strong&gt; J. Clin. Invest. 85: 282-290, 1990. Note: Erratum: J. Clin. Invest. 85: following 1338, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2295701/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2295701&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI114424&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2295701">Willing et al. (1990)</a> described a 5-bp deletion near the 3-prime end of one COL1A1 allele that resulted in a reading frame shift 12 amino acid residues from the normal terminus of the chain and predicted an extension of 84 amino acid residues beyond the normal termination site. Although the abnormal mRNA could be translated in vitro, it proved extremely difficult to identify the abnormal chains in cells; it appeared that although the mRNA was present in normal amount, the protein product was unstable. This mutation provides a model of how many different mutations in the COL1A1 gene could produce the OI type I phenotype by resulting in the synthesis of half the normal amount of a functional pro-alpha-1(I) chain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2873381+8408653+1967900+2295701+2542316+1353940+3474490+3023615+4031065" 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 an effort to further understand the reasons for diminished COL1A1 transcript levels in OI type I, <a href="#115" class="mim-tip-reference" title="Willing, M. C., Slayton, R. L., Pitts, S. H., Deschenes, S. P. &lt;strong&gt;Absence of mutations in the promoter of the COL1A1 gene of type I collagen in patients with osteogenesis imperfecta type I.&lt;/strong&gt; J. Med. Genet. 32: 697-700, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8544188/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8544188&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.32.9.697&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8544188">Willing et al. (1995)</a> investigated whether mutations involving key regulatory sequences in the COL1A1 promoter, such as the TATAAA and CCAAAT boxes, are responsible for the reduced levels of mRNA. They used PCR-amplified genomic DNA in conjunction with denaturing gradient gel electrophoresis and SSCP to screen the 5-prime untranslated domain, exon 1, and a small portion of intron 1 of the COL1A1 gene. In addition, direct sequence analysis was performed on an amplified genomic DNA fragment that included the TATAAA and CCAAAT boxes. In a survey of 40 unrelated probands with OI type I in whom no causative mutation was known, <a href="#115" class="mim-tip-reference" title="Willing, M. C., Slayton, R. L., Pitts, S. H., Deschenes, S. P. &lt;strong&gt;Absence of mutations in the promoter of the COL1A1 gene of type I collagen in patients with osteogenesis imperfecta type I.&lt;/strong&gt; J. Med. Genet. 32: 697-700, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8544188/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8544188&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.32.9.697&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8544188">Willing et al. (1995)</a> identified no mutations in the promoter region and there was 'little evidence of sequence diversity among any of the 40 subjects.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8544188" 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>Although less common than 'functional null' allele mutations, there are several examples in which the synthesis of abnormal procollagen I molecules can produce the OI type I phenotype. In one family (<a href="#66" class="mim-tip-reference" title="Nicholls, A. C., Pope, F. M., Craig, D. &lt;strong&gt;An abnormal collagen alpha-chain containing cysteine in autosomal dominant osteogenesis imperfecta.&lt;/strong&gt; Brit. Med. J. 288: 112-113, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6419811/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6419811&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/bmj.288.6411.112&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6419811">Nicholls et al., 1984</a>), cells cultured from the affected mother and son, but not those from the normal daughter, synthesized alpha-1(I)-chains bearing a cysteine residue within the protease-resistant domain of the collagen molecule, a region from which that residue is normally absent. Although it was initially thought that the cysteine substitution was at the X or Y position of the Gly-X-Y repeating unit of the alpha-1(I) chain in the carboxyl-terminal peptide CB6 (<a href="#96" class="mim-tip-reference" title="Steinmann, B., Nicholls, A., Pope, F. M. &lt;strong&gt;Clinical variability of osteogenesis imperfecta reflecting molecular heterogeneity: cysteine substitutions in the alpha-1(I) collagen chain producing lethal and mild forms.&lt;/strong&gt; J. Biol. Chem. 261: 8958-8964, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3722184/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3722184&lt;/a&gt;]" pmid="3722184">Steinmann et al., 1986</a>), peptide sequence analysis and sequencing of the cDNA demonstrated that the mutation resulted in the substitution of a glycine by cysteine in position 1017 in the telopeptide, 3 amino acid residues from the carboxy-terminal to the end of the triple helix (<a href="#25" class="mim-tip-reference" title="Cohn, D. H., Apone, S., Eyre, D. R., Starman, B. J., Andreassen, P., Charbonneau, H., Nicholls, A. C., Pope, F. M., Byers, P. H. &lt;strong&gt;Substitution of cysteine for glycine within the carboxyl-terminal telopeptide of the alpha1 chain of type I collagen produces mild osteogenesis imperfecta.&lt;/strong&gt; J. Biol. Chem. 263: 14605-14607, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3170557/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3170557&lt;/a&gt;]" pmid="3170557">Cohn et al., 1988</a>; <a href="#48" class="mim-tip-reference" title="Labhard, M. E., Wirtz, M. K., Pope, F. M., Nicholls, A. C., Hollister, D. W. &lt;strong&gt;A cysteine for glycine substitution at position 1017 in an alpha-1(I) chain of type I collagen in a patient with mild dominantly inherited osteogenesis imperfecta.&lt;/strong&gt; Molec. Biol. Med. 5: 197-207, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3244312/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3244312&lt;/a&gt;]" pmid="3244312">Labhard et al., 1988</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3722184+6419811+3244312+3170557" 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>Other substitutions of cysteine for glycine within the triple helical domain of the alpha-1(I) chain at residue 94 (<a href="#95" class="mim-tip-reference" title="Starman, B. J., Eyre, D., Charbonneau, H., Harrylock, M., Weis, M. A., Weiss, L., Graham, J. M., Jr., Byers, P. H. &lt;strong&gt;Osteogenesis imperfecta. The position of substitution for glycine by cysteine in the triple helical domain of the pro-alpha-1(I) chains of type I collagen determines the clinical phenotype.&lt;/strong&gt; J. Clin. Invest. 84: 1206-1214, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2794057/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2794057&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI114286&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2794057">Starman et al., 1989</a>; <a href="#65" class="mim-tip-reference" title="Nicholls, A. C., Oliver, J., Renouf, D., Pope, F. M. &lt;strong&gt;Type I collagen mutation in osteogenesis imperfecta and inherited osteoporosis. (Abstract)&lt;/strong&gt; 4th International Conference on Osteogenesis Imperfecta, Pavia, Italy, September 1990. P. 48."None> Nicholls et al., 1990</a>; <a href="#86" class="mim-tip-reference" title="Shapiro, J. R., Stover, M. L., Burn, V. E., McKinstry, M. B., Burshell, A. L., Chipman, S. D., Rowe, D. W. &lt;strong&gt;An osteopenic nonfracture syndrome with features of mild osteogenesis imperfecta associated with the substitution of a cysteine for glycine at triple helix position 43 in the pro-alpha-1(I) chain of type I collagen.&lt;/strong&gt; J. Clin. Invest. 89: 567-573, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1737847/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1737847&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI115622&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1737847">Shapiro et al., 1992</a>; <a href="#19" class="mim-tip-reference" title="Byers, P. H. &lt;strong&gt;Osteogenesis imperfecta. In: Royce, P. M.; Steinmann, B.: Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects.&lt;/strong&gt; New York: Wiley-Liss (pub.) 1993. Pp. 317-350."None>Byers, 1993</a>) also produce mild forms of OI, perhaps compatible with OI type I (see, e.g., <a href="/entry/120150#0002">120150.0002</a> and <a href="/entry/120500#0038">120500.0038</a>). <a href="#17" class="mim-tip-reference" title="Byers, P. H., Shapiro, J. R., Rowe, D. W., David, K. E., Holbrook, K. A. &lt;strong&gt;Abnormal alpha2-chain in type I collagen from a patient with a form of osteogenesis imperfecta.&lt;/strong&gt; J. Clin. Invest. 71: 689-697, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6826730/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6826730&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/jci110815&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6826730">Byers et al. (1983)</a> described an isolated patient with a mild to moderate form of OI: blue sclerae, a height of 147 cm, deformity as a consequence of poor orthopedic treatment, and hearing loss. Her cells synthesized a pro-alpha-2(I) chain in which approximately 30 amino acid residues were deleted from the triple-helical domain, in the CB4 peptide, a domain in which phosphoproteins important to bone calcification may bind and in which crosslinks may form. Subsequent studies indicated that a point mutation at the consensus splice-donor site resulted in the skipping of exon 12 (amino acids 91-108) from about half the COL1A2 transcripts (<a href="#83" class="mim-tip-reference" title="Rowe, D. W., Stover, M. L., McKinstry, M., Brufsky, A., Kream, B., Chipman, S., Shapiro, J. &lt;strong&gt;Molecular mechanisms (real and imagined) for osteopenic bone disease. (Abstract)&lt;/strong&gt; 4th International Conference on Osteogenesis Imperfecta, Pavia, Italy, September 1990. P. 57."None>Rowe et al., 1990</a>). <a href="#117" class="mim-tip-reference" title="Zhuang, J., Tromp, G., Kuivaniemi, H., Nakayasu, K., Prockop, D. J. &lt;strong&gt;Deletion of 19 base pairs in intron 13 of the gene for the pro-alpha-2(I) chain of type-I procollagen (COL1A2) causes exon skipping in a proband with type-I osteogenesis imperfecta.&lt;/strong&gt; Hum. Genet. 91: 210-216, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7916744/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7916744&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00218258&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7916744">Zhuang et al. (1993)</a> showed that deletion of 19 bp from +4 to +22 of intron 13 of COL1A2 caused skipping of exon 13 in about 88% of the transcripts, whereas 12% of the transcripts were normally spliced; procollagen I containing the mutated pro-alpha-2(I) chain had reduced thermal stability and was only poorly secreted from the cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1737847+6826730+2794057+7916744" 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 woman with 'postmenopausal osteoporosis' was reported by <a href="#93" class="mim-tip-reference" title="Spotila, L. D., Constantinou, C. D., Sereda, L., Ganguly, A., Riggs, B. L., Prockop, D. J. &lt;strong&gt;Mutation in a gene for type I procollagen (COL1A2) in a woman with postmenopausal osteoporosis: evidence for phenotypic and genotypic overlap with mild osteogenesis imperfecta.&lt;/strong&gt; Proc. Nat. Acad. Sci. 88: 5423-5427, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2052622/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2052622&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.88.12.5423&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2052622">Spotila et al. (1991)</a> to be heterozygous for a serine-to glycine substitution at position 661 of the alpha-2(I) triple-helical domain. Since her 3 sons, who inherited the mutation, had experienced fractures as adolescents, the diagnosis of 'mild OI cannot be fully excluded' according to the authors' view; one of the sons was homozygous for the mutation due to partial isodisomy for maternal chromosome 7 (<a href="#94" class="mim-tip-reference" title="Spotila, L. D., Sereda, L., Prockop, D. J. &lt;strong&gt;Partial isodisomy for maternal chromosome 7 and short stature in an individual with a mutation at the COL1A2 locus.&lt;/strong&gt; Am. J. Hum. Genet. 51: 1396-1405, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1463018/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1463018&lt;/a&gt;]" pmid="1463018">Spotila et al., 1992</a>). All these findings suggest that other point mutations in the COL1A1 gene, and perhaps in the COL1A2 gene (as suggested also by linkage studies), could lead to a phenotype similar to that produced by 'functional null' allele mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2052622+1463018" 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 diagnosis is based on clinical and genetic criteria. In sporadic cases, the diagnosis may be difficult, and secondary osteoporosis and nonaccidental injury has to be ruled out. In women with severe 'postmenopausal osteoporosis' careful clinical investigation and a thorough personal and family history quite often reveals OI type I. While the direct molecular characterization is not feasible in the majority of cases at present, demonstration of reduced synthesis of procollagen I by dermal fibroblasts is indicative for the disorder. <a href="#58" class="mim-tip-reference" title="Lynch, J. R., Ogilvie, D., Priestley, L., Baigrie, C., Smith, R., Farndon, P., Sykes, B. &lt;strong&gt;Prenatal diagnosis of osteogenesis imperfecta by identification of the concordant collagen 1 allele.&lt;/strong&gt; J. Med. Genet. 28: 145-150, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2051450/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2051450&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.28.3.145&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2051450">Lynch et al. (1991)</a> discussed the problem of making the prenatal diagnosis of OI type I on the basis of linkage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2051450" 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="De Vos, A., Sermon, K., Van de Velde, H., Joris, H., Vandervorst, M., Lissens, W., De Paepe, A., Liebaers, I., Van Steirteghem, A. &lt;strong&gt;Two pregnancies after preimplantation genetic diagnosis for osteogenesis imperfecta type I and type IV.&lt;/strong&gt; Hum. Genet. 106: 605-613, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10942108/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10942108&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004390000298&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10942108">De Vos et al. (2000)</a> reported the achievement of a normal twin pregnancy after preimplantation genetic diagnosis for osteogenesis imperfecta type I. Because 2 blighted ova were seen on ultrasound at 7 weeks' gestation, the pregnancy was terminated. The female partner with OI type I carried a 1-bp deletion in exon 43 of the COL1A1 gene, resulting in a premature stop codon in exon 46. The nonfunctional allele was predicted to result in the synthesis of too little type I procollagen. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10942108" 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="Byers, P. H., Krakow, D., Nunes, M. E., Pepin, M. &lt;strong&gt;Genetic evaluation of suspected osteogenesis imperfecta (OI).&lt;/strong&gt; Genet. Med. 8: 383-388, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16778601/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16778601&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/01.gim.0000223557.54670.aa&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16778601">Byers et al. (2006)</a> published practice guidelines for the genetic evaluation of suspected OI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16778601" 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>Fractures in OI are treated with standard orthopedic procedures appropriate for the type of fracture and the age, and heal rapidly with evidence of good callus formation (sometimes with hypertrophic callus formation) and without deformity. Regular hearing evaluations after adolescence and early stapedectomy or stapedotomy are recommended. In postmenopausal women with OI, a long-term physical therapy program to strengthen the paraspinal muscles, together with estrogen and progesterone replacement, adequate calcium intake, and perhaps calcitonin or fluoride administration, may be specifically indicated (for review, see <a href="#98" class="mim-tip-reference" title="Steinmann, B., Superti-Furga, A., Royce, P. M. &lt;strong&gt;Heritable disorders of connective tissues. In: Fernandes, J.; Saudubray, J.-M.; Tada, K.: Inborn Metabolic Diseases: Diagnosis and Treatment.&lt;/strong&gt; Berlin: Springer (pub.) 1990. Pp. 525-561."None>Steinmann et al., 1990</a>).</p><p><a href="#8" class="mim-tip-reference" title="Bembi, B., Parma, A., Bottega, M., Ceschel, S., Zanatta, M., Martini, C., Ciana, G. &lt;strong&gt;Intravenous pamidronate treatment in osteogenesis imperfecta.&lt;/strong&gt; J. Pediat. 131: 622-625, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9386671/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9386671&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(97)70074-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9386671">Bembi et al. (1997)</a> described the results of treatment of 3 children with OI type I with cyclic intravenous infusions of aminohydroxypropylidene bisphosphonate (pamidronate). Each of the children had repeated bone fractures and low bone density. The rationale for pamidronate therapy in OI is based on the fact that bisphosphonates inhibit osteoclastic bone resorption; this leads to increased bone density and possibly to reduced risk of fracture. <a href="#8" class="mim-tip-reference" title="Bembi, B., Parma, A., Bottega, M., Ceschel, S., Zanatta, M., Martini, C., Ciana, G. &lt;strong&gt;Intravenous pamidronate treatment in osteogenesis imperfecta.&lt;/strong&gt; J. Pediat. 131: 622-625, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9386671/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9386671&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(97)70074-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9386671">Bembi et al. (1997)</a> reported a clear clinical response over the 22- to 29-month treatments, with a striking reduction in the frequency of new fractures. They also observed an effect on bone density. There were no notable adverse effects during therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9386671" 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 an uncontrolled observational study involving 30 children aged 3 to 16 years with severe osteogenesis imperfecta, <a href="#38" class="mim-tip-reference" title="Glorieux, F. H., Bishop, N. J., Plotkin, H., Chabot, G., Lanoue, G., Travers, R. &lt;strong&gt;Cyclic administration of pamidronate in children with severe osteogenesis imperfecta.&lt;/strong&gt; New Eng. J. Med. 339: 947-952, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9753709/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9753709&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199810013391402&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9753709">Glorieux et al. (1998)</a> administered pamidronate intravenously at 4- to 6-month intervals for 1.3 to 5.0 years. They observed a sustained reduction in serum alkaline phosphatase concentrations and in the urinary excretion of calcium and type I collagen N-telopeptide. Increases in the size of the vertebral bodies suggested that new bone had formed. The mean incidence of radiologically confirmed fractures decreased by 1.7 per year (P less than 0.001). Treatment with pamidronate did not alter the rate of fracture healing, the growth rate, or the appearance of growth plates. Mobility and ambulation improved in 16 children and remained unchanged in the other 14. The children with severe osteogenesis imperfecta treated by <a href="#38" class="mim-tip-reference" title="Glorieux, F. H., Bishop, N. J., Plotkin, H., Chabot, G., Lanoue, G., Travers, R. &lt;strong&gt;Cyclic administration of pamidronate in children with severe osteogenesis imperfecta.&lt;/strong&gt; New Eng. J. Med. 339: 947-952, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9753709/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9753709&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199810013391402&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9753709">Glorieux et al. (1998)</a> fell into the type III (<a href="/entry/259420">259420</a>) and type IV (<a href="/entry/166220">166220</a>) categories of osteogenesis imperfecta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9753709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#60" class="mim-tip-reference" title="Marini, J. C. &lt;strong&gt;Osteogenesis imperfecta--managing brittle bones. (Editorial)&lt;/strong&gt; New Eng. J. Med. 339: 986-987, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9753715/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9753715&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199810013391408&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9753715">Marini (1998)</a> commented that fluoride and calcitonin treatment in OI had proved unsuccessful. The bisphosphonates are synthetic analogs of pyrophosphate, a natural inhibitor of osteoclastic bone resorption. They have been useful in the treatment of osteoporosis, Paget disease of bone, and fibrous dysplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9753715" 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="#50" class="mim-tip-reference" title="Lee, Y.-S., Low, S.-L., Lim, L.-A., Loke, K.-Y. &lt;strong&gt;Cyclic pamidronate infusion improves bone mineralisation and reduces fracture incidence in osteogenesis imperfecta.&lt;/strong&gt; Europ. J. Pediat. 160: 641-644, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11760017/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11760017&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004310100844&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11760017">Lee et al. (2001)</a> performed a prospective open label study to determine the efficacy and safety of pamidronate in 6 children with OI (3 had OI type I, 2 had type III, and 1 had type IV). The dose was 1.5 mg/kg bimonthly over 12 to 23 months. The number of fractures decreased from median of 3 (range 1-12) to 0 fractures per year (range 0-4) and all patients experienced improved bone mineral density and decreased serum alkaline phosphatase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11760017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Astrom, E., Soderhall, S. &lt;strong&gt;Beneficial effect of long term intravenous bisphosphonate treatment of osteogenesis imperfecta.&lt;/strong&gt; Arch. Dis. Child. 86: 356-364, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11970931/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11970931&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11970931[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.86.5.356&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11970931">Astrom and Soderhall (2002)</a> performed a prospective observational study using disodium pamidronate (APD) in 28 children and adolescents (aged 0.6 to 18 years) with severe OI or a milder form of the disease, but with spinal compression fractures. All bone metabolism variables in serum (alkaline phosphatase, osteocalcin, procollagen-1 C-terminal peptide, collagen-1 teleopeptide) and urine (deoxypyridinoline) indicated that there was a decrease in bone turnover. All patients experienced beneficial effects, and the younger patients showed improvement in well-being, pain, and mobility without significant side effects. Vertebral remodeling was also seen. They concluded that APD seemed to be an efficient symptomatic treatment for children and adolescents with OI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11970931" 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="Lindsay, R. &lt;strong&gt;Modeling the benefits of pamidronate in children with osteogenesis imperfecta.&lt;/strong&gt; J. Clin. Invest. 110: 1239-1241, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12417561/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12417561&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12417561[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI17051&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12417561">Lindsay (2002)</a> reviewed the mechanism, effects, risks, and benefits of bisphosphonate therapy in children with OI. He stated that the clinical course and attendant morbidity for many children with severe OI is clearly improved with its judicious use. Nevertheless, since bisphosphonates accumulate in the bone and residual levels are measurable after many years, the long-term safety of this approach was unknown. He recommended that until long-term safety data were available, pamidronate intervention be reserved for those for whom the benefits clearly outweighed the risks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12417561" 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="Rauch, F., Travers, R., Plotkin, H., Glorieux, F. H. &lt;strong&gt;The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta.&lt;/strong&gt; J. Clin. Invest. 110: 1293-1299, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12417568/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12417568&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI15952&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12417568">Rauch et al. (2002)</a> compared parameters of iliac bone histomorphometry in 45 patients (23 girls, 22 boys) with OI types I, III, or IV before and after 2.4 +/- 0.6 years of treatment with cyclical intravenous pamidronate (age at the time of the first biopsy, 1.4 to 17.5 years). There was an increase in bone mass due to increases in cortical width and trabecular number. The bone surface-based indicators of cancellous bone remodeling, however, were decreased. There was no evidence of a mineralization defect in any of the patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12417568" 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="Rauch, F., Plotkin, H., Travers, R., Zeitlin, L., Glorieux, F. H. &lt;strong&gt;Osteogenesis imperfecta types I, III, and IV: effect of pamidronate therapy on bone and mineral metabolism.&lt;/strong&gt; J. Clin. Endocr. Metab. 88: 986-992, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12629073/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12629073&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2002-021371&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12629073">Rauch et al. (2003)</a> evaluated the effect of intravenous therapy with pamidronate on bone and mineral metabolism in 165 patients with OI types I, III, and IV. All patients received intravenous pamidronate infusions on 3 successive days, administered at age-dependent intervals of 2 to 4 months. During the 3 days of the first infusion cycle, serum concentrations of ionized calcium dropped and serum PTH levels transiently almost doubled. Two to 4 months later, ionized calcium had returned to pretreatment levels. During 4 years of pamidronate therapy, ionized calcium levels remained stable, but PTH levels increased by about 30%. <a href="#76" class="mim-tip-reference" title="Rauch, F., Plotkin, H., Travers, R., Zeitlin, L., Glorieux, F. H. &lt;strong&gt;Osteogenesis imperfecta types I, III, and IV: effect of pamidronate therapy on bone and mineral metabolism.&lt;/strong&gt; J. Clin. Endocr. Metab. 88: 986-992, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12629073/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12629073&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2002-021371&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12629073">Rauch et al. (2003)</a> concluded that serum calcium levels can decrease considerably during and after pamidronate infusions, requiring close monitoring especially at the first infusion cycle. In long-term therapy, bone turnover is suppressed to levels lower than those in healthy children. The authors stated that the consequences of chronically low bone turnover in children with OI were unknown. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12629073" 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="Zeitlin, L., Rauch, F., Plotkin, H., Glorieux, F. H. &lt;strong&gt;Height and weight development during four years of therapy with cyclical intravenous pamidronate in children and adolescents with osteogenesis imperfecta types I, III, and IV.&lt;/strong&gt; Pediatrics 111: 1030-1036, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12728084/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12728084&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1542/peds.111.5.1030&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12728084">Zeitlin et al. (2003)</a> analyzed longitudinal growth during cyclical intravenous pamidronate treatment in children and adolescents (ages 0.04 to 15.6 years at baseline) with moderate to severe forms of OI types I, III, and IV and found that 4 years of treatment led to a significant height gain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12728084" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#77" class="mim-tip-reference" title="Rauch, F., Travers, R., Glorieux, F. H. &lt;strong&gt;Pamidronate in children with osteogenesis imperfecta: histomorphometric effects of long-term therapy.&lt;/strong&gt; J. Clin. Endocr. Metab. 91: 511-516, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16291701/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16291701&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2005-2036&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16291701">Rauch et al. (2006)</a> assessed the effect of long-term pamidronate treatment on the bone tissue of children and adolescents with OI. Average areal bone mineral density (aBMD) increased by 72% in the first half of the observation period, but by only 24% in the second half. Mean cortical width and cancellous bone volume increased by 87% and 38%, respectively, between baseline and the first time point during treatment (P less than 0.001 for all changes). <a href="#77" class="mim-tip-reference" title="Rauch, F., Travers, R., Glorieux, F. H. &lt;strong&gt;Pamidronate in children with osteogenesis imperfecta: histomorphometric effects of long-term therapy.&lt;/strong&gt; J. Clin. Endocr. Metab. 91: 511-516, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16291701/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16291701&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2005-2036&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16291701">Rauch et al. (2006)</a> concluded that the gains that can be achieved with pamidronate treatment appear to be realized largely in the first 2 to 4 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16291701" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#75" class="mim-tip-reference" title="Rauch, F., Munns, C., Land, C., Glorieux, F. H. &lt;strong&gt;Pamidronate in children and adolescents with osteogenesis imperfecta: effect of treatment discontinuation.&lt;/strong&gt; J. Clin. Endocr. Metab. 91: 1268-1274, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16434452/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16434452&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2005-2413&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16434452">Rauch et al. (2006)</a> studied the effect of pamidronate discontinuation in pediatric patients with moderate to severe OI types I, III, and IV. In the controlled study, 12 pairs of patients were matched for age, OI severity, and duration of pamidronate treatment. Pamidronate was stopped in one patient of each pair; the other continued to receive treatment. In the observational study, 38 OI patients were examined (mean age, 13.8 years). The intervention was discontinuation of pamidronate treatment for 2 years. The results indicated that bone mass gains continue after treatment is stopped, but that lumbar spine aBMD increases less than in healthy subjects. The size of these effects is growth dependent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16434452" 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 lethal forms of osteogenesis imperfecta caused by mutation in either the COL1A1 gene or the COL1A2 gene, the mutations result in the synthesis of abnormal chains of procollagen that bind to normal chains synthesized by the same cells and destroy their biologic activity in a classic dominant-negative manner. <a href="#24" class="mim-tip-reference" title="Chamberlain, J. R., Schwarze, U., Wang, P.-R., Hirata, R. K., Hankenson, K. D., Pace, J. M., Underwood, R. A., Song, K. M., Sussman, M., Byers, P. H., Russell, D. W. &lt;strong&gt;Gene targeting in stem cells from individuals with osteogenesis imperfecta.&lt;/strong&gt; Science 303: 1198-1201, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14976317/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14976317&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1088757&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14976317">Chamberlain et al. (2004)</a> developed a strategy to inactivate the mutated alleles in cells of the bone marrow called mesenchymal stem cells (MSCs), or marrow stromal cells. They chose MSCs because these cells are easily obtained from a patient, they engraft and differentiate into many tissues after infusion in vivo, and allogeneic MSCs had produced promising results in a previous trial involving patients with osteogenesis imperfecta (<a href="#71" class="mim-tip-reference" title="Prockop, D. J., Gregory, C. A., Spees, J. L. &lt;strong&gt;One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues.&lt;/strong&gt; Proc. Nat. Acad. Sci. 100 (suppl. 1): 11917-11923, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13679583/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13679583&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=13679583[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.1834138100&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13679583">Prockop et al., 2003</a>; <a href="#44" class="mim-tip-reference" title="Horwitz, E. M., Gordon, P. L., Koo, W. K. K., Marx, J. C., Neel, M. D., McNall, R. Y., Muul, L., Hofmann, T. &lt;strong&gt;Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone.&lt;/strong&gt; Proc. Nat. Acad. Sci. 99: 8932-8937, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12084934/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12084934&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12084934[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.132252399&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12084934">Horwitz et al., 2002</a>). <a href="#24" class="mim-tip-reference" title="Chamberlain, J. R., Schwarze, U., Wang, P.-R., Hirata, R. K., Hankenson, K. D., Pace, J. M., Underwood, R. A., Song, K. M., Sussman, M., Byers, P. H., Russell, D. W. &lt;strong&gt;Gene targeting in stem cells from individuals with osteogenesis imperfecta.&lt;/strong&gt; Science 303: 1198-1201, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14976317/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14976317&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1088757&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14976317">Chamberlain et al. (2004)</a> designed a gene construct that targeted exon 1 of the COL1A1 gene. They predicted that, on insertion, the construct would both inactivate COL1A1 and confer resistance to the antibiotic neomycin. To insert the gene construct efficiently into MSCs, they used an adeno-associated virus as a vector. The results obtained with MSCs from 2 patients with osteogenesis imperfecta was highly encouraging. In 31 to 90% of the cells that became resistant to neomycin, the gene construct had inserted itself into either the wildtype or the mutated COL1A1 allele. In all cultures of the neomycin-resistant cells, most signs of the dominant-negative protein defect were corrected--apparently because the cells in which the mutated allele was inactivated began to produce an adequate amount of wildtype collagen. Most importantly, the quality of bones synthesized by the altered MSCs was improved. <a href="#73" class="mim-tip-reference" title="Prockop, D. J. &lt;strong&gt;Targeting gene therapy for osteogenesis imperfecta.&lt;/strong&gt; New Eng. J. Med. 350: 2302-2304, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15163783/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15163783&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMcibr040806&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15163783">Prockop (2004)</a> commented on the promising nature of the approach as well as some of the problems. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13679583+14976317+12084934+15163783" 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 cohort of 540 individuals with OI studied longitudinally, <a href="#7" class="mim-tip-reference" title="Bellur, S., Jain, M., Cuthbertson, D., Krakow, D., Shapiro, J. R., Steiner, R. D., Smith, P. A., Bober, M. B., Hart, T., Krischer, J., Mullins, M., Byers, P. H., Pepin, M., Durigova, M., Glorieux, F. H., Rauch, F., Sutton, V. R., Lee, B., Members of the BBD Consortium, Nagamani, S. C. &lt;strong&gt;Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta.&lt;/strong&gt; Genet. Med. 18: 570-576, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26426884/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26426884&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2015.131&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26426884">Bellur et al. (2016)</a> conducted a study to address whether cesarean delivery has an effect on at-birth fracture rates and whether an antenatal diagnosis of OI influences the choice of delivery method. They compared self-reported at-birth fracture rates among individuals with OI types I, III (<a href="/entry/259420">259420</a>), and IV (<a href="/entry/166220">166220</a>). When accounting for other covariates, at-birth fracture rates did not differ based on whether delivery was vaginal or by cesarean section. Increased birth weight conferred conferred higher risk for fractures irrespective of the delivery method. In utero fracture, maternal history of OI, and breech presentation were strong predictors for choosing cesarean delivery. The authors recommended that cesarean delivery should not be performed for the sole purpose of fracture prevention in OI, but only for other maternal or fetal indications. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26426884" 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 the county of Fyn, where approximately 9% of the Danish population lives, <a href="#2" class="mim-tip-reference" title="Andersen, P. E., Jr., Hauge, M. &lt;strong&gt;Osteogenesis imperfecta: a genetic, radiological, and epidemiological study.&lt;/strong&gt; Clin. Genet. 36: 250-255, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2805382/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2805382&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1989.tb03198.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2805382">Andersen and Hauge (1989)</a> identified 48 patients with osteogenesis imperfecta, of whom 17 were born between January 1, 1970 and December 31, 1983. Of the 17, 12 had type I, 2 had type II, 2 had type III, and 1 had type IV. The point prevalence at birth was 21.8/100,000 and the population prevalence was 10.6/100,000 inhabitants. All ethnic and racial groups seem to be similarly affected (<a href="#19" class="mim-tip-reference" title="Byers, P. H. &lt;strong&gt;Osteogenesis imperfecta. In: Royce, P. M.; Steinmann, B.: Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects.&lt;/strong&gt; New York: Wiley-Liss (pub.) 1993. Pp. 317-350."None>Byers, 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2805382" 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>History</strong>
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<p><a href="#46" class="mim-tip-reference" title="Kozma, C. &lt;strong&gt;Skeletal dysplasia in ancient Egypt.&lt;/strong&gt; Am. J. Med. Genet. 146A: 3104-3112, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19006207/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19006207&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32501&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19006207">Kozma (2008)</a> provided a detailed historical review of skeletal dysplasias in ancient Egypt, with an example of presumed osteogenesis imperfecta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19006207" 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="#11" class="mim-tip-reference" title="Bonadio, J., Saunders, T. L., Tsai, E., Goldstein, S. A., Morris-Wiman, J., Brinkley, L., Dolan, D. F., Altschuler, R. A., Hawkins, J. E., Jr., Bateman, J. F., Mascara, T., Jaenisch, R. &lt;strong&gt;Transgenic mouse model of the mild dominant form of osteogenesis imperfecta.&lt;/strong&gt; Proc. Nat. Acad. Sci. 87: 7145-7149, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2402497/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2402497&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.87.18.7145&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2402497">Bonadio et al. (1990)</a> reported that the heterozygous Mov-13 mouse, which has a murine retrovirus integrated within the first intron of The Col1a1 gene, is a good model for the mild autosomal dominant form of OI. The animals showed morphologic and functional defects in mineralized and nonmineralized connective tissue and progressive hearing loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2402497" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Aihara, M., Lindsey, J. D., Weinreb, R. N. &lt;strong&gt;Ocular hypertension in mice with a targeted type I collagen mutation.&lt;/strong&gt; Invest. Ophthal. Vis. Sci. 44: 1581-1585, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12657595/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12657595&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1167/iovs.02-0759&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12657595">Aihara et al. (2003)</a> demonstrated that mice with a targeted mutation of the Col1a1 gene had ocular hypertension. They suggested an association between intraocular pressure regulation and fibrillar collagen turnover. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12657595" 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="#39" class="mim-tip-reference" title="Gremminger, V. L., Omosule, C. L., Crawford, T. K., Cunningham, R., Rector, R. S., Phillips, C. L. &lt;strong&gt;Skeletal muscle mitochondrial function and whole-body metabolic energetics in the +/G610C mouse model of osteogenesis imperfecta.&lt;/strong&gt; Molec. Genet. Metab. 136: 315-323, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/35725939/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;35725939&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2022.06.004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="35725939">Gremminger et al. (2022)</a> studied muscle bioenergetics and mitochondrial function in 16-week-old mice that were heterozygous for a G610C mutation in the Col1a2 gene. Isolated mitochondria from the gastrocnemius muscle of the mutant mice demonstrated reduced state 3 respiration and increased citrate synthase activity compared to wildtype mice, which <a href="#39" class="mim-tip-reference" title="Gremminger, V. L., Omosule, C. L., Crawford, T. K., Cunningham, R., Rector, R. S., Phillips, C. L. &lt;strong&gt;Skeletal muscle mitochondrial function and whole-body metabolic energetics in the +/G610C mouse model of osteogenesis imperfecta.&lt;/strong&gt; Molec. Genet. Metab. 136: 315-323, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/35725939/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;35725939&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2022.06.004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="35725939">Gremminger et al. (2022)</a> hypothesized may represent a compensatory mechanism to supply substrate to the electron transport chain in the setting of the type I collagen defect. Interestingly, when normalized to body weight, total and average daily expenditure for night and day were not different between wildtype and mutant mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35725939" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="seeAlso" class="mim-anchor"></a>
<h4 href="#mimSeeAlsoFold" id="mimSeeAlsoToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>See Also:</strong>
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<span class="mim-text-font">
<a href="#Beighton1981" class="mim-tip-reference" title="Beighton, P. &lt;strong&gt;Familial dentinogenesis imperfecta, blue sclerae, and wormian bones without fractures: another type of osteogenesis imperfecta?&lt;/strong&gt; J. Med. Genet. 18: 124-128, 1981.">Beighton (1981)</a>; <a href="#Bierring1933" class="mim-tip-reference" title="Bierring, K. &lt;strong&gt;Contribution to the perception of osteogenesis imperfecta congenita and osteopsathyrosis idiopathica as identical disorders.&lt;/strong&gt; Acta Chir. Scand. 70: 481-492, 1933.">Bierring (1933)</a>; <a href="#Byers1982" class="mim-tip-reference" title="Byers, P. H., Barsh, G. S., Holbrook, K. A. &lt;strong&gt;Molecular pathology in inherited disorders of collagen metabolism.&lt;/strong&gt; Hum. Path. 13: 89-95, 1982.">Byers et al. (1982)</a>; <a href="#Byers1981" class="mim-tip-reference" title="Byers, P. H., Barsh, G. S., Peterson, K. E., Holbrook, K. A., Rowe, D. W. &lt;strong&gt;Molecular mechanisms of abnormal bone matrix formation in osteogenesis imperfecta. In: Veis, A.: The Chemistry and Biology of Mineralized Connective Tissues.&lt;/strong&gt; Amsterdam: Elsevier/North Holland (pub.) 1981.">Byers et al.
(1981)</a>; <a href="#Byers1980" class="mim-tip-reference" title="Byers, P. H., Barsh, G. S., Rowe, D. W., Peterson, K. E., Holbrook, K. A., Shapiro, J. &lt;strong&gt;Biochemical heterogeneity in osteogenesis imperfecta. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 32: 37A only, 1980.">Byers et al. (1980)</a>; <a href="#Byers1991" class="mim-tip-reference" title="Byers, P. H., Wallis, G. A., Willing, M. C. &lt;strong&gt;Osteogenesis imperfecta: translation of mutation to phenotype.&lt;/strong&gt; J. Med. Genet. 28: 433-442, 1991.">Byers et al. (1991)</a>; <a href="#Castells1979" class="mim-tip-reference" title="Castells, S., Colbert, C., Chakrabarti, C., Bachtell, R. S., Kassner, E. G., Yasumura, S. &lt;strong&gt;Therapy of osteogenesis imperfecta with synthetic salmon calcitonin.&lt;/strong&gt; J. Pediat. 95: 807-811, 1979.">Castells et al.
(1979)</a>; <a href="#Cetta1977" class="mim-tip-reference" title="Cetta, G., Lenzi, L., Rizzotti, M., Ruggeri, A., Valli, M., Boni, M. &lt;strong&gt;Osteogenesis imperfecta: morphological, histochemical, and biochemical aspects: modifications induced by (+)-catechin.&lt;/strong&gt; Connect. Tissue Res. 5: 51-58, 1977.">Cetta et al. (1977)</a>; <a href="#Cohn1986" class="mim-tip-reference" title="Cohn, D. H., Byers, P. H., Steinmann, B., Gelinas, R. E. &lt;strong&gt;Lethal osteogenesis imperfecta resulting from a single nucleotide change in one human pro-alpha-1(I) collagen allele.&lt;/strong&gt; Proc. Nat. Acad. Sci. 83: 6045-6047, 1986.">Cohn et al. (1986)</a>; <a href="#Delvin1979" class="mim-tip-reference" title="Delvin, E. E., Glorieux, F. H., Lopez, E. &lt;strong&gt;In vitro sulfate turnover in osteogenesis imperfecta congenita and tarda.&lt;/strong&gt; Am. J. Med. Genet. 4: 349-355, 1979.">Delvin et al.
(1979)</a>; <a href="#Francis1975" class="mim-tip-reference" title="Francis, M. J. O., Smith, R. &lt;strong&gt;Polymeric collagen of skin in osteogenesis imperfecta, homocystinuria, Ehlers-Danlos and Marfan syndromes.&lt;/strong&gt; Birth Defects Orig. Art. Ser. XI(6): 15-21, 1975.">Francis et al. (1975)</a>; <a href="#Francis1975" class="mim-tip-reference" title="Francis, M. J. O., Smith, R. &lt;strong&gt;Polymeric collagen of skin in osteogenesis imperfecta, homocystinuria, Ehlers-Danlos and Marfan syndromes.&lt;/strong&gt; Birth Defects Orig. Art. Ser. XI(6): 15-21, 1975.">Francis and Smith (1975)</a>; <a href="#Heys1960" class="mim-tip-reference" title="Heys, F. M., Blattner, R. J., Robinson, H. B. G. &lt;strong&gt;Osteogenesis imperfecta and odontogenesis imperfecta: clinical and genetic aspects in eighteen families.&lt;/strong&gt; J. Pediat. 56: 234-245, 1960.">Heys et al.
(1960)</a>; <a href="#Levin1981" class="mim-tip-reference" title="Levin, L. S., Pyeritz, R. E., Young, R. J., Holliday, M. J., Laspia, C. C. &lt;strong&gt;Dominant osteogenesis imperfecta: heterogeneity and variation in expression. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 33: 66A only, 1981.">Levin et al. (1981)</a>; <a href="#Levin1978" class="mim-tip-reference" title="Levin, L. S., Salinas, C. F., Jorgenson, R. J. &lt;strong&gt;Classification of osteogenesis imperfecta by dental characteristics. (Letter)&lt;/strong&gt; Lancet 311: 332-333, 1978. Note: Originally Volume I.">Levin et al. (1978)</a>; <a href="#Levin1988" class="mim-tip-reference" title="Levin, L. S., Young, R. J., Pyeritz, R. E. &lt;strong&gt;Osteogenesis imperfecta type I with unusual dental abnormalities.&lt;/strong&gt; Am. J. Med. Genet. 31: 921-932, 1988.">Levin et al.
(1988)</a>; <a href="#Lindberg1979" class="mim-tip-reference" title="Lindberg, K. A., Sivarajah, A., Murad, S., Pinnell, S. R. &lt;strong&gt;Abnormal collagen crosslinks in a family with osteogenesis imperfecta. (Abstract)&lt;/strong&gt; Clin. Res. 27: 243A only, 1979.">Lindberg et al. (1979)</a>; <a href="#Lukinmaa1987" class="mim-tip-reference" title="Lukinmaa, P.-L., Ranta, H., Ranta, K., Kaitila, I. &lt;strong&gt;Dental findings in osteogenesis imperfecta: I. Occurrence and expression of type I dentinogenesis imperfecta.&lt;/strong&gt; J. Craniofac. Genet. Dev. Biol. 7: 115-125, 1987.">Lukinmaa et al. (1987)</a>; <a href="#Muller1977" class="mim-tip-reference" title="Muller, P. K., Raisch, K., Matzen, K., Gay, S. &lt;strong&gt;Presence of type III collagen in bone from a patient with osteogenesis imperfecta.&lt;/strong&gt; Europ. J. Pediat. 125: 29-37, 1977.">Muller et al.
(1977)</a>; <a href="#Prockop1984" class="mim-tip-reference" title="Prockop, D. J., Kivirikko, K. I. &lt;strong&gt;Heritable diseases of collagen.&lt;/strong&gt; New Eng. J. Med. 311: 376-386, 1984.">Prockop and Kivirikko (1984)</a>; <a href="#Sauk1980" class="mim-tip-reference" title="Sauk, J. J., Gay, R., Miller, E. J., Gay, S. &lt;strong&gt;Immunohistochemical localization of type III collagen in the dentin of patients with osteogenesis imperfecta and hereditary opalescent dentin.&lt;/strong&gt; J. Oral Path. 9: 210-220, 1980.">Sauk et al. (1980)</a>; <a href="#Shapiro1983" class="mim-tip-reference" title="Shapiro, J. R., Triche, T., Rowe, D. W., Munabi, A., Cattell, H. S., Schlesinger, S. &lt;strong&gt;Osteogenesis imperfecta and Paget&#x27;s disease of bone. Biochemical and morphological studies.&lt;/strong&gt; Arch. Intern. Med. 143: 2250-2257, 1983.">Shapiro et
al. (1983)</a>; <a href="#Sillence1988" class="mim-tip-reference" title="Sillence, D. O. &lt;strong&gt;Osteogenesis imperfecta nosology and genetics.&lt;/strong&gt; Ann. N.Y. Acad. Sci. 543: 1-15, 1988.">Sillence (1988)</a>; <a href="#Solomons1969" class="mim-tip-reference" title="Solomons, C. C., Styner, J. &lt;strong&gt;Osteogenesis imperfecta: effect of magnesium administration on pyrophosphate metabolism.&lt;/strong&gt; Calcif. Tissue Res. 3: 318-326, 1969.">Solomons and Styner (1969)</a>; <a href="#Tsipouras1984" class="mim-tip-reference" title="Tsipouras, P., Borresen, A., Dickson, L. A., Berg, K., Prockop, D. J., Ramirez, F. &lt;strong&gt;Molecular heterogeneity in the mild autosomal dominant forms of osteogenesis imperfecta.&lt;/strong&gt; Am. J. Hum. Genet. 36: 1172-1179, 1984.">Tsipouras et
al. (1984)</a>; <a href="#Tsipouras1983" class="mim-tip-reference" title="Tsipouras, P., Myers, J. C., Ramirez, F., Prockop, D. J. &lt;strong&gt;Restriction fragment length polymorphism associated with the pro-alpha-2(I) gene of human type I procollagen: application to a family with an autosomal dominant form of osteogenesis imperfecta.&lt;/strong&gt; J. Clin. Invest. 72: 1262-1267, 1983.">Tsipouras et al. (1983)</a>; <a href="#Velley1974" class="mim-tip-reference" title="Velley, J. &lt;strong&gt;Etude clinique et genetique de la dentinogenese imparfaite hereditaire.&lt;/strong&gt; Actual. Odontostomatol. (Paris) Sep: 519-532, 1974.">Velley (1974)</a>; <a href="#Willing1993" class="mim-tip-reference" title="Willing, M. C., Pruchno, C. J., Byers, P. H. &lt;strong&gt;Molecular heterogeneity in osteogenesis imperfecta type I.&lt;/strong&gt; Am. J. Med. Genet. 45: 223-227, 1993.">Willing et al.
(1993)</a>
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<a id="references"class="mim-anchor"></a>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Aihara2003" class="mim-anchor"></a>
<div class="">
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Aihara, M., Lindsey, J. D., Weinreb, R. N.
<strong>Ocular hypertension in mice with a targeted type I collagen mutation.</strong>
Invest. Ophthal. Vis. Sci. 44: 1581-1585, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12657595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12657595</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12657595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1167/iovs.02-0759" target="_blank">Full Text</a>]
</p>
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<a id="2" class="mim-anchor"></a>
<a id="Andersen1989" class="mim-anchor"></a>
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<p class="mim-text-font">
Andersen, P. E., Jr., Hauge, M.
<strong>Osteogenesis imperfecta: a genetic, radiological, and epidemiological study.</strong>
Clin. Genet. 36: 250-255, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2805382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2805382</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2805382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.1989.tb03198.x" target="_blank">Full Text</a>]
</p>
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<a id="Astrom2002" class="mim-anchor"></a>
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<p class="mim-text-font">
Astrom, E., Soderhall, S.
<strong>Beneficial effect of long term intravenous bisphosphonate treatment of osteogenesis imperfecta.</strong>
Arch. Dis. Child. 86: 356-364, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11970931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11970931</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11970931[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11970931" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/adc.86.5.356" target="_blank">Full Text</a>]
</p>
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<a id="Barsh1982" class="mim-anchor"></a>
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<p class="mim-text-font">
Barsh, G. S., David, K. E., Byers, P. H.
<strong>Type I osteogenesis imperfecta: a nonfunctional allele for pro-alpha-1(I) chains of type I procollagen.</strong>
Proc. Nat. Acad. Sci. 79: 3838-3842, 1982.
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[<a href="https://doi.org/10.1073/pnas.79.12.3838" target="_blank">Full Text</a>]
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Bellur, S., Jain, M., Cuthbertson, D., Krakow, D., Shapiro, J. R., Steiner, R. D., Smith, P. A., Bober, M. B., Hart, T., Krischer, J., Mullins, M., Byers, P. H., Pepin, M., Durigova, M., Glorieux, F. H., Rauch, F., Sutton, V. R., Lee, B., Members of the BBD Consortium, Nagamani, S. C.
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[<a href="https://doi.org/10.1016/s0022-3476(97)70074-x" target="_blank">Full Text</a>]
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Bierring, K.
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Blumsohn, A., McAllion, S. J., Paterson, C. R.
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[<a href="https://doi.org/10.1002/ajmg.1269" target="_blank">Full Text</a>]
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Bonadio, J., Saunders, T. L., Tsai, E., Goldstein, S. A., Morris-Wiman, J., Brinkley, L., Dolan, D. F., Altschuler, R. A., Hawkins, J. E., Jr., Bateman, J. F., Mascara, T., Jaenisch, R.
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[<a href="https://doi.org/10.1073/pnas.87.18.7145" target="_blank">Full Text</a>]
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Boright, A. P., Lancaster, G. A., Scriver, C. R.
<strong>Osteogenesis imperfecta: a heterogeneous morphologic phenotype in cultured dermal fibroblasts.</strong>
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[<a href="https://doi.org/10.1007/BF00270554" target="_blank">Full Text</a>]
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Byers, P. H., Barsh, G. S., Holbrook, K. A.
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[<a href="https://doi.org/10.1016/s0046-8177(82)80112-3" target="_blank">Full Text</a>]
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Byers, P. H., Barsh, G. S., Peterson, K. E., Holbrook, K. A., Rowe, D. W.
<strong>Molecular mechanisms of abnormal bone matrix formation in osteogenesis imperfecta. In: Veis, A.: The Chemistry and Biology of Mineralized Connective Tissues.</strong>
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Byers, P. H., Barsh, G. S., Rowe, D. W., Peterson, K. E., Holbrook, K. A., Shapiro, J.
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Byers, P. H., Krakow, D., Nunes, M. E., Pepin, M.
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[<a href="https://doi.org/10.1097/01.gim.0000223557.54670.aa" target="_blank">Full Text</a>]
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Byers, P. H., Shapiro, J. R., Rowe, D. W., David, K. E., Holbrook, K. A.
<strong>Abnormal alpha2-chain in type I collagen from a patient with a form of osteogenesis imperfecta.</strong>
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[<a href="https://doi.org/10.1172/jci110815" target="_blank">Full Text</a>]
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Byers, P. H., Wallis, G. A., Willing, M. C.
<strong>Osteogenesis imperfecta: translation of mutation to phenotype.</strong>
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[<a href="https://doi.org/10.1136/jmg.28.7.433" target="_blank">Full Text</a>]
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Byers, P. H.
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Carothers, A. D., McAllion, S. J., Paterson, C. R.
<strong>Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta.</strong>
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[<a href="https://doi.org/10.1136/jmg.23.3.227" target="_blank">Full Text</a>]
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Castells, S., Colbert, C., Chakrabarti, C., Bachtell, R. S., Kassner, E. G., Yasumura, S.
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[<a href="https://doi.org/10.1016/s0022-3476(79)80741-6" target="_blank">Full Text</a>]
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Cetta, G., de Luca, G., Tenni, R., Zanaboni, G., Lenzi, L., Castellani, A. A.
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[<a href="https://doi.org/10.3109/03008208309004847" target="_blank">Full Text</a>]
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Cetta, G., Lenzi, L., Rizzotti, M., Ruggeri, A., Valli, M., Boni, M.
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[<a href="https://doi.org/10.3109/03008207709152612" target="_blank">Full Text</a>]
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Chamberlain, J. R., Schwarze, U., Wang, P.-R., Hirata, R. K., Hankenson, K. D., Pace, J. M., Underwood, R. A., Song, K. M., Sussman, M., Byers, P. H., Russell, D. W.
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[<a href="https://doi.org/10.1126/science.1088757" target="_blank">Full Text</a>]
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Cohn, D. H., Apone, S., Eyre, D. R., Starman, B. J., Andreassen, P., Charbonneau, H., Nicholls, A. C., Pope, F. M., Byers, P. H.
<strong>Substitution of cysteine for glycine within the carboxyl-terminal telopeptide of the alpha1 chain of type I collagen produces mild osteogenesis imperfecta.</strong>
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Cohn, D. H., Byers, P. H., Steinmann, B., Gelinas, R. E.
<strong>Lethal osteogenesis imperfecta resulting from a single nucleotide change in one human pro-alpha-1(I) collagen allele.</strong>
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[<a href="https://doi.org/10.1073/pnas.83.16.6045" target="_blank">Full Text</a>]
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De Vos, A., Sermon, K., Van de Velde, H., Joris, H., Vandervorst, M., Lissens, W., De Paepe, A., Liebaers, I., Van Steirteghem, A.
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[<a href="https://doi.org/10.1007/s004390000298" target="_blank">Full Text</a>]
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Delvin, E. E., Glorieux, F. H., Lopez, E.
<strong>In vitro sulfate turnover in osteogenesis imperfecta congenita and tarda.</strong>
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[<a href="https://doi.org/10.1002/ajmg.1320040406" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(75)90173-7" target="_blank">Full Text</a>]
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<strong>Osteogenesis imperfecta: a new classification.</strong>
Birth Defects Orig. Art. Ser. XI(6): 99-102, 1975.
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<strong>Instability of polymeric skin collagen in osteogenesis imperfecta.</strong>
Brit. Med. J. 1: 421-424, 1974.
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[<a href="https://doi.org/10.1136/bmj.1.5905.421" target="_blank">Full Text</a>]
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Francis, M. J. O., Smith, R.
<strong>Polymeric collagen of skin in osteogenesis imperfecta, homocystinuria, Ehlers-Danlos and Marfan syndromes.</strong>
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<strong>The relative amounts of the collagen chains alpha-1(I), alpha-2 and alpha-1(III) in the skin of 31 patients with osteogenesis imperfecta.</strong>
Clin. Sci. (Lond.) 60: 617-623, 1981.
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[<a href="https://doi.org/10.1042/cs0600617" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1749-6632.1991.tb19594.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1021/ja801670v" target="_blank">Full Text</a>]
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<strong>Detection of mutations in human type I collagen mRNA in osteogenesis imperfecta by indirect RNase protection.</strong>
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<strong>Analysis of cytoplasmatic and nuclear messenger RNA in fibroblasts from patients with type I osteogenesis imperfecta.</strong>
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[<a href="https://doi.org/10.1016/0076-6879(87)45012-x" target="_blank">Full Text</a>]
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<strong>Cyclic administration of pamidronate in children with severe osteogenesis imperfecta.</strong>
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[<a href="https://doi.org/10.1056/NEJM199810013391402" target="_blank">Full Text</a>]
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<strong>Skeletal muscle mitochondrial function and whole-body metabolic energetics in the +/G610C mouse model of osteogenesis imperfecta.</strong>
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[<a href="https://doi.org/10.1016/j.ymgme.2022.06.004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archderm.138.7.909" target="_blank">Full Text</a>]
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<strong>Lack of correlation between the type of COL1A1 or COL1A2 mutation and hearing loss in osteogenesis imperfecta patients.</strong>
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[<a href="https://doi.org/10.1002/humu.20071" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(60)80122-9" target="_blank">Full Text</a>]
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<strong>Cardiovascular involvement in osteogenesis imperfecta.</strong>
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[<a href="https://doi.org/10.1161/01.cir.73.1.54" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.132252399" target="_blank">Full Text</a>]
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<strong>Low ocular rigidity in patients with osteogenesis imperfecta.</strong>
Invest. Ophthal. Vis. Sci. 20: 807-809, 1981.
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[<a href="https://doi.org/10.1002/ajmg.a.32501" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20088" target="_blank">Full Text</a>]
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Labhard, M. E., Wirtz, M. K., Pope, F. M., Nicholls, A. C., Hollister, D. W.
<strong>A cysteine for glycine substitution at position 1017 in an alpha-1(I) chain of type I collagen in a patient with mild dominantly inherited osteogenesis imperfecta.</strong>
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<strong>Dominantly inherited osteogenesis imperfecta in man: an examination of collagen biosynthesis.</strong>
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[<a href="https://doi.org/10.1203/00006450-197502000-00005" target="_blank">Full Text</a>]
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<strong>Cyclic pamidronate infusion improves bone mineralisation and reduces fracture incidence in osteogenesis imperfecta.</strong>
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[<a href="https://doi.org/10.1007/s004310100844" target="_blank">Full Text</a>]
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<a id="Levin1980" class="mim-anchor"></a>
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Levin, L. S., Brady, J. M., Melnick, M.
<strong>Scanning electron microscopy of teeth in dominant osteogenesis imperfecta.</strong>
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[<a href="https://doi.org/10.1002/ajmg.1320050213" target="_blank">Full Text</a>]
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Levin, L. S., Pyeritz, R. E., Young, R. J., Holliday, M. J., Laspia, C. C.
<strong>Dominant osteogenesis imperfecta: heterogeneity and variation in expression. (Abstract)</strong>
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<strong>Classification of osteogenesis imperfecta by dental characteristics. (Letter)</strong>
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[<a href="https://doi.org/10.1016/s0140-6736(78)90108-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320310427" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI17051" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199810013391408" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.27.6.367" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00470603" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/bmj.288.6411.112" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.20.3.203" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000275682" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.3109/01050398409043042" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.72.2.586" target="_blank">Full Text</a>]
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<p class="mim-text-font">
Velley, J.
<strong>Etude clinique et genetique de la dentinogenese imparfaite hereditaire.</strong>
Actual. Odontostomatol. (Paris) Sep: 519-532, 1974.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4455066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4455066</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4455066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="108" class="mim-anchor"></a>
<a id="Vetter1992" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Vetter, U., Pontz, B., Zauner, E., Brenner, R. E., Spranger, J.
<strong>Osteogenesis imperfecta: a clinical study of the first ten years of life.</strong>
Calcif. Tissue Int. 50: 36-41, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1739868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1739868</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1739868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF00297295" target="_blank">Full Text</a>]
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<a id="Wallis1986" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wallis, G., Beighton, P., Boyd, C., Mathew, C. G.
<strong>Mutations linked to the pro alpha2(I) collagen gene are responsible for several cases of osteogenesis imperfecta type I.</strong>
J. Med. Genet. 23: 411-416, 1986.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3023615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3023615</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3023615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.23.5.411" target="_blank">Full Text</a>]
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<a id="110" class="mim-anchor"></a>
<a id="Waltimo-Siren2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Waltimo-Siren, J., Kolkka, M., Pynnonen, S., Kuurila, K., Kaitila, I., Kovero, O.
<strong>Craniofacial features in osteogenesis imperfecta: a cephalometric study.</strong>
Am. J. Med. Genet. 133A: 142-150, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15666304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15666304</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15666304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.30523" target="_blank">Full Text</a>]
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<a id="111" class="mim-anchor"></a>
<a id="Wenstrup1990" class="mim-anchor"></a>
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Wenstrup, R. J., Willing, M. C., Starman, B. J., Byers, P. H.
<strong>Distinct biochemical phenotypes predict clinical severity in nonlethal variants of osteogenesis imperfecta.</strong>
Am. J. Hum. Genet. 46: 975-982, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2339695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2339695</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2339695" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="112" class="mim-anchor"></a>
<a id="Willing1990" class="mim-anchor"></a>
<div class="">
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Willing, M. C., Cohn, D. H., Byers, P. H.
<strong>Frameshift mutation near the 3-prime end of the COL1A1 gene of type I collagen predicts an elongated pro-alpha-1(I) chain and results in osteogenesis imperfecta type I.</strong>
J. Clin. Invest. 85: 282-290, 1990. Note: Erratum: J. Clin. Invest. 85: following 1338, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2295701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2295701</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2295701" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI114424" target="_blank">Full Text</a>]
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<a id="113" class="mim-anchor"></a>
<a id="Willing1992" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Willing, M. C., Pruchno, C. J., Atkinson, M., Byers, P. H.
<strong>Osteogenesis imperfecta type I is commonly due to a COL1A1 null allele of type I collagen.</strong>
Am. J. Hum. Genet. 51: 508-515, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1353940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1353940</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1353940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="114" class="mim-anchor"></a>
<a id="Willing1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Willing, M. C., Pruchno, C. J., Byers, P. H.
<strong>Molecular heterogeneity in osteogenesis imperfecta type I.</strong>
Am. J. Med. Genet. 45: 223-227, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8456806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8456806</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8456806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320450214" target="_blank">Full Text</a>]
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<a id="115" class="mim-anchor"></a>
<a id="Willing1995" class="mim-anchor"></a>
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Willing, M. C., Slayton, R. L., Pitts, S. H., Deschenes, S. P.
<strong>Absence of mutations in the promoter of the COL1A1 gene of type I collagen in patients with osteogenesis imperfecta type I.</strong>
J. Med. Genet. 32: 697-700, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8544188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8544188</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8544188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.32.9.697" target="_blank">Full Text</a>]
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<a id="116" class="mim-anchor"></a>
<a id="Zeitlin2003" class="mim-anchor"></a>
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Zeitlin, L., Rauch, F., Plotkin, H., Glorieux, F. H.
<strong>Height and weight development during four years of therapy with cyclical intravenous pamidronate in children and adolescents with osteogenesis imperfecta types I, III, and IV.</strong>
Pediatrics 111: 1030-1036, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12728084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12728084</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12728084" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1542/peds.111.5.1030" target="_blank">Full Text</a>]
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<a id="117" class="mim-anchor"></a>
<a id="Zhuang1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zhuang, J., Tromp, G., Kuivaniemi, H., Nakayasu, K., Prockop, D. J.
<strong>Deletion of 19 base pairs in intron 13 of the gene for the pro-alpha-2(I) chain of type-I procollagen (COL1A2) causes exon skipping in a proband with type-I osteogenesis imperfecta.</strong>
Hum. Genet. 91: 210-216, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7916744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7916744</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7916744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF00218258" target="_blank">Full Text</a>]
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<span class="mim-text-font">
Hilary J. Vernon - updated : 10/03/2022
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Ada Hamosh - updated : 10/23/2018<br>Cassandra L. Kniffin - updated : 12/30/2008<br>Ada Hamosh - updated : 7/9/2008<br>Marla J. F. O'Neill - updated : 1/2/2008<br>Ada Hamosh - updated : 7/25/2007<br>Marla J. F. O'Neill - updated : 6/12/2007<br>John A. Phillips, III - updated : 5/7/2007<br>John A. Phillips, III - updated : 3/21/2007<br>Victor A. McKusick - updated : 3/23/2005<br>Victor A. McKusick - updated : 9/2/2004<br>Victor A. McKusick - updated : 6/11/2004<br>Natalie E. Krasikov - updated : 2/10/2004<br>John A. Phillips, III - updated : 9/12/2003<br>Jane Kelly - updated : 8/19/2003<br>Victor A. McKusick - updated : 8/5/2003<br>Denise L. M. Goh - updated : 4/1/2003<br>Denise L. M. Goh - updated : 2/19/2003<br>Gary A. Bellus - updated : 2/3/2003<br>Ada Hamosh - updated : 1/30/2002<br>Sonja A. Rasmussen - updated : 6/8/2001<br>Victor A. McKusick - updated : 8/16/2000<br>Victor A. McKusick - updated : 10/2/1998<br>Moyra Smith - updated : 12/18/1997<br>Beat Steinmann - updated : 4/18/1994
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Creation Date:
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Victor A. McKusick : 6/23/1986
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alopez : 12/07/2023
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carol : 04/18/2023<br>carol : 01/17/2023<br>carol : 10/04/2022<br>carol : 10/03/2022<br>carol : 05/23/2019<br>alopez : 10/23/2018<br>carol : 06/27/2018<br>alopez : 06/26/2018<br>carol : 10/27/2016<br>carol : 06/17/2016<br>carol : 6/15/2016<br>carol : 12/7/2015<br>carol : 3/17/2015<br>terry : 4/4/2013<br>terry : 4/4/2013<br>terry : 6/6/2012<br>carol : 4/13/2012<br>terry : 1/13/2011<br>terry : 10/12/2010<br>terry : 9/8/2010<br>terry : 6/3/2010<br>terry : 6/3/2010<br>terry : 6/3/2010<br>ckniffin : 1/20/2010<br>terry : 6/3/2009<br>terry : 2/4/2009<br>wwang : 1/7/2009<br>ckniffin : 12/30/2008<br>wwang : 7/18/2008<br>terry : 7/9/2008<br>carol : 1/2/2008<br>alopez : 8/2/2007<br>terry : 7/25/2007<br>carol : 6/12/2007<br>carol : 5/7/2007<br>carol : 3/21/2007<br>alopez : 3/20/2007<br>carol : 8/18/2006<br>carol : 1/13/2006<br>tkritzer : 3/23/2005<br>terry : 3/23/2005<br>alopez : 3/9/2005<br>terry : 2/14/2005<br>alopez : 9/5/2004<br>terry : 9/2/2004<br>tkritzer : 6/25/2004<br>terry : 6/11/2004<br>carol : 2/10/2004<br>cwells : 9/12/2003<br>carol : 8/19/2003<br>tkritzer : 8/6/2003<br>tkritzer : 8/5/2003<br>tkritzer : 8/5/2003<br>carol : 4/1/2003<br>carol : 2/19/2003<br>joanna : 2/12/2003<br>alopez : 2/3/2003<br>mgross : 10/7/2002<br>alopez : 2/4/2002<br>terry : 1/30/2002<br>mcapotos : 6/12/2001<br>mcapotos : 6/8/2001<br>carol : 8/29/2000<br>terry : 8/16/2000<br>terry : 5/20/1999<br>terry : 5/3/1999<br>carol : 11/24/1998<br>carol : 10/7/1998<br>terry : 10/2/1998<br>dkim : 7/24/1998<br>mark : 1/30/1998<br>mark : 1/30/1998<br>alopez : 11/25/1997<br>alopez : 6/3/1997<br>joanna : 8/4/1996<br>mark : 10/22/1995<br>carol : 1/23/1995<br>davew : 7/27/1994<br>terry : 5/3/1994<br>warfield : 4/21/1994
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<span class="mim-font">
<strong>#</strong> 166200
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<span class="mim-font">
OSTEOGENESIS IMPERFECTA, TYPE I; OI1
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<span class="mim-font">
<em>Alternative titles; symbols</em>
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<span class="mim-font">
OI, TYPE I<br />
OSTEOGENESIS IMPERFECTA TARDA<br />
OSTEOGENESIS IMPERFECTA WITH BLUE SCLERAE
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<span class="mim-text-font">
<strong>SNOMEDCT:</strong> 385482004; &nbsp;
<strong>ORPHA:</strong> 216796, 666; &nbsp;
<strong>DO:</strong> 0110334; &nbsp;
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<h4>
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<th>
Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<td>
<span class="mim-font">
17q21.33
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Osteogenesis imperfecta, type I
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166200
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Autosomal dominant
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3
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COL1A1
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120150
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because OI type I (OI1) is caused by heterozygous mutation in the COL1A1 gene (120150) or the COL1A2 gene (120160).</p>
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<strong>Description</strong>
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<p>Osteogenesis imperfecta type I (OI1) is a dominantly inherited, generalized connective tissue disorder characterized mainly by bone fragility and blue sclerae. In most cases, 'functional null' alleles of COL1A1 on chromosome 17 or COL1A2 on chromosome 7 lead to reduced amounts of normal collagen I.</p>
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<strong>Clinical Features</strong>
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<p>Osteogenesis imperfecta (see Byers, 1993) is characterized chiefly by multiple bone fractures, usually resulting from minimal trauma. Affected individuals have blue sclerae, normal teeth, and normal or near-normal stature (for growth curves, see Vetter et al., 1992). Fractures are rare in the neonatal period; fracture tendency is constant from childhood to puberty, decreases thereafter, and often increases following menopause in women and after the sixth decade in men. Fractures heal rapidly with evidence of a good callus formation, and, with good orthopedic care, without deformity. Hearing loss of conductive or mixed type occurs in about 50% of families, beginning in the late teens and leading, gradually, to profound deafness, tinnitus, and vertigo by the end of the fourth to fifth decade. Additional clinical findings may be thin, easily bruised skin, moderate joint hypermobility and kyphoscoliosis, hernias, and arcus senilis. Mitral valve prolapse, aortic valvular insufficiency, and a slightly larger than normal aortic root diameter have been identified in some individuals (Hortop et al., 1986), but it is not clear that these disorders are significantly more frequent than in the general population. </p><p>Radiologically, wormian bones are common but bone morphology is generally normal at birth, although mild osteopenia and femoral bowing may be present. Vertebral body morphology in the adult is normal initially, but often develops the classic 'cod-fish' appearance (Steinmann et al., 1991).</p><p><strong><em>EYES</em></strong></p><p>
Individuals with OI type I have distinctly blue sclerae which remain intensely blue throughout life, in contrast to the sclerae in OI type III and OI type IV which may also be blue at birth and during infancy. The intensity of the blue fades with time such that these individuals may have sclerae of normal hue by adolescence and adult life (Sillence et al., 1993). In a likely heterogeneous group of 16 patients with OI syndromes, Kaiser-Kupfer et al. (1981) found low ocular rigidity and small corneal diameter and globe length; no correlation was found between rigidity of the eyeball and blueness of the sclera. The central corneal thickness was found to be significantly lower in 53 patients with OI than that in 35 patients with otosclerosis and in 35 control subjects (Pedersen and Bramsen, 1984). </p><p>Hartikka et al. (2004) found that patients with COL1A1 mutations more frequently had blue sclerae than those with COL1A2 mutations. In addition, patients with COL1A2 mutations tended to be shorter than those with COL1A1 mutations. </p><p><strong><em>CARDIOVASCULAR SYSTEM</em></strong></p><p>
The prevalence and severity of cardiovascular involvement in OI type I was determined in a prospective study of patients of all ages (Pyeritz and Levin, 1981). Mitral valve prolapse occurred in 18% (3 times the prevalence in unaffected relatives) and rarely progressed to mitral regurgitation. Mean aortic root diameter was slightly but significantly increased and was associated with aortic regurgitation in 1 to 2%. No patient had suffered a dissection. Later, Hortop et al. (1986) studied 109 persons with nonlethal OI from 66 families. They could demonstrate no definite increase in the frequency of mitral valve prolapse over that to be expected in any group of persons. Aortic root dilatation was found by echocardiogram to be present in 8 of 66 persons with OI syndrome; dilatation was mild and unrelated to age of the patient but was strikingly aggregated in families. Of 109 persons surveyed, valvular disease was evident clinically in only 4 persons (aortic regurgitation in 2, aortic stenosis in one, and mitral valve prolapse in one). Hortop et al. (1986) stated that aortic root dilatation was seen in each of the different OI syndromes but strikingly segregated within certain families. They concluded that the mild and apparently nonprogressive nature of this lesion in OI argues against the use of beta-adrenergic blockade in affected individuals in the absence of systemic arterial hypertension. </p><p>Mayer et al. (1996) reported a 35-year-old woman with a mild form of OI1 who presented with spontaneous dissection of the right internal carotid artery and the right vertebral artery after scuba diving. She had no obvious head or neck trauma. Other than a history of easy bruising and bluish sclerae, she had no evidence of a connective tissue disorder. There had been no bone fractures or dental problems nor was there family history of vasculopathy. Genetic analysis identified a heterozygous mutation in the COL1A1 gene (G13A; 120150.0052). </p><p><strong><em>EARS</em></strong></p><p>
In likely heterogeneous groups of patients with OI, about half of affected individuals have hearing loss that begins during the second decade as a conductive loss; older individuals have sensorineural losses (Riedner et al., 1980; Pedersen, 1984). In only 1 major study was a majority of patients with sensorineural pattern observed (Shapiro et al., 1982). A female-to-male preponderance of 2:1 has been reported (Shea and Postma, 1982). Hearing loss is different from otosclerosis. </p><p>Vertigo is frequently associated with otosclerosis in which the hearing loss clinically resembles that in OI. Vertigo is also common in basilar impression found in up to 25% of adult OI patients. To evaluate the cause, frequency, and characteristics of vertigo in OI, Kuurila et al. (2003) studied 42 patients by interview, clinical examination, and audiologic examination supplemented with electronystagmography (ENG) and lateral skull radiography. Audiometry showed hearing loss in 25 patients (59.5%). In 9 patients (21%), abnormal skull base anatomy was found in the forms of basilar impression, basilar invagination, or both. Vertigo, mostly of floating or rotational sensation of short duration, was reported by 22 patients (52.4%). Patients with hearing loss tended to have more vertigo than patients with normal hearing. Vertigo was not correlated with type of hearing loss or auditory brainstem response pathology. ENG was abnormal in 14 patients (33.3%). Kuurila et al. (2003) concluded that vertigo is common in patients with OI and that in most cases, it is secondary to inner ear pathology. </p><p>Hartikka et al. (2004) reported a correlative analysis between types of mutation in the COL1A1 and COL1A2 genes and OI-associated hearing loss. A total of 54 Finnish OI patients with previously diagnosed hearing loss or age 35 or more years were analyzed for mutations in COL1A1 or COL1A2. Altogether 49 mutations were identified, of which 41 were novel. No correlation was found between the mutated gene or mutation type and hearing pattern. The authors interpreted this to mean that the basis of hearing loss in OI is complex, and that it is a result of multifactorial, still unknown genetic effects. </p><p><strong><em>SKIN</em></strong></p><p>
Using a suction-cup technique, Hansen and Jemec (2002) performed quantitative studies of skin mechanics (elasticity, distensibility, and hysteresis) in 10 patients with OI, 8 with type I and 2 with type III (259420), and 24 age-matched controls. Skin elasticity, distensibility, and hysteresis were significantly decreased in patients versus controls. OI type I patients had decreased distensibility and hysteresis but increased elasticity in comparison to the type III patients. The authors concluded that the skin of patients with OI is more stiff and less elastic than normal skin. These changes differ from age-related changes, which have been described as increased distensibility and viscosity (similar to hysteresis). </p><p><strong><em>CRANIOFACIAL AND DENTAL FEATURES</em></strong></p><p>
To obtain baseline information on craniofacial development in OI patients who had not received bisphosphonate treatment, Waltimo-Siren et al. (2005) used lateral radiographs to analyze the size and form of the bony structures in heads of 59 consecutive patients with OI types I, III, or IV (Sillence classification). In OI type I they found linear measurements that were smaller than normal, indicating a general growth deficiency, but no remarkable craniofacial deformity. In OI types III and IV, the growth impairment was pronounced and the craniofacial form was altered as a result of differential growth deficiency and bending of the skeletal head structures. They found strong support both for an abnormally ventral position of the sella region due to bending of the cranial base and for a closing mandibular growth rotation. Vertical underdevelopment of the dentoalveolar structures and the condylar process were identified as the main reasons for the relative mandibular prognathism in OI. Waltimo-Siren et al. (2005) concluded that facial growth impairment would probably remain characteristic for many OI patients despite the widespread intervention with bisphosphonates and that orthodontic treatment should be further developed. </p><p><strong><em>CLINICAL VARIABILITY</em></strong></p><p>
The disorder may exhibit considerable interfamilial and intrafamilial variability in the number of fractures and degree of disability. Rowe et al. (1985) reported a spectrum of disease severity within a 5-generation family. Those most severely affected exhibited more severe short stature and a mild degree of scoliosis relative to those who were less severely affected. Most striking were identical twins, the offspring of a mildly affected mother. Twin B was born small for gestational age, had had 12 fractures and was 150 cm tall (3rd centile) at 11 years of age. Her twin was born appropriate for gestational age and had had only 2 fractures at age 8 and 9 secondary to strenuous exercise; her current height was 162 cm (50th centile). This family study suggested that the severity of the disease is roughly correlated with the reduction in collagen I synthesis. </p><p>Willing et al. (1990) described 5 affected individuals of a 3-generation family with marked clinical variability. They wondered if there might be subtle biochemical differences between the family members with respect to the amount of the abnormal pro-alpha-1(I) chains produced or their intracellular fate, but no differences were observed. They noticed that the more severely affected family members had children with both mild and severe phenotypes, while the mildly affected individual had an offspring with a mild phenotype. This suggested to them that there might be some other, not identified, factor segregating independently in this family that acts to modulate the final phenotype. </p><p><strong><em>CLASSIFICATION</em></strong></p><p>
Using clinical, radiographic, and genetic criteria, Sillence et al. (1979) developed the classification currently in use into types I to IV: a dominant form with blue sclerae, type I; a dominant form with normal sclerae, type IV (166220); a perinatally lethal OI syndrome, type II (166210); and a progressively deforming form with normal sclerae, type III. The biochemical and linkage studies support the broad validity of the classification but confirm that it is incomplete. Although biochemical and genetic studies will provide the basis of the most rational classification, even such a detailed scheme probably will never predict correctly the evolution of OI in every affected individual, because of the still unexplained variability of expression seen in many families (Byers, 1993). </p><p>Bauze et al. (1975) divided their 42 patients with OI into mild, moderate, and severe groups according to deformity of long bones. None of the 17 patients in the mild group had scoliosis or white sclerae. The terms 'congenita' and 'tarda' now have limited usefulness, since they do not specify the mode of inheritance or basic biochemical defects. </p><p>Levin et al. (1980) concluded that dominant type I OI separates clearly into families in which affected persons have opalescent teeth and those in which dentinogenesis imperfecta (DGI) is absent. In 5 families, all members whose teeth were studied radiographically and by scanning electron microscopy had opalescent teeth. In 2 families the teeth of all affected persons were normal. Some members of both classes of families had blue sclerae and others did not. These 2 forms of OI were designated type IA and IB, depending on the presence or absence, respectively, of DGI. Paterson et al. (1983) found that patients with associated DGI (type IA) have more severe disease, with a greater fracture rate and greater likelihood of growth impairment, than do type IB patients. </p><p>Superti-Furga et al. (2007) discussed the 2006 revisions to the Nosology of Constitutional Disorders of Bone by the Nosology Group of the International Skeletal Dysplasia Society and provided a comprehensive table of the new classification scheme. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Biochemical Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Byers (1993) summarized that 'functional null' alleles, i.e., silent alleles or mutations leading to excluded proteins, are the most common biochemical and genetic features of OI type I, although structural mutations in COL1A1 and COL1A2 leading to the synthesis of abnormal procollagen I can occasionally produce the OI type I phenotype.</p><p>Assessing reports of biochemical findings in the OI syndromes is difficult because the phenotype and genetics generally are not specified. Most studies deal, no doubt, with heterogeneous groups of patients. Several forms of OI were among the earliest of the inherited disorders of collagen biosynthesis and structure to be studied using cultured dermal fibroblasts from affected individuals (Martin et al., 1971; Penttinen et al., 1975). Cells cultured from patients who, in retrospect, would be considered to have OI type I, synthesized less procollagen I than did controls, but the mechanism by which production was decreased was not determined. These studies were extended from culture to tissue. </p><p>Francis et al. (1974) concluded that patients with OI and blue sclerae tend to have a reduced amount of collagen that has normal stability, as measured by resistance to depolymerization by pronase, heat, or cold alkali, whereas those with white sclerae have a normal amount of collagen with reduced stability; they suggested that a defect in cross-linking of collagen is present in the severe form of the disease. </p><p>Sykes et al. (1977) and, in a slightly extended study, Francis et al. (1981), found an increased ratio of collagen III to I in dermis and interpreted this as indicating a deficiency of collagen I. In studies of 44 patients with OI, Cetta et al. (1983) found in the largest category, the mild form, also an increased ratio of collagens III to I in skin and, in addition, an increased ratio of hydroxylysine diglycoside to monoglycoside in skin collagen. </p><p>Rowe et al. (1981) proposed that an additional criterion for OI type I is the production of a reduced quantity of collagen I. Among the cases of osteogenesis imperfecta with reduced synthesis of pro-alpha-1 chains, considerable heterogeneity is likely to emerge at the level of gene structure, as in the case of the globin genes in the thalassemias. Barsh et al. (1982) found that cultured skin fibroblasts from 3 patients produced half-normal levels of procollagen type I. Furthermore, the OI cells contained equimolar amounts of pro-alpha-1(I) and pro-alpha-2(I) chains, which suggested that trimer assembly and secretion were limited by the level of pro-alpha-1(I) chain synthesis. The 'extra' pro-alpha-2(I) chain in the OI cells was in a non-disulfide bonded configuration and apparently contributed to an increased level of intracellular degradation. The results of Barsh et al. (1982) suggested that the stoichiometry of the pro-alpha chains in procollagen I is determined by the conformation of the chains rather than by the ratio in which they are synthesized, that molecules containing more than a single pro-alpha-2(I) chain are not assembled, and that the production of collagen I can be regulated by controlling synthesis of only one of its subunits. </p><p>Rowe et al. (1985) demonstrated that reductions in collagen I production and in the ratio of alpha-1(I) to alpha-2(I) mRNA are clearly segregated with affected individuals within the 5 generation family. Rowe et al. (1985) further suggested that the severity of the disorder is roughly correlated with the reduction in collagen I synthesis. </p><p>Wenstrup et al. (1990) correlated clinical severity in nonlethal variants of OI with the nature of the alteration in the alpha chains of procollagen I secreted by cultured fibroblasts. Cells from 40 probands secreted about half the normal amount of normal procollagen I and no identifiable abnormal molecules; these patients were generally of normal stature, rarely had bone deformity or dentinogenesis imperfecta, and had blue sclerae. Cells from 74 other probands produced and secreted normal and abnormal procollagen I molecules; these patients were usually short and had bone deformity and dentinogenesis imperfecta, and many had gray or blue-gray sclerae. In cells from yet another 18 probands, Wenstrup et al. (1990) were unable to identify altered procollagen I synthesis or structure. </p><p>Gauba and Hartgerink (2008) reported the design of a novel model system based upon collagen-like heterotrimers that can mimic the glycine mutations present in either the alpha-1 or alpha-2 chains of type I collagen. The design utilized an electrostatic recognition motif in 3 chains that can force the interaction of any 3 peptides, including AAA (all same), AAB (2 same and 1 different), or ABC (all different) triple helices. Therefore, the component peptides could be designed in such a way that glycine mutations were present in zero, 1, 2, or all 3 chains of the triple helix. They reported collagen mutants containing 1 or 2 glycine substitutions with structures relevant to native forms of OI. Gauba and Hartgerink (2008) demonstrated the difference in thermal stability and refolding half-life times between triple helices that vary only in the frequency of glycine mutations at a particular position. </p><p>By differential scanning calorimetry and circular dichroism, Makareeva et al. (2008) measured and mapped changes in the collagen melting temperature (delta-T(m)) for 41 different glycine substitutions from 47 OI patients. In contrast to peptides, they found no correlation of delta-T(m) with the identity of the substituting residue but instead observed regular variations in delta-T(m) with the substitution location on different triple helix regions. To relate the delta-T(m) map to peptide-based stability predictions, the authors extracted the activation energy of local helix unfolding from the reported peptide data and constructed the local helix unfolding map and tested it by measuring the hydrogen-deuterium exchange rate for glycine NH residues involved in interchain hydrogen bonds. Makareeva et al. (2008) delineated regional variations in the collagen triple helix stability. Two large, flexible regions deduced from the delta-T(m) map aligned with the regions important for collagen fibril assembly and ligand binding. One of these regions also aligned with a lethal region for Gly substitutions in the alpha-1(I) chain. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Other Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Dickson et al. (1975) reported a quantitative and qualitative abnormality of noncollagenous proteins of bone. </p><p>Lancaster et al. (1975) found a consistent morphologic abnormality of cultured skin fibroblasts: irregular packing of aggregated cells and an irregular tessellated appearance of individual fibroblasts. Boright et al. (1984) showed that dermal fibroblasts derived from individuals with OI type I take longer than control cells to reach confluency, have a lower cell density at stationary phase and have an abnormal cell shape as judged by the increased ratio of width to length. An increase in population doubling time of fibroblasts derived from individuals with the milder form of OI was also observed by Rowe and Shapiro (1982). </p>
</span>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
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</h4>
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<span class="mim-text-font">
<p>The mode of inheritance is autosomal dominant. Penetrance of blue sclerae is 100 percent, while penetrance of hearing loss is clearly age-dependent (Garretsen and Cremers, 1991). Paternal age effect for increased risk of new mutations has been documented although it appears to be considerably lower than, for example, in achondroplasia (100800). In 10 cases with OI type I presumed to have arisen by new mutation, the mean paternal age was increased by 2.1 years (Sillence et al., 1979), whereas in 38 other cases it was significantly increased by 2.9 years (Carothers et al., 1986). </p><p>Blumsohn et al. (2001) confirmed the presence of a small paternal age effect in apparently sporadic OI. The study evaluated patients born in England, Wales, and Scotland between 1961 and 1998. For 357 apparently sporadic cases among 730 eligible cases, the mean age of fathers at the birth of their children was 0.87 years greater than expected (p = 0.01). The relative risk was 1.62 for fathers in the highest quintile of paternal age compared with fathers in the lowest quintile. </p>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
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</h4>
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<span class="mim-text-font">
<p>In all but 1 of 11 families with OI tarda, Sykes et al. (1986) found that the disorder segregated with either the COL1A1 locus or the COL1A2 locus. In 1 small family, segregation occurred with both genes, but this disorder clearly cannot be linked to both; had further meioses been available, the OI gene would probably have segregated independently of at least 1 of the 2 loci. Tsipouras (1987), also, concluded that mild OI is genetically heterogeneous and that 1 or more loci other than COL1A1 and COL1A2 may be involved in the causation of phenotypically indistinguishable autosomal dominant OI. </p><p>Sykes et al. (1990) studied segregation of the COL1A1 and COL1A2 genes in 38 dominant osteogenesis imperfecta pedigrees. None of the 38 pedigrees showed recombination between the OI gene and both collagen loci. All 8 pedigrees with OI type IV (166220) segregated with COL1A2. On the other hand, 17 type I pedigrees segregated with COL1A1 and 7 with COL1A2. The concordant locus was uncertain in the remaining 6 OI type I pedigrees. The presence or absence of presenile hearing loss was the best predictor of the mutant locus in OI type I families, with 13 of the 17 COL1A1 segregants and none of the 7 COL1A2 segregants showing this feature. By linkage analysis in 7 autosomal dominant osteogenesis imperfecta families in Italy, Mottes et al. (1990) showed that the COL1A1 gene was implicated in 2 families and the COL1A2 gene in 1 family with OI type I. The COL1A2 gene was implicated in 2 families with OI type IV. In 2 OI type I families, the molecular genetic data were insufficient for exclusion of one gene. </p>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Byers (1993) summarized that 'functional null' alleles are the most common genetic features of OI type I. The mechanism by which the synthesis of pro-alpha-1(I) chains is decreased remains a difficult problem to solve. A variety of mutations, such as deletion of an allele, promoter and enhancer mutations, splicing mutations, premature termination, as well as other mutations that result in the inability of pro-alpha-1(I) chains to assemble into molecules, would presumably result in the same biochemical picture and the same phenotype.</p><p>In some individuals, the decreased production of pro-alpha-1(I) chains by fibroblasts results from about half-normal steady-state levels of the mRNA (Rowe et al., 1985). Later studies on these cells indicated that there is a defect in splicing of the pre-mRNA of COL1A1 that prohibits transport of the product of the mutant allele to the cytoplasm; the ratio of pro-alpha-1(I) to pro-alpha-2(I) mRNA was 1:1 in the cytoplasm instead of the normal 2:1, whereas the ratio was 4:1 in the nucleus instead of the normal 2:1 (Genovese and Rowe, 1987). Furthermore, a novel species of alpha-1(I) mRNA present in the nuclear compartment was not collinear with a cDNA probe (Genovese et al., 1989). In another individual with OI type I, Stover et al. (1993) demonstrated a G-A transition in the first position of the splice donor site of intron 26 which resulted in inclusion of the entire succeeding intron in the mature mRNA that accumulated in the nuclear compartment; apparently because no abnormal pro-alpha-1(I) chains were synthesized from the mutant allele, the clinical phenotype of this individual was mild. In a large study, Willing et al. (1992) showed that among 70 individuals with OI type I 23 from 21 families were heterozygous at the COL1A1 polymorphic MnlI site. As shown by primer extension with nucleotide-specific chain termination, there was in each case marked diminution in steady-state mRNA levels from one COL1A1 allele. Loss of an allele through deletion or rearrangement was not the cause of the diminished COL1A1 mRNA levels. Only in one family has the causative mutation been identified; an A-G transition in the obligatory acceptor splice site of intron 16 resulted in skipping of exon 17 in the mRNA which represented only 10% of the total COL1A1 mRNA. Further, linkage studies in 38 additional families have demonstrated no evidence of deletion of those regions of the COL1A1 gene used for linkage analysis (Sykes et al. (1986, 1990)) and confirmed that most individuals with the OI type I phenotype have mutations linked to the COL1A1 gene. In some families, a similar phenotype is thought to result from mutations in the COL1A2 gene (Sykes et al. (1986, 1990); Wallis et al., 1986), but the clinical criteria by which the diagnosis of OI type I is made are not always clear. Willing et al. (1990) described a 5-bp deletion near the 3-prime end of one COL1A1 allele that resulted in a reading frame shift 12 amino acid residues from the normal terminus of the chain and predicted an extension of 84 amino acid residues beyond the normal termination site. Although the abnormal mRNA could be translated in vitro, it proved extremely difficult to identify the abnormal chains in cells; it appeared that although the mRNA was present in normal amount, the protein product was unstable. This mutation provides a model of how many different mutations in the COL1A1 gene could produce the OI type I phenotype by resulting in the synthesis of half the normal amount of a functional pro-alpha-1(I) chain. </p><p>In an effort to further understand the reasons for diminished COL1A1 transcript levels in OI type I, Willing et al. (1995) investigated whether mutations involving key regulatory sequences in the COL1A1 promoter, such as the TATAAA and CCAAAT boxes, are responsible for the reduced levels of mRNA. They used PCR-amplified genomic DNA in conjunction with denaturing gradient gel electrophoresis and SSCP to screen the 5-prime untranslated domain, exon 1, and a small portion of intron 1 of the COL1A1 gene. In addition, direct sequence analysis was performed on an amplified genomic DNA fragment that included the TATAAA and CCAAAT boxes. In a survey of 40 unrelated probands with OI type I in whom no causative mutation was known, Willing et al. (1995) identified no mutations in the promoter region and there was 'little evidence of sequence diversity among any of the 40 subjects.' </p><p>Although less common than 'functional null' allele mutations, there are several examples in which the synthesis of abnormal procollagen I molecules can produce the OI type I phenotype. In one family (Nicholls et al., 1984), cells cultured from the affected mother and son, but not those from the normal daughter, synthesized alpha-1(I)-chains bearing a cysteine residue within the protease-resistant domain of the collagen molecule, a region from which that residue is normally absent. Although it was initially thought that the cysteine substitution was at the X or Y position of the Gly-X-Y repeating unit of the alpha-1(I) chain in the carboxyl-terminal peptide CB6 (Steinmann et al., 1986), peptide sequence analysis and sequencing of the cDNA demonstrated that the mutation resulted in the substitution of a glycine by cysteine in position 1017 in the telopeptide, 3 amino acid residues from the carboxy-terminal to the end of the triple helix (Cohn et al., 1988; Labhard et al., 1988). </p><p>Other substitutions of cysteine for glycine within the triple helical domain of the alpha-1(I) chain at residue 94 (Starman et al., 1989; Nicholls et al., 1990; Shapiro et al., 1992; Byers, 1993) also produce mild forms of OI, perhaps compatible with OI type I (see, e.g., 120150.0002 and 120500.0038). Byers et al. (1983) described an isolated patient with a mild to moderate form of OI: blue sclerae, a height of 147 cm, deformity as a consequence of poor orthopedic treatment, and hearing loss. Her cells synthesized a pro-alpha-2(I) chain in which approximately 30 amino acid residues were deleted from the triple-helical domain, in the CB4 peptide, a domain in which phosphoproteins important to bone calcification may bind and in which crosslinks may form. Subsequent studies indicated that a point mutation at the consensus splice-donor site resulted in the skipping of exon 12 (amino acids 91-108) from about half the COL1A2 transcripts (Rowe et al., 1990). Zhuang et al. (1993) showed that deletion of 19 bp from +4 to +22 of intron 13 of COL1A2 caused skipping of exon 13 in about 88% of the transcripts, whereas 12% of the transcripts were normally spliced; procollagen I containing the mutated pro-alpha-2(I) chain had reduced thermal stability and was only poorly secreted from the cells. </p><p>A woman with 'postmenopausal osteoporosis' was reported by Spotila et al. (1991) to be heterozygous for a serine-to glycine substitution at position 661 of the alpha-2(I) triple-helical domain. Since her 3 sons, who inherited the mutation, had experienced fractures as adolescents, the diagnosis of 'mild OI cannot be fully excluded' according to the authors' view; one of the sons was homozygous for the mutation due to partial isodisomy for maternal chromosome 7 (Spotila et al., 1992). All these findings suggest that other point mutations in the COL1A1 gene, and perhaps in the COL1A2 gene (as suggested also by linkage studies), could lead to a phenotype similar to that produced by 'functional null' allele mutations. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Diagnosis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>The diagnosis is based on clinical and genetic criteria. In sporadic cases, the diagnosis may be difficult, and secondary osteoporosis and nonaccidental injury has to be ruled out. In women with severe 'postmenopausal osteoporosis' careful clinical investigation and a thorough personal and family history quite often reveals OI type I. While the direct molecular characterization is not feasible in the majority of cases at present, demonstration of reduced synthesis of procollagen I by dermal fibroblasts is indicative for the disorder. Lynch et al. (1991) discussed the problem of making the prenatal diagnosis of OI type I on the basis of linkage. </p><p>De Vos et al. (2000) reported the achievement of a normal twin pregnancy after preimplantation genetic diagnosis for osteogenesis imperfecta type I. Because 2 blighted ova were seen on ultrasound at 7 weeks' gestation, the pregnancy was terminated. The female partner with OI type I carried a 1-bp deletion in exon 43 of the COL1A1 gene, resulting in a premature stop codon in exon 46. The nonfunctional allele was predicted to result in the synthesis of too little type I procollagen. </p><p>Byers et al. (2006) published practice guidelines for the genetic evaluation of suspected OI. </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Management</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Fractures in OI are treated with standard orthopedic procedures appropriate for the type of fracture and the age, and heal rapidly with evidence of good callus formation (sometimes with hypertrophic callus formation) and without deformity. Regular hearing evaluations after adolescence and early stapedectomy or stapedotomy are recommended. In postmenopausal women with OI, a long-term physical therapy program to strengthen the paraspinal muscles, together with estrogen and progesterone replacement, adequate calcium intake, and perhaps calcitonin or fluoride administration, may be specifically indicated (for review, see Steinmann et al., 1990).</p><p>Bembi et al. (1997) described the results of treatment of 3 children with OI type I with cyclic intravenous infusions of aminohydroxypropylidene bisphosphonate (pamidronate). Each of the children had repeated bone fractures and low bone density. The rationale for pamidronate therapy in OI is based on the fact that bisphosphonates inhibit osteoclastic bone resorption; this leads to increased bone density and possibly to reduced risk of fracture. Bembi et al. (1997) reported a clear clinical response over the 22- to 29-month treatments, with a striking reduction in the frequency of new fractures. They also observed an effect on bone density. There were no notable adverse effects during therapy. </p><p>In an uncontrolled observational study involving 30 children aged 3 to 16 years with severe osteogenesis imperfecta, Glorieux et al. (1998) administered pamidronate intravenously at 4- to 6-month intervals for 1.3 to 5.0 years. They observed a sustained reduction in serum alkaline phosphatase concentrations and in the urinary excretion of calcium and type I collagen N-telopeptide. Increases in the size of the vertebral bodies suggested that new bone had formed. The mean incidence of radiologically confirmed fractures decreased by 1.7 per year (P less than 0.001). Treatment with pamidronate did not alter the rate of fracture healing, the growth rate, or the appearance of growth plates. Mobility and ambulation improved in 16 children and remained unchanged in the other 14. The children with severe osteogenesis imperfecta treated by Glorieux et al. (1998) fell into the type III (259420) and type IV (166220) categories of osteogenesis imperfecta. </p><p>Marini (1998) commented that fluoride and calcitonin treatment in OI had proved unsuccessful. The bisphosphonates are synthetic analogs of pyrophosphate, a natural inhibitor of osteoclastic bone resorption. They have been useful in the treatment of osteoporosis, Paget disease of bone, and fibrous dysplasia. </p><p>Lee et al. (2001) performed a prospective open label study to determine the efficacy and safety of pamidronate in 6 children with OI (3 had OI type I, 2 had type III, and 1 had type IV). The dose was 1.5 mg/kg bimonthly over 12 to 23 months. The number of fractures decreased from median of 3 (range 1-12) to 0 fractures per year (range 0-4) and all patients experienced improved bone mineral density and decreased serum alkaline phosphatase. </p><p>Astrom and Soderhall (2002) performed a prospective observational study using disodium pamidronate (APD) in 28 children and adolescents (aged 0.6 to 18 years) with severe OI or a milder form of the disease, but with spinal compression fractures. All bone metabolism variables in serum (alkaline phosphatase, osteocalcin, procollagen-1 C-terminal peptide, collagen-1 teleopeptide) and urine (deoxypyridinoline) indicated that there was a decrease in bone turnover. All patients experienced beneficial effects, and the younger patients showed improvement in well-being, pain, and mobility without significant side effects. Vertebral remodeling was also seen. They concluded that APD seemed to be an efficient symptomatic treatment for children and adolescents with OI. </p><p>Lindsay (2002) reviewed the mechanism, effects, risks, and benefits of bisphosphonate therapy in children with OI. He stated that the clinical course and attendant morbidity for many children with severe OI is clearly improved with its judicious use. Nevertheless, since bisphosphonates accumulate in the bone and residual levels are measurable after many years, the long-term safety of this approach was unknown. He recommended that until long-term safety data were available, pamidronate intervention be reserved for those for whom the benefits clearly outweighed the risks. </p><p>Rauch et al. (2002) compared parameters of iliac bone histomorphometry in 45 patients (23 girls, 22 boys) with OI types I, III, or IV before and after 2.4 +/- 0.6 years of treatment with cyclical intravenous pamidronate (age at the time of the first biopsy, 1.4 to 17.5 years). There was an increase in bone mass due to increases in cortical width and trabecular number. The bone surface-based indicators of cancellous bone remodeling, however, were decreased. There was no evidence of a mineralization defect in any of the patients. </p><p>Rauch et al. (2003) evaluated the effect of intravenous therapy with pamidronate on bone and mineral metabolism in 165 patients with OI types I, III, and IV. All patients received intravenous pamidronate infusions on 3 successive days, administered at age-dependent intervals of 2 to 4 months. During the 3 days of the first infusion cycle, serum concentrations of ionized calcium dropped and serum PTH levels transiently almost doubled. Two to 4 months later, ionized calcium had returned to pretreatment levels. During 4 years of pamidronate therapy, ionized calcium levels remained stable, but PTH levels increased by about 30%. Rauch et al. (2003) concluded that serum calcium levels can decrease considerably during and after pamidronate infusions, requiring close monitoring especially at the first infusion cycle. In long-term therapy, bone turnover is suppressed to levels lower than those in healthy children. The authors stated that the consequences of chronically low bone turnover in children with OI were unknown. </p><p>Zeitlin et al. (2003) analyzed longitudinal growth during cyclical intravenous pamidronate treatment in children and adolescents (ages 0.04 to 15.6 years at baseline) with moderate to severe forms of OI types I, III, and IV and found that 4 years of treatment led to a significant height gain. </p><p>Rauch et al. (2006) assessed the effect of long-term pamidronate treatment on the bone tissue of children and adolescents with OI. Average areal bone mineral density (aBMD) increased by 72% in the first half of the observation period, but by only 24% in the second half. Mean cortical width and cancellous bone volume increased by 87% and 38%, respectively, between baseline and the first time point during treatment (P less than 0.001 for all changes). Rauch et al. (2006) concluded that the gains that can be achieved with pamidronate treatment appear to be realized largely in the first 2 to 4 years. </p><p>Rauch et al. (2006) studied the effect of pamidronate discontinuation in pediatric patients with moderate to severe OI types I, III, and IV. In the controlled study, 12 pairs of patients were matched for age, OI severity, and duration of pamidronate treatment. Pamidronate was stopped in one patient of each pair; the other continued to receive treatment. In the observational study, 38 OI patients were examined (mean age, 13.8 years). The intervention was discontinuation of pamidronate treatment for 2 years. The results indicated that bone mass gains continue after treatment is stopped, but that lumbar spine aBMD increases less than in healthy subjects. The size of these effects is growth dependent. </p><p>In lethal forms of osteogenesis imperfecta caused by mutation in either the COL1A1 gene or the COL1A2 gene, the mutations result in the synthesis of abnormal chains of procollagen that bind to normal chains synthesized by the same cells and destroy their biologic activity in a classic dominant-negative manner. Chamberlain et al. (2004) developed a strategy to inactivate the mutated alleles in cells of the bone marrow called mesenchymal stem cells (MSCs), or marrow stromal cells. They chose MSCs because these cells are easily obtained from a patient, they engraft and differentiate into many tissues after infusion in vivo, and allogeneic MSCs had produced promising results in a previous trial involving patients with osteogenesis imperfecta (Prockop et al., 2003; Horwitz et al., 2002). Chamberlain et al. (2004) designed a gene construct that targeted exon 1 of the COL1A1 gene. They predicted that, on insertion, the construct would both inactivate COL1A1 and confer resistance to the antibiotic neomycin. To insert the gene construct efficiently into MSCs, they used an adeno-associated virus as a vector. The results obtained with MSCs from 2 patients with osteogenesis imperfecta was highly encouraging. In 31 to 90% of the cells that became resistant to neomycin, the gene construct had inserted itself into either the wildtype or the mutated COL1A1 allele. In all cultures of the neomycin-resistant cells, most signs of the dominant-negative protein defect were corrected--apparently because the cells in which the mutated allele was inactivated began to produce an adequate amount of wildtype collagen. Most importantly, the quality of bones synthesized by the altered MSCs was improved. Prockop (2004) commented on the promising nature of the approach as well as some of the problems. </p><p>In a cohort of 540 individuals with OI studied longitudinally, Bellur et al. (2016) conducted a study to address whether cesarean delivery has an effect on at-birth fracture rates and whether an antenatal diagnosis of OI influences the choice of delivery method. They compared self-reported at-birth fracture rates among individuals with OI types I, III (259420), and IV (166220). When accounting for other covariates, at-birth fracture rates did not differ based on whether delivery was vaginal or by cesarean section. Increased birth weight conferred conferred higher risk for fractures irrespective of the delivery method. In utero fracture, maternal history of OI, and breech presentation were strong predictors for choosing cesarean delivery. The authors recommended that cesarean delivery should not be performed for the sole purpose of fracture prevention in OI, but only for other maternal or fetal indications. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In the county of Fyn, where approximately 9% of the Danish population lives, Andersen and Hauge (1989) identified 48 patients with osteogenesis imperfecta, of whom 17 were born between January 1, 1970 and December 31, 1983. Of the 17, 12 had type I, 2 had type II, 2 had type III, and 1 had type IV. The point prevalence at birth was 21.8/100,000 and the population prevalence was 10.6/100,000 inhabitants. All ethnic and racial groups seem to be similarly affected (Byers, 1993). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Kozma (2008) provided a detailed historical review of skeletal dysplasias in ancient Egypt, with an example of presumed osteogenesis imperfecta. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Bonadio et al. (1990) reported that the heterozygous Mov-13 mouse, which has a murine retrovirus integrated within the first intron of The Col1a1 gene, is a good model for the mild autosomal dominant form of OI. The animals showed morphologic and functional defects in mineralized and nonmineralized connective tissue and progressive hearing loss. </p><p>Aihara et al. (2003) demonstrated that mice with a targeted mutation of the Col1a1 gene had ocular hypertension. They suggested an association between intraocular pressure regulation and fibrillar collagen turnover. </p><p>Gremminger et al. (2022) studied muscle bioenergetics and mitochondrial function in 16-week-old mice that were heterozygous for a G610C mutation in the Col1a2 gene. Isolated mitochondria from the gastrocnemius muscle of the mutant mice demonstrated reduced state 3 respiration and increased citrate synthase activity compared to wildtype mice, which Gremminger et al. (2022) hypothesized may represent a compensatory mechanism to supply substrate to the electron transport chain in the setting of the type I collagen defect. Interestingly, when normalized to body weight, total and average daily expenditure for night and day were not different between wildtype and mutant mice. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Beighton (1981); Bierring (1933); Byers et al. (1982); Byers et al.
(1981); Byers et al. (1980); Byers et al. (1991); Castells et al.
(1979); Cetta et al. (1977); Cohn et al. (1986); Delvin et al.
(1979); Francis et al. (1975); Francis and Smith (1975); Heys et al.
(1960); Levin et al. (1981); Levin et al. (1978); Levin et al.
(1988); Lindberg et al. (1979); Lukinmaa et al. (1987); Muller et al.
(1977); Prockop and Kivirikko (1984); Sauk et al. (1980); Shapiro et
al. (1983); Sillence (1988); Solomons and Styner (1969); Tsipouras et
al. (1984); Tsipouras et al. (1983); Velley (1974); Willing et al.
(1993)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
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<div>
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Byers, P. H., Barsh, G. S., Holbrook, K. A.
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Hum. Path. 13: 89-95, 1982.
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Byers, P. H., Barsh, G. S., Peterson, K. E., Holbrook, K. A., Rowe, D. W.
<strong>Molecular mechanisms of abnormal bone matrix formation in osteogenesis imperfecta. In: Veis, A.: The Chemistry and Biology of Mineralized Connective Tissues.</strong>
Amsterdam: Elsevier/North Holland (pub.) 1981.
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<p class="mim-text-font">
Byers, P. H., Barsh, G. S., Rowe, D. W., Peterson, K. E., Holbrook, K. A., Shapiro, J.
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Am. J. Hum. Genet. 32: 37A only, 1980.
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Byers, P. H., Krakow, D., Nunes, M. E., Pepin, M.
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Byers, P. H., Shapiro, J. R., Rowe, D. W., David, K. E., Holbrook, K. A.
<strong>Abnormal alpha2-chain in type I collagen from a patient with a form of osteogenesis imperfecta.</strong>
J. Clin. Invest. 71: 689-697, 1983.
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Byers, P. H., Wallis, G. A., Willing, M. C.
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Byers, P. H.
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Carothers, A. D., McAllion, S. J., Paterson, C. R.
<strong>Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta.</strong>
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Castells, S., Colbert, C., Chakrabarti, C., Bachtell, R. S., Kassner, E. G., Yasumura, S.
<strong>Therapy of osteogenesis imperfecta with synthetic salmon calcitonin.</strong>
J. Pediat. 95: 807-811, 1979.
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Cetta, G., de Luca, G., Tenni, R., Zanaboni, G., Lenzi, L., Castellani, A. A.
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Cetta, G., Lenzi, L., Rizzotti, M., Ruggeri, A., Valli, M., Boni, M.
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<p class="mim-text-font">
Chamberlain, J. R., Schwarze, U., Wang, P.-R., Hirata, R. K., Hankenson, K. D., Pace, J. M., Underwood, R. A., Song, K. M., Sussman, M., Byers, P. H., Russell, D. W.
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Cohn, D. H., Byers, P. H., Steinmann, B., Gelinas, R. E.
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De Vos, A., Sermon, K., Van de Velde, H., Joris, H., Vandervorst, M., Lissens, W., De Paepe, A., Liebaers, I., Van Steirteghem, A.
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Delvin, E. E., Glorieux, F. H., Lopez, E.
<strong>In vitro sulfate turnover in osteogenesis imperfecta congenita and tarda.</strong>
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Dickson, I. R., Millar, E. A., Veis, A.
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Francis, M. J. O., Bauze, R. J., Smith, R.
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Francis, M. J. O., Smith, R., Bauze, R. J.
<strong>Instability of polymeric skin collagen in osteogenesis imperfecta.</strong>
Brit. Med. J. 1: 421-424, 1974.
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</p>
</li>
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<p class="mim-text-font">
Francis, M. J. O., Smith, R.
<strong>Polymeric collagen of skin in osteogenesis imperfecta, homocystinuria, Ehlers-Danlos and Marfan syndromes.</strong>
Birth Defects Orig. Art. Ser. XI(6): 15-21, 1975.
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Francis, M. J. O., Williams, K. J., Sykes, B. C., Smith, R.
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Garretsen, T. J. T. M., Cremers, C. W. R. J.
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<li>
<p class="mim-text-font">
Gauba, V., Hartgerink, J. D.
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</p>
</li>
<li>
<p class="mim-text-font">
Genovese, C., Brufsky, A., Shapiro, J., Rowe, D.
<strong>Detection of mutations in human type I collagen mRNA in osteogenesis imperfecta by indirect RNase protection.</strong>
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[PubMed: 2542316]
</p>
</li>
<li>
<p class="mim-text-font">
Genovese, C., Rowe, D.
<strong>Analysis of cytoplasmatic and nuclear messenger RNA in fibroblasts from patients with type I osteogenesis imperfecta.</strong>
Methods Enzymol. 145: 223-235, 1987.
[PubMed: 3474490]
[Full Text: https://doi.org/10.1016/0076-6879(87)45012-x]
</p>
</li>
<li>
<p class="mim-text-font">
Glorieux, F. H., Bishop, N. J., Plotkin, H., Chabot, G., Lanoue, G., Travers, R.
<strong>Cyclic administration of pamidronate in children with severe osteogenesis imperfecta.</strong>
New Eng. J. Med. 339: 947-952, 1998.
[PubMed: 9753709]
[Full Text: https://doi.org/10.1056/NEJM199810013391402]
</p>
</li>
<li>
<p class="mim-text-font">
Gremminger, V. L., Omosule, C. L., Crawford, T. K., Cunningham, R., Rector, R. S., Phillips, C. L.
<strong>Skeletal muscle mitochondrial function and whole-body metabolic energetics in the +/G610C mouse model of osteogenesis imperfecta.</strong>
Molec. Genet. Metab. 136: 315-323, 2022.
[PubMed: 35725939]
[Full Text: https://doi.org/10.1016/j.ymgme.2022.06.004]
</p>
</li>
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Sykes, B., Ogilvie, D., Wordsworth, P., Wallis, G., Mathew, C., Beighton, P., Nicholls, A., Pope, F. M., Thompson, E., Tsipouras, P., Schwartz, R., Jensson, O., Arnason, A., Borresen, A.-L., Heiberg, A., Frey, D., Steinmann, B.
<strong>Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2.</strong>
Am. J. Hum. Genet. 46: 293-307, 1990.
[PubMed: 1967900]
</p>
</li>
<li>
<p class="mim-text-font">
Tsipouras, P., Borresen, A., Dickson, L. A., Berg, K., Prockop, D. J., Ramirez, F.
<strong>Molecular heterogeneity in the mild autosomal dominant forms of osteogenesis imperfecta.</strong>
Am. J. Hum. Genet. 36: 1172-1179, 1984.
[PubMed: 6097110]
</p>
</li>
<li>
<p class="mim-text-font">
Tsipouras, P., Myers, J. C., Ramirez, F., Prockop, D. J.
<strong>Restriction fragment length polymorphism associated with the pro-alpha-2(I) gene of human type I procollagen: application to a family with an autosomal dominant form of osteogenesis imperfecta.</strong>
J. Clin. Invest. 72: 1262-1267, 1983.
[PubMed: 6313757]
[Full Text: https://doi.org/10.1172/JCI111082]
</p>
</li>
<li>
<p class="mim-text-font">
Tsipouras, P.
<strong>Genetic heterogeneity of mild osteogenesis imperfecta (OI types I and IV): linkage to COL1A1, COL1A2 and possibly other loci. (Abstract)</strong>
Cytogenet. Cell Genet. 46: 706 only, 1987.
</p>
</li>
<li>
<p class="mim-text-font">
Velley, J.
<strong>Etude clinique et genetique de la dentinogenese imparfaite hereditaire.</strong>
Actual. Odontostomatol. (Paris) Sep: 519-532, 1974.
[PubMed: 4455066]
</p>
</li>
<li>
<p class="mim-text-font">
Vetter, U., Pontz, B., Zauner, E., Brenner, R. E., Spranger, J.
<strong>Osteogenesis imperfecta: a clinical study of the first ten years of life.</strong>
Calcif. Tissue Int. 50: 36-41, 1992.
[PubMed: 1739868]
[Full Text: https://doi.org/10.1007/BF00297295]
</p>
</li>
<li>
<p class="mim-text-font">
Wallis, G., Beighton, P., Boyd, C., Mathew, C. G.
<strong>Mutations linked to the pro alpha2(I) collagen gene are responsible for several cases of osteogenesis imperfecta type I.</strong>
J. Med. Genet. 23: 411-416, 1986.
[PubMed: 3023615]
[Full Text: https://doi.org/10.1136/jmg.23.5.411]
</p>
</li>
<li>
<p class="mim-text-font">
Waltimo-Siren, J., Kolkka, M., Pynnonen, S., Kuurila, K., Kaitila, I., Kovero, O.
<strong>Craniofacial features in osteogenesis imperfecta: a cephalometric study.</strong>
Am. J. Med. Genet. 133A: 142-150, 2005.
[PubMed: 15666304]
[Full Text: https://doi.org/10.1002/ajmg.a.30523]
</p>
</li>
<li>
<p class="mim-text-font">
Wenstrup, R. J., Willing, M. C., Starman, B. J., Byers, P. H.
<strong>Distinct biochemical phenotypes predict clinical severity in nonlethal variants of osteogenesis imperfecta.</strong>
Am. J. Hum. Genet. 46: 975-982, 1990.
[PubMed: 2339695]
</p>
</li>
<li>
<p class="mim-text-font">
Willing, M. C., Cohn, D. H., Byers, P. H.
<strong>Frameshift mutation near the 3-prime end of the COL1A1 gene of type I collagen predicts an elongated pro-alpha-1(I) chain and results in osteogenesis imperfecta type I.</strong>
J. Clin. Invest. 85: 282-290, 1990. Note: Erratum: J. Clin. Invest. 85: following 1338, 1990.
[PubMed: 2295701]
[Full Text: https://doi.org/10.1172/JCI114424]
</p>
</li>
<li>
<p class="mim-text-font">
Willing, M. C., Pruchno, C. J., Atkinson, M., Byers, P. H.
<strong>Osteogenesis imperfecta type I is commonly due to a COL1A1 null allele of type I collagen.</strong>
Am. J. Hum. Genet. 51: 508-515, 1992.
[PubMed: 1353940]
</p>
</li>
<li>
<p class="mim-text-font">
Willing, M. C., Pruchno, C. J., Byers, P. H.
<strong>Molecular heterogeneity in osteogenesis imperfecta type I.</strong>
Am. J. Med. Genet. 45: 223-227, 1993.
[PubMed: 8456806]
[Full Text: https://doi.org/10.1002/ajmg.1320450214]
</p>
</li>
<li>
<p class="mim-text-font">
Willing, M. C., Slayton, R. L., Pitts, S. H., Deschenes, S. P.
<strong>Absence of mutations in the promoter of the COL1A1 gene of type I collagen in patients with osteogenesis imperfecta type I.</strong>
J. Med. Genet. 32: 697-700, 1995.
[PubMed: 8544188]
[Full Text: https://doi.org/10.1136/jmg.32.9.697]
</p>
</li>
<li>
<p class="mim-text-font">
Zeitlin, L., Rauch, F., Plotkin, H., Glorieux, F. H.
<strong>Height and weight development during four years of therapy with cyclical intravenous pamidronate in children and adolescents with osteogenesis imperfecta types I, III, and IV.</strong>
Pediatrics 111: 1030-1036, 2003.
[PubMed: 12728084]
[Full Text: https://doi.org/10.1542/peds.111.5.1030]
</p>
</li>
<li>
<p class="mim-text-font">
Zhuang, J., Tromp, G., Kuivaniemi, H., Nakayasu, K., Prockop, D. J.
<strong>Deletion of 19 base pairs in intron 13 of the gene for the pro-alpha-2(I) chain of type-I procollagen (COL1A2) causes exon skipping in a proband with type-I osteogenesis imperfecta.</strong>
Hum. Genet. 91: 210-216, 1993.
[PubMed: 7916744]
[Full Text: https://doi.org/10.1007/BF00218258]
</p>
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Hilary J. Vernon - updated : 10/03/2022<br>Ada Hamosh - updated : 10/23/2018<br>Cassandra L. Kniffin - updated : 12/30/2008<br>Ada Hamosh - updated : 7/9/2008<br>Marla J. F. O&#x27;Neill - updated : 1/2/2008<br>Ada Hamosh - updated : 7/25/2007<br>Marla J. F. O&#x27;Neill - updated : 6/12/2007<br>John A. Phillips, III - updated : 5/7/2007<br>John A. Phillips, III - updated : 3/21/2007<br>Victor A. McKusick - updated : 3/23/2005<br>Victor A. McKusick - updated : 9/2/2004<br>Victor A. McKusick - updated : 6/11/2004<br>Natalie E. Krasikov - updated : 2/10/2004<br>John A. Phillips, III - updated : 9/12/2003<br>Jane Kelly - updated : 8/19/2003<br>Victor A. McKusick - updated : 8/5/2003<br>Denise L. M. Goh - updated : 4/1/2003<br>Denise L. M. Goh - updated : 2/19/2003<br>Gary A. Bellus - updated : 2/3/2003<br>Ada Hamosh - updated : 1/30/2002<br>Sonja A. Rasmussen - updated : 6/8/2001<br>Victor A. McKusick - updated : 8/16/2000<br>Victor A. McKusick - updated : 10/2/1998<br>Moyra Smith - updated : 12/18/1997<br>Beat Steinmann - updated : 4/18/1994
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Victor A. McKusick : 6/23/1986
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