2241 lines
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Entry
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- #613571 - DISORDERED STEROIDOGENESIS DUE TO CYTOCHROME P450 OXIDOREDUCTASE DEFICIENCY
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- OMIM
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<p>
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<span class="h4">#613571</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=DISORDERED STEROIDOGENESIS DUE TO CYTOCHROME P450 OXIDOREDUCTASE DEFICIENCY" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=648&Typ=Pat" title="Congenital adrenal hyperplasia" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Congenital adrenal hyperpl… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=12654&Typ=Pat" title="Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Congenital adrenal hyperpl… </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1419/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/8271" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=613571[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=418" title="Congenital adrenal hyperplasia" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Congenital adrenal hyperpl…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=95699" title="Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Congenital adrenal hyperpl…</a></div>
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</div>
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</div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0080925" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/613571" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0080925" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 715733000<br />
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<strong>ORPHA:</strong> 418, 95699<br />
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<strong>DO:</strong> 0080925<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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613571
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
|
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<span class="mim-font">
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|
DISORDERED STEROIDOGENESIS DUE TO CYTOCHROME P450 OXIDOREDUCTASE DEFICIENCY
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
ADRENAL HYPERPLASIA, CONGENITAL, DUE TO CYTOCHROME P450 OXIDOREDUCTASE DEFICIENCY<br />
|
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DISORDERED STEROIDOGENESIS DUE TO POR DEFICIENCY
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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<td>
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<span class="mim-font">
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<a href="/geneMap/7/351?start=-3&limit=10&highlight=351">
|
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7q11.23
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Disordered steroidogenesis due to cytochrome P450 oxidoreductase
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/613571"> 613571 </a>
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</span>
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<p>A number sign (#) is used with this entry because this form of disordered steroidogenesis is caused by homozygous or compound heterozygous mutations in the POR gene (<a href="/entry/124015">124015</a>), which encodes cytochrome p450 oxidoreductase, on chromosome 7q11.2. Mutations in this gene also result in a form of Antley-Bixler syndrome (ABS1; <a href="/entry/201750">201750</a>).</p>
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<p>This rare variant of congenital adrenal hyperplasia, caused by mutations in the POR gene, results in apparent combined deficiency of P450C17 (<a href="/entry/609300">609300</a>) and P450C21 (<a href="/entry/613815">613815</a>) and accumulation of steroid metabolites. The most striking phenotypic feature is that affected girls are born with ambiguous genitalia, indicating intrauterine androgen excess. After birth, however, virilization does not progress and amounts of circulating androgens are low or normal. Affected boys are sometimes born undermasculinized. Boys and girls can present with bone malformations, sometimes suggesting the pattern seen in patients with Antley-Bixler syndrome (see <a href="/entry/207410">207410</a>) (summary by <a href="#1" class="mim-tip-reference" title="Arlt, W., Walker, E. A., Draper, N., Ivison, H. E., Ride, J. P., Hammer, F., Chalder, S. M., Borucka-Mankiewicz, M., Hauffa, B. P., Malunowicz, E. M., Stewart, P. M., Shackleton, C. H. L. <strong>Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.</strong> Lancet 363: 2128-2135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15220035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15220035</a>] [<a href="https://doi.org/10.1016/S0140-6736(04)16503-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15220035">Arlt et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15220035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 6-month-old 46,XY infant with a female phenotype and ambiguous genitalia, <a href="#6" class="mim-tip-reference" title="Peterson, R. E., Imperato-McGinley, J., Gautier, T., Shackleton, C. <strong>Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases: a new variant of congenital adrenal hyperplasia.</strong> New Eng. J. Med. 313: 1182-1191, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2932643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2932643</a>] [<a href="https://doi.org/10.1056/NEJM198511073131903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2932643">Peterson et al. (1985)</a> found an unusual pattern of plasma and urinary steroids indicating that the child had multiple abnormalities of steroid-biosynthetic microsomal mixed-function oxidases: 21-hydroxylase, 17-alpha-hydroxylase, and 17,20-desmolase. Individually, each is responsible for a form of congenital adrenal hypoplasia; see <a href="/entry/201910">201910</a> and <a href="/entry/202110">202110</a>. The deficit in activities of the first 2 enzymes resulted in decreased cortisol synthesis with subsequent increased ACTH secretion and adrenocortical hyperplasia. The male pseudohermaphroditism results from deficient testosterone synthesis due to deficiency of 17-alpha-hydroxylase and 17,20-desmolase. The family resided in the Dominican Republic. The mother and 2 sisters of the affected child, with normal phenotype, had mild 17-alpha-hydroxylase deficiency. The father had a normal urinary steroid profile. <a href="#6" class="mim-tip-reference" title="Peterson, R. E., Imperato-McGinley, J., Gautier, T., Shackleton, C. <strong>Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases: a new variant of congenital adrenal hyperplasia.</strong> New Eng. J. Med. 313: 1182-1191, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2932643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2932643</a>] [<a href="https://doi.org/10.1056/NEJM198511073131903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2932643">Peterson et al. (1985)</a> proposed that since cytochrome P450 is the terminal oxidase for all 3 of these steroid microsomal mixed-function oxidases, impairment of translocation of P450 into the endoplasmic reticulum of the adrenocortical microsomes may represent a single defect affecting the activity of the 3 oxidases. Insertion of newly synthesized cytochrome P-450 into liver microsomes is known to require a signal-recognition particle bound to P-450 (<a href="#7" class="mim-tip-reference" title="Sakaguchi, M., Mihara, K., Sato, R. <strong>Signal recognition particle is required for co-translational insertion of cytochrome P-450 into microsomal membranes.</strong> Proc. Nat. Acad. Sci. 81: 3361-3364, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6587354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6587354</a>] [<a href="https://doi.org/10.1073/pnas.81.11.3361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6587354">Sakaguchi et al., 1984</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2932643+6587354" 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="Arlt, W., Walker, E. A., Draper, N., Ivison, H. E., Ride, J. P., Hammer, F., Chalder, S. M., Borucka-Mankiewicz, M., Hauffa, B. P., Malunowicz, E. M., Stewart, P. M., Shackleton, C. H. L. <strong>Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.</strong> Lancet 363: 2128-2135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15220035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15220035</a>] [<a href="https://doi.org/10.1016/S0140-6736(04)16503-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15220035">Arlt et al. (2004)</a> described 3 patients with apparent combined P450C17 and P450C21 deficiency. In 1 family an affected sister showed bony changes similar to those seen in Antley-Bixler syndrome, as well as ambiguous genitalia; her brother with congenital adrenal hyperplasia had normal male genitalia at birth and no skeletal abnormalities. In a third sporadic case, the girl showed at 13 years of age a marfanoid habitus, scoliosis, arachnodactyly, dysplastic ears, and long slim limbs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15220035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Williamson, L., Arlt, W., Shackleton, C., Kelley, R. I., Braddock, S. R. <strong>Linking Antley-Bixler syndrome and congenital adrenal hyperplasia: a novel case of P450 oxidoreductase deficiency.</strong> Am. J. Med. Genet. 140A: 1797-1803, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16906539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16906539</a>] [<a href="https://doi.org/10.1002/ajmg.a.31385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16906539">Williamson et al. (2006)</a> reported a girl with a mild Antley-Bixler-like phenotype, ambiguous genitalia, impaired steroidogenesis, and compound heterozygosity for mutations in the POR gene. There was brachycephaly with a flat occiput, frontal bossing, and broad forehead. In addition, there was significant midface hypoplasia with a small mouth. Cranial, ovarian, uterine, and adrenal sonograms were normal. Skeletal survey at 5 weeks was normal except for advanced bone age of 6 months. There was no evidence of craniosynostosis, femoral bowing, or radiohumeral synostosis. Her ratio of pregnanediol to cortisol metabolites was more than twice normal and her other steroid ratios were higher than normal, but not as high as other published cases, demonstrating that the spectrum of biochemical severity is wider than previously suggested. The mother had undetectable serum unconjugated estriol at 18 weeks' gestation, but fetal morphology was normal on ultrasound at 20 weeks. <a href="#9" class="mim-tip-reference" title="Williamson, L., Arlt, W., Shackleton, C., Kelley, R. I., Braddock, S. R. <strong>Linking Antley-Bixler syndrome and congenital adrenal hyperplasia: a novel case of P450 oxidoreductase deficiency.</strong> Am. J. Med. Genet. 140A: 1797-1803, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16906539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16906539</a>] [<a href="https://doi.org/10.1002/ajmg.a.31385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16906539">Williamson et al. (2006)</a> stated that a very low or negligible maternal serum unconjugated estriol is highly suspicious and warrants investigation for POR deficiency even in the presence of a normal fetal ultrasound. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16906539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Hershkovitz, E., Parvari, R., Wudy, S. A., Hartmann, M. F., Gomes, L. G., Loewental, N., Miller, W. L. <strong>Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency.</strong> J. Clin. Endocr. Metab. 93: 3584-3588, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559916</a>] [<a href="https://doi.org/10.1210/jc.2008-0051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18559916">Hershkovitz et al. (2008)</a> reported 4 undervirilized males of an extended Bedouin family. All 4 were 46,XY. None of the mothers became virilized during their pregnancies. Onset of puberty was normal in 2 patients, but inadequate virilization required testosterone replacement in both. One patient retained one dysfunctional testis and a small penis. No skeletal malformation, dysmorphism, or limited limb movements were found, and X-rays showed no radioulnar or radiohumeral synostosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18559916" 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="#8" class="mim-tip-reference" title="Shackleton, C., Marcos, J., Arlt, W., Hauffa, B. P. <strong>Prenatal diagnosis of P450 oxidoreductase deficiency (ORD): a disorder causing low pregnancy estriol, maternal and fetal virilization, and the Antley-Bixler syndrome phenotype.</strong> Am. J. Med. Genet. 129A: 105-112, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15316970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15316970</a>] [<a href="https://doi.org/10.1002/ajmg.a.30171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15316970">Shackleton et al. (2004)</a> monitored the second pregnancy of the mother of 2 children with P450 oxidoreductase deficiency reported by <a href="#1" class="mim-tip-reference" title="Arlt, W., Walker, E. A., Draper, N., Ivison, H. E., Ride, J. P., Hammer, F., Chalder, S. M., Borucka-Mankiewicz, M., Hauffa, B. P., Malunowicz, E. M., Stewart, P. M., Shackleton, C. H. L. <strong>Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.</strong> Lancet 363: 2128-2135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15220035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15220035</a>] [<a href="https://doi.org/10.1016/S0140-6736(04)16503-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15220035">Arlt et al. (2004)</a>. The mother's estriol excretion failed to increase normally and she showed signs of virilization at 23 weeks of gestation, but there was no evidence for aromatase deficiency. Urine steroid analysis showed gradually increasing excretion of epiallopregnanediol, which the authors believed was the maternal urinary excretion product of fetal 5-pregnene-3-beta,20-alpha-diol, the principal metabolite of pregnenolone. <a href="#8" class="mim-tip-reference" title="Shackleton, C., Marcos, J., Arlt, W., Hauffa, B. P. <strong>Prenatal diagnosis of P450 oxidoreductase deficiency (ORD): a disorder causing low pregnancy estriol, maternal and fetal virilization, and the Antley-Bixler syndrome phenotype.</strong> Am. J. Med. Genet. 129A: 105-112, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15316970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15316970</a>] [<a href="https://doi.org/10.1002/ajmg.a.30171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15316970">Shackleton et al. (2004)</a> proposed that excessive excretion of epiallopregnanediol together with low estriol may be diagnostic for fetal P450 oxidoreductase deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15220035+15316970" 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 transmission pattern of disordered steroidogenesis in the families reported by <a href="#3" class="mim-tip-reference" title="Fluck, C. E., Tajima, T., Pandey, A. V., Arlt, W., Okuhara, K., Verge, C. F., Jabs, E. W., Mendonca, B. B., Fujieda, K., Miller, W. L. <strong>Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome.</strong> Nature Genet. 36: 228-230, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14758361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14758361</a>] [<a href="https://doi.org/10.1038/ng1300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14758361">Fluck et al. (2004)</a> and <a href="#1" class="mim-tip-reference" title="Arlt, W., Walker, E. A., Draper, N., Ivison, H. E., Ride, J. P., Hammer, F., Chalder, S. M., Borucka-Mankiewicz, M., Hauffa, B. P., Malunowicz, E. M., Stewart, P. M., Shackleton, C. H. L. <strong>Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.</strong> Lancet 363: 2128-2135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15220035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15220035</a>] [<a href="https://doi.org/10.1016/S0140-6736(04)16503-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15220035">Arlt et al. (2004)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15220035+14758361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a phenotypically normal woman with amenorrhea and disordered steroidogenesis, <a href="#3" class="mim-tip-reference" title="Fluck, C. E., Tajima, T., Pandey, A. V., Arlt, W., Okuhara, K., Verge, C. F., Jabs, E. W., Mendonca, B. B., Fujieda, K., Miller, W. L. <strong>Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome.</strong> Nature Genet. 36: 228-230, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14758361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14758361</a>] [<a href="https://doi.org/10.1038/ng1300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14758361">Fluck et al. (2004)</a> found compound heterozygosity for mutations in the POR gene (<a href="/entry/124015#0003">124015.0003</a>-<a href="/entry/124015#0004">124015.0004</a>). <a href="#3" class="mim-tip-reference" title="Fluck, C. E., Tajima, T., Pandey, A. V., Arlt, W., Okuhara, K., Verge, C. F., Jabs, E. W., Mendonca, B. B., Fujieda, K., Miller, W. L. <strong>Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome.</strong> Nature Genet. 36: 228-230, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14758361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14758361</a>] [<a href="https://doi.org/10.1038/ng1300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14758361">Fluck et al. (2004)</a> hypothesized that milder mutations in POR may manifest as mild disorders of steroid synthesis, whereas severe mutations in POR without associated disorders of FGF receptors are sufficient to cause the ABS phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14758361" 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>All 3 patients with apparent combined P450C17 and P450C21 deficiency described by <a href="#1" class="mim-tip-reference" title="Arlt, W., Walker, E. A., Draper, N., Ivison, H. E., Ride, J. P., Hammer, F., Chalder, S. M., Borucka-Mankiewicz, M., Hauffa, B. P., Malunowicz, E. M., Stewart, P. M., Shackleton, C. H. L. <strong>Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.</strong> Lancet 363: 2128-2135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15220035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15220035</a>] [<a href="https://doi.org/10.1016/S0140-6736(04)16503-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15220035">Arlt et al. (2004)</a> were compound heterozygotes (see <a href="/entry/124015#0005">124015.0005</a> and <a href="/entry/124015#0007">124015.0007</a>-<a href="/entry/124015#0009">124015.0009</a>), whereas their parents and an unaffected sib were heterozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15220035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Hershkovitz, E., Parvari, R., Wudy, S. A., Hartmann, M. F., Gomes, L. G., Loewental, N., Miller, W. L. <strong>Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency.</strong> J. Clin. Endocr. Metab. 93: 3584-3588, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559916</a>] [<a href="https://doi.org/10.1210/jc.2008-0051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18559916">Hershkovitz et al. (2008)</a> reported 4 undervirilized males of an extended Bedouin family. One of these had been reported (<a href="#2" class="mim-tip-reference" title="Biason-Lauber, A., Leiberman, E., Zachmann, M. <strong>A single amino acid substitution in the putative redox partner-binding site of P450c17 as cause of isolated 17,20-lyase deficiency.</strong> J. Clin. Endocr. Metab. 82: 3807-3812, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9360545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9360545</a>] [<a href="https://doi.org/10.1210/jcem.82.11.4380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9360545">Biason-Lauber et al., 1997</a>) to carry mutations in the CYP17A1 gene (<a href="/entry/609300">609300</a>), encoding P450c17, causing isolated 17,20-lyase deficiency (<a href="/entry/202110">202110</a>). Gas chromatography-mass spectrometry (GC-MS) urinary steroid profiling and serum steroid measurements showed combined deficiencies of 17,20-lyase and 21-hydroxylase. Sequencing of exons 1 and 8 of CYP17A1 in 2 different laboratories showed no mutations. Sequencing of the POR gene showed that all 4 patients were homozygous for G539R (<a href="/entry/124015#0016">124015.0016</a>), which was shown by <a href="#5" class="mim-tip-reference" title="Huang, N., Pandey, A. V., Agrawal, V., Reardon, W., Lapunzina, P. D., Mowat, D., Jabs, E. W., Van Vliet, G., Sack, J., Fluck, C. E., Miller, W. L. <strong>Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.</strong> Am. J. Hum. Genet. 76: 729-749, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15793702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15793702</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15793702[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/429417" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15793702">Huang et al. (2005)</a> to retain 46% of normal 17-alpha-hydroxylase activity but only 8% of the 17,20-lyase activity of P450c17. <a href="#4" class="mim-tip-reference" title="Hershkovitz, E., Parvari, R., Wudy, S. A., Hartmann, M. F., Gomes, L. G., Loewental, N., Miller, W. L. <strong>Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency.</strong> J. Clin. Endocr. Metab. 93: 3584-3588, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559916</a>] [<a href="https://doi.org/10.1210/jc.2008-0051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18559916">Hershkovitz et al. (2008)</a> conclude that POR deficiency can masquerade clinically as isolated 17,20-lyase deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18559916+15793702+9360545" 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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Arlt, W., Walker, E. A., Draper, N., Ivison, H. E., Ride, J. P., Hammer, F., Chalder, S. M., Borucka-Mankiewicz, M., Hauffa, B. P., Malunowicz, E. M., Stewart, P. M., Shackleton, C. H. L.
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<strong>Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.</strong>
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Lancet 363: 2128-2135, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15220035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15220035</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15220035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/S0140-6736(04)16503-3" target="_blank">Full Text</a>]
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Biason-Lauber, A., Leiberman, E., Zachmann, M.
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<strong>A single amino acid substitution in the putative redox partner-binding site of P450c17 as cause of isolated 17,20-lyase deficiency.</strong>
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J. Clin. Endocr. Metab. 82: 3807-3812, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9360545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9360545</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9360545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jcem.82.11.4380" target="_blank">Full Text</a>]
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Fluck, C. E., Tajima, T., Pandey, A. V., Arlt, W., Okuhara, K., Verge, C. F., Jabs, E. W., Mendonca, B. B., Fujieda, K., Miller, W. L.
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<strong>Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome.</strong>
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Nature Genet. 36: 228-230, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14758361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14758361</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14758361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1300" target="_blank">Full Text</a>]
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Hershkovitz, E., Parvari, R., Wudy, S. A., Hartmann, M. F., Gomes, L. G., Loewental, N., Miller, W. L.
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<strong>Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency.</strong>
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J. Clin. Endocr. Metab. 93: 3584-3588, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559916</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18559916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2008-0051" target="_blank">Full Text</a>]
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Huang, N., Pandey, A. V., Agrawal, V., Reardon, W., Lapunzina, P. D., Mowat, D., Jabs, E. W., Van Vliet, G., Sack, J., Fluck, C. E., Miller, W. L.
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<strong>Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.</strong>
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Am. J. Hum. Genet. 76: 729-749, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15793702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15793702</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15793702[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=15793702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/429417" target="_blank">Full Text</a>]
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Peterson, R. E., Imperato-McGinley, J., Gautier, T., Shackleton, C.
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<strong>Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases: a new variant of congenital adrenal hyperplasia.</strong>
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New Eng. J. Med. 313: 1182-1191, 1985.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2932643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2932643</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2932643" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM198511073131903" target="_blank">Full Text</a>]
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Sakaguchi, M., Mihara, K., Sato, R.
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<strong>Signal recognition particle is required for co-translational insertion of cytochrome P-450 into microsomal membranes.</strong>
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Proc. Nat. Acad. Sci. 81: 3361-3364, 1984.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6587354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6587354</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6587354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.81.11.3361" target="_blank">Full Text</a>]
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Shackleton, C., Marcos, J., Arlt, W., Hauffa, B. P.
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<strong>Prenatal diagnosis of P450 oxidoreductase deficiency (ORD): a disorder causing low pregnancy estriol, maternal and fetal virilization, and the Antley-Bixler syndrome phenotype.</strong>
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Am. J. Med. Genet. 129A: 105-112, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15316970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15316970</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15316970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.30171" target="_blank">Full Text</a>]
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Williamson, L., Arlt, W., Shackleton, C., Kelley, R. I., Braddock, S. R.
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<strong>Linking Antley-Bixler syndrome and congenital adrenal hyperplasia: a novel case of P450 oxidoreductase deficiency.</strong>
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Am. J. Med. Genet. 140A: 1797-1803, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16906539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16906539</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16906539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31385" target="_blank">Full Text</a>]
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Anne M. Stumpf : 9/22/2010
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carol : 12/27/2021
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alopez : 03/08/2012<br>alopez : 10/6/2011<br>alopez : 3/23/2011<br>alopez : 9/24/2010
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<strong>#</strong> 613571
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DISORDERED STEROIDOGENESIS DUE TO CYTOCHROME P450 OXIDOREDUCTASE DEFICIENCY
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ADRENAL HYPERPLASIA, CONGENITAL, DUE TO CYTOCHROME P450 OXIDOREDUCTASE DEFICIENCY<br />
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DISORDERED STEROIDOGENESIS DUE TO POR DEFICIENCY
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<strong>SNOMEDCT:</strong> 715733000;
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<strong>ORPHA:</strong> 418, 95699;
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<strong>DO:</strong> 0080925;
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<strong>Phenotype-Gene Relationships</strong>
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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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7q11.23
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<span class="mim-font">
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Disordered steroidogenesis due to cytochrome P450 oxidoreductase
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<span class="mim-font">
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613571
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3
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<span class="mim-font">
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POR
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<span class="mim-font">
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124015
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because this form of disordered steroidogenesis is caused by homozygous or compound heterozygous mutations in the POR gene (124015), which encodes cytochrome p450 oxidoreductase, on chromosome 7q11.2. Mutations in this gene also result in a form of Antley-Bixler syndrome (ABS1; 201750).</p>
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<strong>Description</strong>
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<p>This rare variant of congenital adrenal hyperplasia, caused by mutations in the POR gene, results in apparent combined deficiency of P450C17 (609300) and P450C21 (613815) and accumulation of steroid metabolites. The most striking phenotypic feature is that affected girls are born with ambiguous genitalia, indicating intrauterine androgen excess. After birth, however, virilization does not progress and amounts of circulating androgens are low or normal. Affected boys are sometimes born undermasculinized. Boys and girls can present with bone malformations, sometimes suggesting the pattern seen in patients with Antley-Bixler syndrome (see 207410) (summary by Arlt et al., 2004). </p>
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<strong>Clinical Features</strong>
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<p>In a 6-month-old 46,XY infant with a female phenotype and ambiguous genitalia, Peterson et al. (1985) found an unusual pattern of plasma and urinary steroids indicating that the child had multiple abnormalities of steroid-biosynthetic microsomal mixed-function oxidases: 21-hydroxylase, 17-alpha-hydroxylase, and 17,20-desmolase. Individually, each is responsible for a form of congenital adrenal hypoplasia; see 201910 and 202110. The deficit in activities of the first 2 enzymes resulted in decreased cortisol synthesis with subsequent increased ACTH secretion and adrenocortical hyperplasia. The male pseudohermaphroditism results from deficient testosterone synthesis due to deficiency of 17-alpha-hydroxylase and 17,20-desmolase. The family resided in the Dominican Republic. The mother and 2 sisters of the affected child, with normal phenotype, had mild 17-alpha-hydroxylase deficiency. The father had a normal urinary steroid profile. Peterson et al. (1985) proposed that since cytochrome P450 is the terminal oxidase for all 3 of these steroid microsomal mixed-function oxidases, impairment of translocation of P450 into the endoplasmic reticulum of the adrenocortical microsomes may represent a single defect affecting the activity of the 3 oxidases. Insertion of newly synthesized cytochrome P-450 into liver microsomes is known to require a signal-recognition particle bound to P-450 (Sakaguchi et al., 1984). </p><p>Arlt et al. (2004) described 3 patients with apparent combined P450C17 and P450C21 deficiency. In 1 family an affected sister showed bony changes similar to those seen in Antley-Bixler syndrome, as well as ambiguous genitalia; her brother with congenital adrenal hyperplasia had normal male genitalia at birth and no skeletal abnormalities. In a third sporadic case, the girl showed at 13 years of age a marfanoid habitus, scoliosis, arachnodactyly, dysplastic ears, and long slim limbs. </p><p>Williamson et al. (2006) reported a girl with a mild Antley-Bixler-like phenotype, ambiguous genitalia, impaired steroidogenesis, and compound heterozygosity for mutations in the POR gene. There was brachycephaly with a flat occiput, frontal bossing, and broad forehead. In addition, there was significant midface hypoplasia with a small mouth. Cranial, ovarian, uterine, and adrenal sonograms were normal. Skeletal survey at 5 weeks was normal except for advanced bone age of 6 months. There was no evidence of craniosynostosis, femoral bowing, or radiohumeral synostosis. Her ratio of pregnanediol to cortisol metabolites was more than twice normal and her other steroid ratios were higher than normal, but not as high as other published cases, demonstrating that the spectrum of biochemical severity is wider than previously suggested. The mother had undetectable serum unconjugated estriol at 18 weeks' gestation, but fetal morphology was normal on ultrasound at 20 weeks. Williamson et al. (2006) stated that a very low or negligible maternal serum unconjugated estriol is highly suspicious and warrants investigation for POR deficiency even in the presence of a normal fetal ultrasound. </p><p>Hershkovitz et al. (2008) reported 4 undervirilized males of an extended Bedouin family. All 4 were 46,XY. None of the mothers became virilized during their pregnancies. Onset of puberty was normal in 2 patients, but inadequate virilization required testosterone replacement in both. One patient retained one dysfunctional testis and a small penis. No skeletal malformation, dysmorphism, or limited limb movements were found, and X-rays showed no radioulnar or radiohumeral synostosis. </p>
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<strong>Biochemical Features</strong>
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<p>Shackleton et al. (2004) monitored the second pregnancy of the mother of 2 children with P450 oxidoreductase deficiency reported by Arlt et al. (2004). The mother's estriol excretion failed to increase normally and she showed signs of virilization at 23 weeks of gestation, but there was no evidence for aromatase deficiency. Urine steroid analysis showed gradually increasing excretion of epiallopregnanediol, which the authors believed was the maternal urinary excretion product of fetal 5-pregnene-3-beta,20-alpha-diol, the principal metabolite of pregnenolone. Shackleton et al. (2004) proposed that excessive excretion of epiallopregnanediol together with low estriol may be diagnostic for fetal P450 oxidoreductase deficiency. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of disordered steroidogenesis in the families reported by Fluck et al. (2004) and Arlt et al. (2004) was consistent with autosomal recessive inheritance. </p>
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>In a phenotypically normal woman with amenorrhea and disordered steroidogenesis, Fluck et al. (2004) found compound heterozygosity for mutations in the POR gene (124015.0003-124015.0004). Fluck et al. (2004) hypothesized that milder mutations in POR may manifest as mild disorders of steroid synthesis, whereas severe mutations in POR without associated disorders of FGF receptors are sufficient to cause the ABS phenotype. </p><p>All 3 patients with apparent combined P450C17 and P450C21 deficiency described by Arlt et al. (2004) were compound heterozygotes (see 124015.0005 and 124015.0007-124015.0009), whereas their parents and an unaffected sib were heterozygotes. </p><p>Hershkovitz et al. (2008) reported 4 undervirilized males of an extended Bedouin family. One of these had been reported (Biason-Lauber et al., 1997) to carry mutations in the CYP17A1 gene (609300), encoding P450c17, causing isolated 17,20-lyase deficiency (202110). Gas chromatography-mass spectrometry (GC-MS) urinary steroid profiling and serum steroid measurements showed combined deficiencies of 17,20-lyase and 21-hydroxylase. Sequencing of exons 1 and 8 of CYP17A1 in 2 different laboratories showed no mutations. Sequencing of the POR gene showed that all 4 patients were homozygous for G539R (124015.0016), which was shown by Huang et al. (2005) to retain 46% of normal 17-alpha-hydroxylase activity but only 8% of the 17,20-lyase activity of P450c17. Hershkovitz et al. (2008) conclude that POR deficiency can masquerade clinically as isolated 17,20-lyase deficiency. </p>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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Arlt, W., Walker, E. A., Draper, N., Ivison, H. E., Ride, J. P., Hammer, F., Chalder, S. M., Borucka-Mankiewicz, M., Hauffa, B. P., Malunowicz, E. M., Stewart, P. M., Shackleton, C. H. L.
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<strong>Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.</strong>
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Lancet 363: 2128-2135, 2004.
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[PubMed: 15220035]
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[Full Text: https://doi.org/10.1016/S0140-6736(04)16503-3]
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<p class="mim-text-font">
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Biason-Lauber, A., Leiberman, E., Zachmann, M.
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<strong>A single amino acid substitution in the putative redox partner-binding site of P450c17 as cause of isolated 17,20-lyase deficiency.</strong>
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J. Clin. Endocr. Metab. 82: 3807-3812, 1997.
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[PubMed: 9360545]
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[Full Text: https://doi.org/10.1210/jcem.82.11.4380]
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</li>
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<li>
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<p class="mim-text-font">
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Fluck, C. E., Tajima, T., Pandey, A. V., Arlt, W., Okuhara, K., Verge, C. F., Jabs, E. W., Mendonca, B. B., Fujieda, K., Miller, W. L.
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<strong>Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome.</strong>
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Nature Genet. 36: 228-230, 2004.
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[PubMed: 14758361]
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[Full Text: https://doi.org/10.1038/ng1300]
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<li>
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<p class="mim-text-font">
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Hershkovitz, E., Parvari, R., Wudy, S. A., Hartmann, M. F., Gomes, L. G., Loewental, N., Miller, W. L.
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<strong>Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency.</strong>
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J. Clin. Endocr. Metab. 93: 3584-3588, 2008.
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[PubMed: 18559916]
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[Full Text: https://doi.org/10.1210/jc.2008-0051]
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</li>
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<li>
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<p class="mim-text-font">
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Huang, N., Pandey, A. V., Agrawal, V., Reardon, W., Lapunzina, P. D., Mowat, D., Jabs, E. W., Van Vliet, G., Sack, J., Fluck, C. E., Miller, W. L.
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<strong>Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.</strong>
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Am. J. Hum. Genet. 76: 729-749, 2005.
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[PubMed: 15793702]
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[Full Text: https://doi.org/10.1086/429417]
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</li>
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<li>
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<p class="mim-text-font">
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Peterson, R. E., Imperato-McGinley, J., Gautier, T., Shackleton, C.
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<strong>Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases: a new variant of congenital adrenal hyperplasia.</strong>
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New Eng. J. Med. 313: 1182-1191, 1985.
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[PubMed: 2932643]
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[Full Text: https://doi.org/10.1056/NEJM198511073131903]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Sakaguchi, M., Mihara, K., Sato, R.
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<strong>Signal recognition particle is required for co-translational insertion of cytochrome P-450 into microsomal membranes.</strong>
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Proc. Nat. Acad. Sci. 81: 3361-3364, 1984.
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[PubMed: 6587354]
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[Full Text: https://doi.org/10.1073/pnas.81.11.3361]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Shackleton, C., Marcos, J., Arlt, W., Hauffa, B. P.
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<strong>Prenatal diagnosis of P450 oxidoreductase deficiency (ORD): a disorder causing low pregnancy estriol, maternal and fetal virilization, and the Antley-Bixler syndrome phenotype.</strong>
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Am. J. Med. Genet. 129A: 105-112, 2004.
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[PubMed: 15316970]
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[Full Text: https://doi.org/10.1002/ajmg.a.30171]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Williamson, L., Arlt, W., Shackleton, C., Kelley, R. I., Braddock, S. R.
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<strong>Linking Antley-Bixler syndrome and congenital adrenal hyperplasia: a novel case of P450 oxidoreductase deficiency.</strong>
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Am. J. Med. Genet. 140A: 1797-1803, 2006.
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[PubMed: 16906539]
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[Full Text: https://doi.org/10.1002/ajmg.a.31385]
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Anne M. Stumpf : 9/22/2010
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