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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="SLC26A2-Related Multiple Epiphyseal Dysplasia" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2023/01/19" /><meta name="citation_author" content="Sheila Unger" /><meta name="citation_author" content="Andrea Superti-Furga" /><meta name="citation_pmid" content="20301483" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1306/" /><meta name="citation_keywords" content="SLC26A2-Related Recessive MED (SLC26A2-rMED)" /><meta name="citation_keywords" content="SLC26A2-Related Recessive MED (SLC26A2-rMED)" /><meta name="citation_keywords" content="Sulfate transporter" /><meta name="citation_keywords" content="SLC26A2" /><meta name="citation_keywords" content="SLC26A2-Related Multiple Epiphyseal Dysplasia" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="SLC26A2-Related Multiple Epiphyseal Dysplasia" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Sheila Unger" /><meta name="DC.Contributor" content="Andrea Superti-Furga" /><meta name="DC.Date" content="2023/01/19" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1306/" /><meta name="description" content="SLC26A2-related multiple epiphyseal dysplasia (SLC26A2-MED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have an abnormal finding at birth, including clubfoot, clinodactyly, or (rarely) cystic ear swelling. Onset of articular pain is variable but usually occurs in late childhood. Stature is usually within the normal range prior to puberty; in adulthood, stature is only slightly diminished and ranges from 150 to 180 cm. Functional disability is mild." /><meta name="og:title" content="SLC26A2-Related Multiple Epiphyseal Dysplasia" /><meta name="og:type" content="book" /><meta name="og:description" content="SLC26A2-related multiple epiphyseal dysplasia (SLC26A2-MED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have an abnormal finding at birth, including clubfoot, clinodactyly, or (rarely) cystic ear swelling. Onset of articular pain is variable but usually occurs in late childhood. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK1306_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1306_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/ao2/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/pendred/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK1306_"><span class="title" itemprop="name"><i>SLC26A2</i>-Related Multiple Epiphyseal Dysplasia</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: <i>SLC26A2</i>-Related Recessive MED (<i>SLC26A2</i>-rMED)</div><p class="contrib-group"><span itemprop="author">Sheila Unger</span>, MD and <span itemprop="author">Andrea Superti-Furga</span>, MD.</p><a data-jig="ncbitoggler" href="#__NBK1306_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1306_ai__"><div class="contrib half_rhythm"><span itemprop="author">Sheila Unger</span>, MD<div class="affiliation small">Associate Professor of Genetics<br />University of Lausanne;<br />Lausanne University Hospital<br />Lausanne, Switzerland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="hc.vuhc@regnu.aliehs" class="oemail">hc.vuhc@regnu.aliehs</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Andrea Superti-Furga</span>, MD<div class="affiliation small">Professor of Pediatrics and Genetics<br />University of Lausanne;<br />Lausanne University Hospital<br />Lausanne, Switzerland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="hc.linu@itrepusa" class="oemail">hc.linu@itrepusa</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">August 29, 2002</span>; Last Update: <span itemprop="dateModified">January 19, 2023</span>.</p><p><em>Estimated reading time: 19 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="edm.Summary" itemprop="description"><h2 id="_edm_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>SLC26A2</i>-related multiple epiphyseal dysplasia (<i>SLC26A2</i>-MED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have an abnormal finding at birth, including clubfoot, clinodactyly, or (rarely) cystic ear swelling. Onset of articular pain is variable but usually occurs in late childhood. Stature is usually within the normal range prior to puberty; in adulthood, stature is only slightly diminished and ranges from 150 to 180 cm. Functional disability is mild.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>Diagnosis of <i>SLC26A2</i>-MED is based on detection of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> variants in <i>SLC26A2</i> by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> in an individual with compatible clinical and radiographic findings.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Physiotherapy for muscular strengthening and maintaining mobility; cautious use of analgesic medications such as nonsteroidal anti-inflammatory drugs; orthopedic surgery (joint replacement) as indicated; career counseling.</p><p><i>Prevention of secondary complications</i>: Intensive physiotherapy may help in delaying joint contractures and maintaining mobility.</p><p><i>Surveillance:</i> Radiographs as indicated.</p><p><i>Agents/circumstances to avoid:</i> Sports involving joint overload.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>SLC26A2</i>-MED is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner. If both parents are known to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for an <i>SLC26A2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier. Once the <i>SLC26A2</i> pathogenic variants have been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/carrier-testing/">carrier testing</a> for at-risk relatives and prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p></div></div><div id="edm.Diagnosis"><h2 id="_edm_Diagnosis_">Diagnosis</h2><div id="edm.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>SLC26A2</i>-related multiple epiphyseal dysplasia (<i>SLC26A2</i>-MED) <b>should be suspected</b> in individuals with the following clinical and radiographic features.</p><p>
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<b>Clinical features</b>
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</p><ul><li class="half_rhythm"><div>Joint pain (usually in the hips and knees). Onset of pain is variable, but usually occurs in late childhood. Some individuals have no pain.</div></li><li class="half_rhythm"><div>Deformity of hands, feet, and knees</div></li><li class="half_rhythm"><div>Scoliosis</div></li></ul><p>
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<b>Radiographic features</b>
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</p><ul><li class="half_rhythm"><div>Flat epiphyses with early arthritis (degenerative and painful changes in the articular cartilage of the hip joint)</div></li><li class="half_rhythm"><div>Mild brachydactyly</div></li><li class="half_rhythm"><div>Double-layered patella (i.e., presence of a separate anterior and posterior ossification layer) (see <a class="figpopup" href="/books/NBK1306/figure/edm.F1/?report=objectonly" target="object" rid-figpopup="figedmF1" rid-ob="figobedmF1">Figure 1</a>). Observed in approximately 60% of individuals on lateral knee radiographs, the presence of a double-layered patella is a quite specific, although not highly sensitive, sign of <i>SLC26A2</i>-MED [<a class="bk_pop" href="#edm.REF.m_kitie.2003.187">Mäkitie et al 2003</a>]. This finding appears to be age related and may disappear in adults.</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col fig" id="figedmF1" co-legend-rid="figlgndedmF1"><a href="/books/NBK1306/figure/edm.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figedmF1" rid-ob="figobedmF1"><img class="small-thumb" src="/books/NBK1306/bin/edm-Image001.gif" src-large="/books/NBK1306/bin/edm-Image001.jpg" alt="Figure 1. " /></a><div class="icnblk_cntnt" id="figlgndedmF1"><h4 id="edm.F1"><a href="/books/NBK1306/figure/edm.F1/?report=objectonly" target="object" rid-ob="figobedmF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">Double-layered patella Ballhausen et al [2003]; reprinted with permission from the BMJ Publishing Group</p></div></div><p><b>Family history</b> is consistent with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> inheritance (e.g., affected sibs and/or parental <a class="def" href="/books/n/gene/glossary/def-item/consanguinity/">consanguinity</a>). Absence of a known family history does not preclude the diagnosis.</p></div><div id="edm.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>SLC26A2</i>-MED <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with the characteristic clinical and radiographic features described in <a href="#edm.Suggestive_Findings">Suggestive Findings</a> and <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variants in <i>SLC26A2</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK1306/table/edm.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobedmTmoleculargenetictestingusedin">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variants" are synonymous in a clinical setting, meaning that both are considered diagnostic, and both can be used for clinical decision making [<a class="bk_pop" href="#edm.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>SLC26A2</i> variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> (or of one known <i>SLC26A2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and one <i>SLC26A2</i> variant of uncertain significance) does not establish or rule out the diagnosis of the disorder.</p><p>Molecular genetic testing approaches can include a combination of <b><a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing</b> (single-gene testing, <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>) and <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>) depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p><p>Gene-targeted testing requires that the clinician determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing does not. Individuals with the distinctive findings described in <a href="#edm.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#edm.Option_1">Option 1</a>), whereas those with a <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> indistinguishable from many other skeletal dysplasias are more likely to be diagnosed using genomic testing (see <a href="#edm.Option_2">Option 2</a>).</p><div id="edm.Option_1"><h4>Option 1</h4><p><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of <i>SLC26A2</i> detects small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants. Typically, if only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> to detect <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> and whole-gene deletions or duplications; however, to date such variants have not been identified as a cause of this disorder.</p><p><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>SLC26A2</i> and other genes of interest (see <a href="#edm.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests.</p><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</p></div><div id="edm.Option_2"><h4>Option 2</h4><p>When the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> is indistinguishable from other skeletal dysplasias, <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b>, which does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> is likely involved, is the best option. <b>Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="edm.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>SLC26A2</i>-Related Multiple Epiphyseal Dysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1306/table/edm.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__edm.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_edm.T.molecular_genetic_testing_used_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_edm.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_edm.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_edm.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SLC26A2</i>
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</td><td headers="hd_h_edm.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_edm.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <sup>4, 5</sup></td></tr><tr><td headers="hd_h_edm.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>6</sup></td><td headers="hd_h_edm.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported <sup>7</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="edm.TF.1.1"><p class="no_margin">See <a href="/books/NBK1306/#edm.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="edm.TF.1.2"><p class="no_margin">See <a href="#edm.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="edm.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="edm.TF.1.4"><p class="no_margin">The four most common <i>SLC26A2</i> pathogenic variants (<a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">p.Arg279Trp</a>, <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">c.-26+2T>C</a>, <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">p.Arg178Ter</a>, and <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">p.Cys653Ser</a>) account for approximately 70% of disease alleles in all <i>SLC26A2</i>-related dysplasias. Targeted analysis of these four variants identified at least one <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in nearly 100% of individuals with <i>SLC26A2</i>-MED (80% of individuals with <i>SLC26A2</i>-MED have two of the most common pathogenic variants, and another 16% have one common pathogenic variant in compound heterozygosity with another pathogenic variant).</p></div></dd><dt>5. </dt><dd><div id="edm.TF.1.5"><p class="no_margin">
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<a class="bk_pop" href="#edm.REF.rossi.2001.159">Rossi & Superti-Furga [2001]</a>
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</p></div></dd><dt>6. </dt><dd><div id="edm.TF.1.6"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd><dt>7. </dt><dd><div id="edm.TF.1.7"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bk_pop" href="#edm.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd></dl></div></div></div></div></div></div><div id="edm.Clinical_Characteristics"><h2 id="_edm_Clinical_Characteristics_">Clinical Characteristics</h2><div id="edm.Clinical_Description"><h3>Clinical Description</h3><p><i>SLC26A2</i>-related multiple epiphyseal dysplasia (<i>SLC26A2</i>-MED) is characterized by early-onset joint pain, malformations of hands, feet, and knees, and scoliosis. Approximately 50% of affected individuals have an abnormal finding at birth, including clubfoot, clinodactyly, cleft palate, or (rarely) cystic ear swelling. However, only half of those with findings at birth are suspected of having a skeletal dysplasia.</p><p><b>Skeletal manifestations.</b> Chronic joint pain most often occurs in the hips, knees, wrists, and fingers. The onset of joint pain is variable; adolescents are usually symptomatic in multiple joints, and joint pain increases after physical exercise.</p><p>Waddling gait, hand/foot deformities (mild brachydactyly, clinodactyly, clubfoot, broadening of the space between the first and second toes), and mild scoliosis are also reported. Brachydactyly is evident after puberty in most individuals. Habitus is unremarkable in most affected individuals, except for genu valgum in some.</p><p><b>Stature</b> is usually within the normal range prior to puberty. In adulthood, stature is only slightly diminished, with the median height shifting from the 50th to the tenth centile; range of adult height is 150-180 cm. Approximately one third of affected adults have proportionately short stature that is two standard deviations below the mean for age.</p><p><b>Craniofacial features.</b> Facies are typically normal. Cleft palate may be present. Cystic ear swelling rarely occurs.</p><p><b>Progression.</b> Functional disability is mild or absent in childhood and adolescence [<a class="bk_pop" href="#edm.REF.ballhausen.2003.65">Ballhausen et al 2003</a>]; joint involvement progresses slightly in young adults, but hip and knee surgery is usually not needed. Bowing of the extremities is not observed.</p></div><div id="edm.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>Genotype-<a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype in this spectrum of disorders, which extends from lethal <a href="/books/n/gene/achon1b/">achondrogenesis type 1B</a> (ACG1B) to mild <i>SLC26A2</i>-MED. Homozygosity or compound heterozygosity for pathogenic variants predicting stop codons or structural pathogenic variants in transmembrane domains of the sulfate transporter are associated with ACG1B, while pathogenic variants located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5'-flanking region of the <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> result in less severe phenotypes [<a class="bk_pop" href="#edm.REF.supertifurga.1996.144">Superti-Furga et al 1996</a>, <a class="bk_pop" href="#edm.REF.karniski.2001.1485">Karniski 2001</a>, <a class="bk_pop" href="#edm.REF.maeda.2006.1143">Maeda et al 2006</a>].</p><p>The <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">p.Arg279Trp</a> is the most common <i>SLC26A2</i> variant found outside of Finland (45% of alleles); it results in the mild <i>SLC26A2</i>-MED <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> when <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> and mostly in <a href="/books/n/gene/diastrophic-d/">diastrophic dysplasia</a> (DTD) and <a href="/books/n/gene/ao2/">atelosteogenesis type 2</a> (AO2) phenotypes when found in the <a class="def" href="/books/n/gene/glossary/def-item/compound-heterozygous/">compound heterozygous</a> state [<a class="bk_pop" href="#edm.REF.barbosa.2011.550">Barbosa et al 2011</a>].</p><p>Pathogenic variant <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">p.Arg178Ter</a> is the second most common variant (9% of alleles) and is associated with a more severe DTD <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> or even the perinatal-lethal AO2 phenotype, particularly when combined in <a class="def" href="/books/n/gene/glossary/def-item/trans/"><i>trans</i></a> with the <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">p.Arg279Trp</a> variant.</p><p>Pathogenic variants <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">p.Cys653Ser</a> and <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">c.-26+2T>C</a> are the third most common variants (8% of alleles).</p><p>Pathogenic variant <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">p.Cys653Ser</a> results in <i>SLC26A2</i>-MED when <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> and in <i>SLC26A2</i>-MED or DTD when present in <a class="def" href="/books/n/gene/glossary/def-item/trans/"><i>trans</i></a> with other pathogenic variants [<a class="bk_pop" href="#edm.REF.czarnyratajczak.2010.3036">Czarny-Ratajczak et al 2010</a>].</p><p>Pathogenic variant <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">c.-26+2T>C</a> is sometimes referred to as the "Finnish" variant because it is much more frequent in Finland than in the remainder of the world population. It produces low levels of correctly spliced <a class="def" href="/books/n/gene/glossary/def-item/mrna/">mRNA</a> and results in DTD when <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a>. It is the only variant that has been identified in all four <i>SLC26A2</i>-related dysplasias, in compound heterozygosity with mild (<i>SLC26A2</i>-MED and DTD) or severe (AO2 and ACG1B) alleles [<a class="bk_pop" href="#edm.REF.dwyer.2010.3043">Dwyer et al 2010</a>].</p><p>The same pathogenic variants found in the ACG1B <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> can also be found in the milder phenotypes (AO2 and DTD) if the second <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> is a relatively mild variant. Indeed, <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants located outside of the transmembrane <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a> of the sulfate transporter are often associated with residual activity that can "rescue" the effect of a <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> allele [<a class="bk_pop" href="#edm.REF.rossi.2001.159">Rossi & Superti-Furga 2001</a>].</p></div><div id="edm.Nomenclature"><h3>Nomenclature</h3><p>Multiple epiphyseal dysplasia (MED) is a disorder with clinical and genetic heterogeneity. In the past, the disorder was clinically subdivided into the milder Ribbing type, with flattened epiphysis and normal or near-normal stature; the more severe Fairbank type, with round, small epiphyses and short stature; and the unclassified types [<a class="bk_pop" href="#edm.REF.international_working_group_on_constitutional_diseases_of_bone.1998.376">International Working Group on Constitutional Diseases of Bone 1998</a>].</p><p>The genetic dissection of this heterogeneous group of conditions in recent years has provided a molecular-pathogenic classification of the different subtypes according to the <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> involved:</p><ul><li class="half_rhythm"><div><i>SLC26A2-</i>related multiple epiphyseal dysplasia (<i>SLC26A2</i>-MED) is classified in the sulfation disorders group of the 2023 revised Nosology of Genetic Skeletal Disorders [<a class="bk_pop" href="#edm.REF.unger.2023">Unger et al 2023</a>]. It accounts for approximately 25% of cases of MED.</div></li><li class="half_rhythm"><div><i>SLC26A2</i>-MED was originally referred to as recessive MED (rMED), and this term continues to be used regularly in the medical literature. However, in order to avoid confusion with the <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> <i>CANT1-</i>related <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> that is also described as multiple epiphyseal dysplasia (MED) and to move toward dyadic naming, rMED caused by <i>SLC26A2</i> pathogenic variants is now designated "multiple epiphyseal dysplasia, <i>SLC26A2</i>-related" in the 2023 revised nosology [<a class="bk_pop" href="#edm.REF.unger.2023">Unger et al 2023</a>].</div></li><li class="half_rhythm"><div>The other subtypes of MED are classified in the pseudoachondroplasia and the multiple epiphyseal dysplasias group in the 2023 revised nosology [<a class="bk_pop" href="#edm.REF.unger.2023">Unger et al 2023</a>]. The most frequent form of MED is caused by <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> pathogenic variants in <i>COMP</i> (~50% of cases). The remaining 20%-25% of cases are split between <i>MATN3</i>, <i>COL9A1</i>, <i>COL9A2</i>, and <i>COL9A3</i>.</div></li><li class="half_rhythm"><div>Some individuals with MED do not have pathogenic variants in a known <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> [<a class="bk_pop" href="#edm.REF.zankl.2007.150">Zankl et al 2007</a>, <a class="bk_pop" href="#edm.REF.unger.2008.19">Unger et al 2008</a>]; in these individuals, MED remains unclassified.</div></li></ul></div><div id="edm.Prevalence"><h3>Prevalence</h3><p>Exact data about the prevalence of MED and its subtypes are not available. Based on the number of individuals seen in growth clinics, rheumatology clinics, and genetics clinics, and compared to conditions whose incidences are more precisely known (e.g., <a href="/books/n/gene/achondroplasia/">achondroplasia</a>, <a href="/books/n/gene/oi/">osteogenesis imperfecta</a>), it seems reasonable to estimate an overall prevalence of 1:20,000 [<a class="bk_pop" href="#edm.REF.unger.2008.19">Unger et al 2008</a>]. This prevalence is probably an underestimation, as <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases (i.e., a single occurrence in a family) may remain undiagnosed. <i>SLC26A2</i>-MED is one of the most frequent forms of MED, accounting for almost 25% of all individuals diagnosed with MED [<a class="bk_pop" href="#edm.REF.jackson.2012.144">Jackson et al 2012</a>].</p></div></div><div id="edm.Genetically_Related_Allelic_Disorder"><h2 id="_edm_Genetically_Related_Allelic_Disorder_">Genetically Related (Allelic) Disorders</h2><p><i>SLC26A2</i>-related multiple epiphyseal dysplasia (<i>SLC26A2</i>-MED) is the mildest <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> in the spectrum of <i>SLC26A2</i>-related <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> skeletal disorders (see <a href="/books/NBK1306/table/edm.T.slc26a2_skeletal_disorder_spectrum/?report=objectonly" target="object" rid-ob="figobedmTslc26a2skeletaldisorderspectrum">Table 2</a>).</p><div id="edm.T.slc26a2_skeletal_disorder_spectrum" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p><i>SLC26A2</i> Skeletal Disorder Spectrum</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1306/table/edm.T.slc26a2_skeletal_disorder_spectrum/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__edm.T.slc26a2_skeletal_disorder_spectrum_lrgtbl__"><table><thead><tr><th id="hd_h_edm.T.slc26a2_skeletal_disorder_spectrum_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_edm.T.slc26a2_skeletal_disorder_spectrum_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_edm.T.slc26a2_skeletal_disorder_spectrum_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/achon1b/">Achondrogenesis type 1B</a>
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</td><td headers="hd_h_edm.T.slc26a2_skeletal_disorder_spectrum_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Extremely short limbs w/short fingers & toes; hypoplasia of the thorax; & protuberant abdomen</div></li><li class="half_rhythm"><div>Hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton</div></li><li class="half_rhythm"><div>Death occurs prenatally or shortly after birth</div></li></ul>
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</td></tr><tr><td headers="hd_h_edm.T.slc26a2_skeletal_disorder_spectrum_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<a href="/books/n/gene/ao2/">Atelosteogenesis type 2</a>
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||
</td><td headers="hd_h_edm.T.slc26a2_skeletal_disorder_spectrum_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Commonly lethal in perinatal period</div></li><li class="half_rhythm"><div>Presents around birth or before</div></li><li class="half_rhythm"><div>Chondrodysplasia w/clinical & histologic characteristics resembling those of DTD but more pronounced</div></li></ul>
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||
</td></tr><tr><td headers="hd_h_edm.T.slc26a2_skeletal_disorder_spectrum_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/diastrophic-d/">Diastrophic dysplasia</a> (DTD)</td><td headers="hd_h_edm.T.slc26a2_skeletal_disorder_spectrum_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Short limb type of dwarfism assoc w/clubfeet & other joint restrictions incl "hitchhiker thumbs"</div></li><li class="half_rhythm"><div>Progressive scoliosis in childhood</div></li></ul>
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</td></tr><tr><td headers="hd_h_edm.T.slc26a2_skeletal_disorder_spectrum_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>SLC26A2</i>-related multiple epiphyseal dysplasia</td><td headers="hd_h_edm.T.slc26a2_skeletal_disorder_spectrum_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Topic of this <i>GeneReview</i></td></tr></tbody></table></div></div></div><div id="edm.Differential_Diagnosis"><h2 id="_edm_Differential_Diagnosis_">Differential Diagnosis</h2><p><i>SLC26A2</i>-related multiple epiphyseal dysplasia (<i>SLC26A2</i>-MED) needs to be distinguished from the more common <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> forms of multiple epiphyseal dysplasia (MED). Clinical and radiographic differences between the genetically distinct forms of these skeletal dysplasias may allow clinicians to distinguish between them (see <a href="/books/NBK1306/table/edm.T.autosomal_dominant_multiple_epiphy/?report=objectonly" target="object" rid-ob="figobedmTautosomaldominantmultipleepiphy">Table 3</a>).</p><p>Note: In contrast to <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> MED, prepubertal children with <i>SLC26A2</i>-MED usually do not have short stature.</p><div id="edm.T.autosomal_dominant_multiple_epiphy" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Autosomal Dominant Multiple Epiphyseal Dysplasia *</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1306/table/edm.T.autosomal_dominant_multiple_epiphy/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__edm.T.autosomal_dominant_multiple_epiphy_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_edm.T.autosomal_dominant_multiple_epiphy_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_edm.T.autosomal_dominant_multiple_epiphy_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Features</th></tr></thead><tbody><tr><td headers="hd_h_edm.T.autosomal_dominant_multiple_epiphy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL9A1</i>
|
||
</td><td headers="hd_h_edm.T.autosomal_dominant_multiple_epiphy_1_1_1_2" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/edm-ad/"><i>COL9A1</i>-, <i>COL9A2</i>-, & <i>COL9A3</i>-MED</a> appear to have more severe knee involvement but relative sparing of the hips, resulting in a milder course than MED assoc w/<i>COMP</i> or <i>SLC26A2</i> pathogenic variants.</td></tr><tr><td headers="hd_h_edm.T.autosomal_dominant_multiple_epiphy_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL9A2</i>
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||
</td></tr><tr><td headers="hd_h_edm.T.autosomal_dominant_multiple_epiphy_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL9A3</i>
|
||
</td></tr><tr><td headers="hd_h_edm.T.autosomal_dominant_multiple_epiphy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COMP</i>
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||
</td><td headers="hd_h_edm.T.autosomal_dominant_multiple_epiphy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/edm-ad/"><i>COMP</i>-MED</a> is usually assoc w/significant involvement at the capital femoral epiphyses & irregular acetabula. <sup>1</sup></td></tr><tr><td headers="hd_h_edm.T.autosomal_dominant_multiple_epiphy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MATN3</i>
|
||
</td><td headers="hd_h_edm.T.autosomal_dominant_multiple_epiphy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/edm-ad/"><i>MATN3</i>-MED</a> appears to be the mildest form of MED identified to date & is assoc w/a high degree of <a class="def" href="/books/n/gene/glossary/def-item/intrafamilial-variability/">intrafamilial variability</a>.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">* See <a href="/books/n/gene/edm-ad/">Multiple Epiphyseal Dysplasia, Autosomal Dominant</a>.</p></div></dd><dt></dt><dd><div><p class="no_margin">MED = multiple epiphyseal dysplasia</p></div></dd><dt>1. </dt><dd><div id="edm.TF.3.1"><p class="no_margin">Pathogenic variants in <i>COMP</i> are also associated with the more severe disorder <a href="/books/n/gene/psach/">pseudoachondroplasia</a>.</p></div></dd></dl></div></div></div><p><b><i>CANT1</i>-related MED.</b> Homozygous <i>CANT1</i> <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants were reported in four individuals from two families with radiographic phenotypes described as compatible with MED [<a class="bk_pop" href="#edm.REF.balasubramanian.2017.2415">Balasubramanian et al 2017</a>]. No further individuals have yet been described; thus, given the paucity of available data, no clear clinical and radiographic delineation can be made.</p><p><b>Unclassified</b>
|
||
<b>MED.</b> Some individuals with MED do not have pathogenic variants in a known <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> [<a class="bk_pop" href="#edm.REF.zankl.2007.150">Zankl et al 2007</a>, <a class="bk_pop" href="#edm.REF.unger.2008.19">Unger et al 2008</a>]; in these individuals, MED remains unclassified.</p></div><div id="edm.Management"><h2 id="_edm_Management_">Management</h2><div id="edm.Evaluations_Following_Initial_Diagno"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease in an individual diagnosed with <i>SLC26A2</i>-related multiple epiphyseal dysplasia (<i>SLC26A2</i>-MED), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:</p><ul><li class="half_rhythm"><div>Height measurement</div></li><li class="half_rhythm"><div>Elicitation of pain history</div></li><li class="half_rhythm"><div>Radiographs of the entire spine (AP and lateral), pelvis (AP), and knees (AP and lateral), to determine the extent and severity of joint involvement</div></li><li class="half_rhythm"><div>Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>, and implications of <i>SLC26A2</i>-MED to facilitate medical and personal decision making</div></li></ul></div><div id="edm.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Symptomatic individuals should be seen by a physical therapist and an orthopedist to assess the possibility of treatment (physiotherapy for muscular strengthening and maintaining mobility, cautious use of analgesic medications such as nonsteroidal anti-inflammatory drugs) and the optimal time for surgery (joint replacement), if indicated.</p><p>Intensive physiotherapy may delay joint contractures and help maintain mobility.</p><p>Psychosocial support addressing issues of chronic pain and career counseling is warranted.</p></div><div id="edm.Surveillance"><h3>Surveillance</h3><p>Radiographic surveillance by an orthopedist is appropriate.</p></div><div id="edm.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Sports involving joint overload are to be avoided.</p></div><div id="edm.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>Predictive testing of at-risk sibs is not indicated because no preventive measures or therapeutic interventions to reduce morbidity are available.</p><p>See <a href="#edm.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="edm.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Women affected by <i>SLC26A2</i>-MED may suffer from chronic joint pain that may increase during pregnancy as a result of maternal weight gain. Appropriate pain management should be offered, and physical therapy should be intensified.</p><p>See <a href="https://www.mothertobaby.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MotherToBaby</a> for further information on medication use during pregnancy.</p></div><div id="edm.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="edm.Genetic_Counseling"><h2 id="_edm_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="edm.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>SLC26A2</i>-related multiple epiphyseal dysplasia (<i>SLC26A2</i>-MED) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div><div id="edm.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>The parents of an affected individual are presumed to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for an <i>SLC26A2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> to confirm that both parents are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for an <i>SLC26A2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and to allow reliable <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> assessment.</div></li><li class="half_rhythm"><div>If a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> occurred as a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> event in the proband or as a <a class="def" href="/books/n/gene/glossary/def-item/postzygotic/">postzygotic</a> <i>de novo</i> event in a mosaic parent [<a class="bk_pop" href="#edm.REF.j_nsson.2017.519">Jónsson et al 2017</a>]. If the proband appears to have <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:</div><ul><li class="half_rhythm"><div>A single- or multiexon <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> that was not detected by <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> and that resulted in the artifactual appearance of homozygosity;</div></li><li class="half_rhythm"><div>Uniparental isodisomy for the parental <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> with the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> that resulted in homozygosity for the pathogenic variant in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li></ul></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and have normal stature. No evidence that carriers are at increased risk of developing degenerative joint disease has been presented.</div></li></ul><p>
|
||
<b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>If both parents are known to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for an <i>SLC26A2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and have normal stature. No evidence that carriers are at increased risk of developing degenerative joint disease has been presented.</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Unless an affected individual's reproductive partner also has <i>SLC26A2</i>-MED or is a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, offspring will be obligate heterozygotes (carriers) for a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>SLC26A2</i>.</p><p><b>Other family members.</b> Each sib of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents is at a 50% risk of being a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> of an <i>SLC26A2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div><div id="edm.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>SLC26A2</i> pathogenic variants in the family.</p></div><div id="edm.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.</div></li><li class="half_rhythm"><div>Carrier testing for reproductive partners of known carriers should be considered.</div></li><li class="half_rhythm"><div>A <i>SLC26A2</i> <a class="def" href="/books/n/gene/glossary/def-item/founder-variant/">founder variant</a> has been identified in individuals of Finnish heritage (see <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">Table 4</a> and <a href="/books/n/gene/founder_finnish/">Resources for Genetics Professionals — Genetic Disorders Associated with Founder Variants Common in the Finnish Population</a>).</div></li></ul></div><div id="edm.Prenatal_Testing_and_Preimplantation"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>SLC26A2</i> pathogenic variants have been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p><p>Differences in perspective may exist among medical professionals and in families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="edm.Resources"><h2 id="_edm_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>MedlinePlus</b>
|
||
</div><div>
|
||
<a href="https://medlineplus.gov/genetics/condition/multiple-epiphyseal-dysplasia/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Multiple epiphyseal dysplasia</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Human Growth Foundation</b>
|
||
</div><div>
|
||
<a href="https://www.hgfound.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">hgfound.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Little People of America</b>
|
||
</div><div><b>Phone:</b> 888-LPA-2001; 714-368-3689</div><div><b>Fax:</b> 707-721-1896</div><div><b>Email:</b> info@lpaonline.org</div><div>
|
||
<a href="https://www.lpaonline.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">lpaonline.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>MAGIC Foundation</b>
|
||
</div><div><b>Phone:</b> 630-836-8200</div><div><b>Email:</b> contactus@magicfoundation.org</div><div>
|
||
<a href="https://www.magicfoundation.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">magicfoundation.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>UCLA International Skeletal Dysplasia Registry (ISDR)</b>
|
||
</div><div><b>Phone:</b> 310-825-8998</div><div>
|
||
<a href="https://www.uclahealth.org/ortho/isdr" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">International Skeletal Dysplasia Registry</a>
|
||
</div></li></ul>
|
||
</div><div id="edm.Molecular_Genetics"><h2 id="_edm_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="edm.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>SLC26A2-Related Multiple Epiphyseal Dysplasia: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1306/table/edm.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__edm.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_edm.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_edm.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_edm.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_edm.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_edm.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_edm.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/1836" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>SLC26A2</i>
|
||
</a>
|
||
</td><td headers="hd_b_edm.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=1836" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">5q32</a>
|
||
</td><td headers="hd_b_edm.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P50443" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Sulfate transporter</a>
|
||
</td><td headers="hd_b_edm.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=SLC26A2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SLC26A2</a>
|
||
</td><td headers="hd_b_edm.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=SLC26A2[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SLC26A2</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="edm.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="edm.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for SLC26A2-Related Multiple Epiphyseal Dysplasia (<a href="/omim/226900,606718" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1306/table/edm.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__edm.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/226900" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">226900</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EPIPHYSEAL DYSPLASIA, MULTIPLE, 4; EDM4</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/606718" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">606718</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SOLUTE CARRIER FAMILY 26 (SULFATE TRANSPORTER), MEMBER 2; SLC26A2</td></tr></tbody></table></div></div><div id="edm.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>SLC26A2</i> pathogenic variants are responsible for the family of chondrodysplasias including <a href="/books/n/gene/achon1b/">achondrogenesis type 1B</a> (ACG1B), <a href="/books/n/gene/ao2/">atelosteogenesis type 2</a> (AO2), <a href="/books/n/gene/diastrophic-d/">diastrophic dysplasia</a> (DTD), and <i>SLC26A2-</i>related multiple epiphyseal dysplasia (<i>SLC26A2</i>-MED). Impaired activity of the sulfate transporter in chondrocytes and fibroblasts results in the synthesis of proteoglycans that are not sulfated or are insufficiently sulfated [<a class="bk_pop" href="#edm.REF.rossi.1998.361">Rossi et al 1998</a>, <a class="bk_pop" href="#edm.REF.satoh.1998.12307">Satoh et al 1998</a>], most likely because of intracellular sulfate depletion [<a class="bk_pop" href="#edm.REF.rossi.1996.18456">Rossi et al 1996</a>, <a class="bk_pop" href="#edm.REF.gualeni.2010.453">Gualeni et al 2010</a>]. Undersulfation of proteoglycans affects the composition of the extracellular matrix and leads to impairment of proteoglycan deposition, which is necessary for proper endochondral bone formation [<a class="bk_pop" href="#edm.REF.corsi.2001.1375">Corsi et al 2001</a>, <a class="bk_pop" href="#edm.REF.forlino.2005.859">Forlino et al 2005</a>, <a class="bk_pop" href="#edm.REF.dawson.2011.653">Dawson 2011</a>]. The clinical severity can be correlated with the residual activities of the sulfate transporter resulting from different pathogenic variants [<a class="bk_pop" href="#edm.REF.rossi.1996.18456">Rossi et al 1996</a>, <a class="bk_pop" href="#edm.REF.rossi.1997.741">Rossi et al 1997</a>, <a class="bk_pop" href="#edm.REF.corsi.2001.1375">Corsi et al 2001</a>, <a class="bk_pop" href="#edm.REF.rossi.2001.159">Rossi & Superti-Furga 2001</a>, <a class="bk_pop" href="#edm.REF.rossi.2003.311">Rossi et al 2003</a>, <a class="bk_pop" href="#edm.REF.karniski.2004.2165">Karniski 2004</a>, <a class="bk_pop" href="#edm.REF.maeda.2006.1143">Maeda et al 2006</a>].</p><p>In a <i>Xenopus</i> oocyte model, the <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">p.Arg178Ter</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> was shown to abolish sulfate transporter activity, and the <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">p.Val341del</a> pathogenic variant showed detectable but very low activity (17% of the <a class="def" href="/books/n/gene/glossary/def-item/wild_type/">wild type</a>) of the sulfate transporter [<a class="bk_pop" href="#edm.REF.karniski.2001.1485">Karniski 2001</a>]. The same variants associated in some individuals with the ACG1B <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> can be found in individuals with a milder phenotype (AO2 and DTD) if the second <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> is a relatively mild variant. Indeed, <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants located outside the transmembrane <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a> of the sulfate transporter are often associated with residual activity that can "rescue" the effect of a <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> allele. Other conclusions from the <i>Xenopus</i> study are at odds with consistent clinical observations, the discrepancy probably being the result of temperature and cellular processing differences between <i>Xenopus</i> oocytes and humans (20 °C vs 37 °C) [<a class="bk_pop" href="#edm.REF.supertifurga.1996.144">Superti-Furga et al 1996</a>, <a class="bk_pop" href="#edm.REF.rossi.2001.159">Rossi & Superti-Furga 2001</a>, <a class="bk_pop" href="#edm.REF.supertifurga.2001">Superti-Furga 2001</a>, <a class="bk_pop" href="#edm.REF.supertifurga.2002">Superti-Furga 2002</a>]. Similar studies conducted in mammalian cells [<a class="bk_pop" href="#edm.REF.karniski.2004.2165">Karniski 2004</a>] have produced results that are much more consistent with clinical <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a>. These studies have essentially confirmed predictions that ACG1B-causing variants are associated with no residual transport activity, while the milder phenotypes result from either different combinations of "null" variants with other alleles that allow for some residual activity or from two variants with residual activity. Original observations were: (1) intracellular retention of the sulfate transporter protein with the variant <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">p.Gly678Val</a>; and (2) abnormal molecular weight of the sulfate transporter with <a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobedmTnotableslc26a2pathogenicvariant">p.Gln454Pro</a>, possibly indicating protease sensitivity or aberrant glycosylation.</p><p><b>Mechanism of disease causation.</b> Loss of function</p><div id="edm.T.notable_slc26a2_pathogenic_variant" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Notable <i>SLC26A2</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1306/table/edm.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__edm.T.notable_slc26a2_pathogenic_variant_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change<br />(Alias <sup>1</sup>)</th><th id="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change<br />(Alias <sup>1</sup>)</th><th id="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000112.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000112<wbr style="display:inline-block"></wbr>.3</a>
|
||
</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.-26+2T>C</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Founder variant in Finland; only variant that has been identified in all 4 <i>SLC26A2</i>-related dysplasias, in compound heterozygosity w/mild (<i>SLC26A2</i>-MED & <a href="/books/n/gene/diastrophic-d/">DTD</a>) or severe (<a href="/books/n/gene/ao2/">AO2</a> & <a href="/books/n/gene/achon1b/">ACG1B</a>) alleles [<a class="bk_pop" href="#edm.REF.dwyer.2010.3043">Dwyer et al 2010</a>]</td></tr><tr><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_1" rowspan="6" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000112.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000112<wbr style="display:inline-block"></wbr>.3</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000103.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000103<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.532C>T<br />(559C>T)</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg178Ter</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Second most common variant (9% of alleles); assoc w/more severe DTD <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> or perinatal-lethal AO2, esp when combined in trans w/variant p.Arg279Trp</td></tr><tr><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.835C>T<br />(c.862C>T)</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg279Trp</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Most common variant found outside of Finland (45% of alleles); mild <i>SLC26A2</i>-MED when <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> & mostly DTD & AO2 when found in <a class="def" href="/books/n/gene/glossary/def-item/compound-heterozygous/">compound heterozygous</a> state [<a class="bk_pop" href="#edm.REF.barbosa.2011.550">Barbosa et al 2011</a>]</td></tr><tr><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1020_1022delTGT<br />(1045-1047delGTT)</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Val341del</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_4" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#edm.Molecular_Pathogenesis">Molecular Pathogenesis</a>.</td></tr><tr><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1361A>C<br />(1388A>C)</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gln454Pro</td></tr><tr><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1957T>A<br />(1984T>A)</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Cys653Ser</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Third most common variant (8% of alleles); <i>SLC26A2</i>-MED when <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> & <i>SLC26A2</i>-MED or DTD when present in <a class="def" href="/books/n/gene/glossary/def-item/trans/"><i>trans</i></a> w/other pathogenic variants [<a class="bk_pop" href="#edm.REF.czarnyratajczak.2010.3036">Czarny-Ratajczak et al 2010</a>]</td></tr><tr><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2033G>T<br />(2060G>T)</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly678Val</td><td headers="hd_h_edm.T.notable_slc26a2_pathogenic_variant_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#edm.Molecular_Pathogenesis">Molecular Pathogenesis</a>.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ACG1B = achondrogenesis type 1B; AO2 = atelosteogenesis type 2; DTD = diastrophic dysplasia; MED = multiple epiphyseal dysplasia</p></div></dd><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd><dt>1. </dt><dd><div id="edm.TF.4.1"><p class="no_margin">Variant designation that does not conform to current naming conventions</p></div></dd></dl></div></div></div></div></div><div id="edm.Chapter_Notes"><h2 id="_edm_Chapter_Notes_">Chapter Notes</h2><div id="edm.Author_History"><h3>Author History</h3><p>Diana Ballhausen, MD; Lausanne University Hospital (2002-2023)<br />Luisa Bonafé, MD, PhD; Lausanne University Hospital (2002-2023)<br />Lauréane Mittaz-Crettol, PhD; Lausanne University Hospital (2002-2023)<br />Andrea Superti-Furga, MD (2002-present)<br />Sheila Unger, MD (2023-present)</p></div><div id="edm.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>19 January 2023 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>23 January 2014 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>18 March 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>27 December 2006 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>20 July 2004 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>29 August 2002 (me) Review posted live</div></li><li class="half_rhythm"><div>25 February 2002 (db) Original submission</div></li></ul></div></div><div id="edm.References"><h2 id="_edm_References_">References</h2><div id="edm.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="edm.REF.balasubramanian.2017.2415">Balasubramanian K, Li B, Krakow D, Nevarez L, Ho PJ, Ainsworth JA, Nickerson DA, Bamshad MJ, Immken L, Lachman RS, Cohn DH. MED resulting from recessively inherited mutations in the gene encoding calcium-activated nucleotidase CANT1. <span><span class="ref-journal">Am J Med Genet A. </span>2017;<span class="ref-vol">173</span>:2415–21.</span> [<a href="/pmc/articles/PMC5564418/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5564418</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28742282" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28742282</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="edm.REF.ballhausen.2003.65">Ballhausen D, Bonafé L, Terhal P, Unger SL, Bellus G, Classen M, Hamel BC, Spranger J, Zabel B, Cohn DH, Cole WG, Hecht JT, Superti-Furga A. 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New York, NY: McGraw-Hill; 2001:5189-201.</div></li><li class="half_rhythm"><div class="bk_ref" id="edm.REF.supertifurga.2002">Superti-Furga A. Skeletal dysplasias related to defects in sulfate metabolism. In: Royce P, Steinmann B, eds. <em>Connective Tissue and Its Heritable Disorders.</em> 2 ed. New York, NY: Wiley-Liss, Inc; 2002:939-60.</div></li><li class="half_rhythm"><div class="bk_ref" id="edm.REF.supertifurga.1996.144">Superti-Furga A, Rossi A, Steinmann B, Gitzelmann R. A chondrodysplasia family produced by mutations in the diastrophic dysplasia sulfate transporter gene: genotype/phenotype correlations. <span><span class="ref-journal">Am J Med Genet. </span>1996;<span class="ref-vol">63</span>:144–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8723100" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8723100</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="edm.REF.unger.2008.19">Unger S, Bonafé L, Superti-Furga A. Multiple epiphyseal dysplasia: clinical and radiographic features, differential diagnosis and molecular basis. <span><span class="ref-journal">Best Pract Res Clin Rheumatol. </span>2008;<span class="ref-vol">22</span>:19–32.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18328978" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18328978</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="edm.REF.unger.2023">Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, Cohn DH, Cormier-Daire V, Girisha KM, Hall C, Krakow D, Makitie O, Mundlos S, Nishimura G, Robertson SP, Savarirayan R, Sillence D, Simon M, Sutton VR, Warman ML, Superti-Furga A. Nosology of genetic skeletal disorders: 2023 revision. <span><span class="ref-journal">Am J Med Genet A. </span>2023.</span> Epub ahead of print. [<a href="/pmc/articles/PMC10081954/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10081954</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/36779427" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36779427</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="edm.REF.zankl.2007.150">Zankl A, Jackson GC, Crettol LM, Taylor J, Elles R, Mortier GR, Spranger J, Zabel B, Unger S, Merrer ML, Cormier-Daire V, Hall CM, Wright MJ, Bonafé L, Superti-Furga A, Briggs MD. Preselection of cases through expert clinical and radiographic review significantly increases mutation detection rate in multiple epiphyseal dysplasia. <span><span class="ref-journal">Eur J Hum Genet. </span>2007;<span class="ref-vol">15</span>:150–4.</span> [<a href="/pmc/articles/PMC2670452/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2670452</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17133256" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17133256</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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