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<meta name="ncbi_db" content="books" /><meta name="ncbi_pdid" content="book-part" /><meta name="ncbi_acc" content="NBK1317" /><meta name="ncbi_domain" content="gene" /><meta name="ncbi_report" content="record" /><meta name="ncbi_type" content="fulltext" /><meta name="ncbi_objectid" content="" /><meta name="ncbi_pcid" content="/NBK1317/" /><meta name="ncbi_pagename" content="SLC26A2-Related Atelosteogenesis - GeneReviews® - NCBI Bookshelf" /><meta name="ncbi_bookparttype" content="chapter" /><meta name="ncbi_app" content="bookshelf" />
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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 Atelosteogenesis" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2023/03/16" /><meta name="citation_author" content="Andrea Superti-Furga" /><meta name="citation_author" content="Sheila Unger" /><meta name="citation_pmid" content="20301493" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1317/" /><meta name="citation_keywords" content="Sulfate transporter" /><meta name="citation_keywords" content="SLC26A2" /><meta name="citation_keywords" content="SLC26A2-Related Atelosteogenesis" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="SLC26A2-Related Atelosteogenesis" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Andrea Superti-Furga" /><meta name="DC.Contributor" content="Sheila Unger" /><meta name="DC.Date" content="2023/03/16" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1317/" /><meta name="description" content="Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia). Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. SLC26A2-related atelosteogenesis is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia. However, it exists in a continuous phenotypic spectrum with SLC26A2-related diastrophic dysplasia, and long-term survivors have been reported." /><meta name="og:title" content="SLC26A2-Related Atelosteogenesis" /><meta name="og:type" content="book" /><meta name="og:description" content="Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia). Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. SLC26A2-related atelosteogenesis is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia. 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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="#__NBK1317_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1317_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/slc25a24-fps/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/edm/" 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="_NBK1317_"><span class="title" itemprop="name"><i>SLC26A2</i>-Related Atelosteogenesis</span></h1><p class="contrib-group"><span itemprop="author">Andrea Superti-Furga</span>, MD and <span itemprop="author">Sheila Unger</span>, MD, FRCPC.</p><a data-jig="ncbitoggler" href="#__NBK1317_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1317_ai__"><div class="contrib half_rhythm"><span itemprop="author">Andrea Superti-Furga</span>, MD<div class="affiliation small">Professor of Pediatrics, Department of Pediatrics<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 class="contrib half_rhythm"><span itemprop="author">Sheila Unger</span>, MD, FRCPC<div class="affiliation small">Division of Genetic Medicine<br />University of Lausanne<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><p class="small">Initial Posting: <span itemprop="datePublished">August 30, 2002</span>; Last Revision: <span itemprop="dateModified">March 16, 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="ao2.Summary" itemprop="description"><h2 id="_ao2_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Clinical features of <i>SLC26A2</i>-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia). Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. <i>SLC26A2</i>-related atelosteogenesis is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia. However, it exists in a continuous phenotypic spectrum with <i>SLC26A2</i>-related diastrophic dysplasia, and long-term survivors have been reported.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>SLC26A2</i>-related atelosteogenesis is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with characteristic clinical, radiologic, and histopathologic features and <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>SLC26A2</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> There is no specific treatment currently available, and the aim of therapy (supportive versus palliative) will depend on clinical status and respiratory prognosis of the individual patient.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>SLC26A2</i>-related atelosteogenesis 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 a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with <i>SLC26A2</i>-related atelosteogenesis 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. Carrier testing for at-risk relatives and prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> for a pregnancy at increased risk are possible if both pathogenic variants in the family are known. Ultrasound examination early in pregnancy is a reasonable complement or alternative to molecular genetic <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>.</p></div></div><div id="ao2.Diagnosis"><h2 id="_ao2_Diagnosis_">Diagnosis</h2><div id="ao2.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>SLC26A2</i>-related atelosteogenesis is usually lethal at birth or shortly thereafter because of pulmonary hypoplasia and tracheobronchomalacia. <i>SLC26A2</i>-related atelosteogenesis <b>should be suspected</b> when the following are present.</p><p>
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<b>Clinical features</b>
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</p><ul><li class="half_rhythm"><div>Rhizomelic limb shortening with normal-sized skull</div></li><li class="half_rhythm"><div>Hitchhiker thumbs</div></li><li class="half_rhythm"><div>Small chest</div></li><li class="half_rhythm"><div>Protuberant abdomen</div></li><li class="half_rhythm"><div>Cleft palate</div></li><li class="half_rhythm"><div>Distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia)</div></li></ul><p>Other usual findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot.</p><p>
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<b>Radiographic findings</b>
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</p><ul><li class="half_rhythm"><div>Normal-sized skull with disproportionately short skeleton</div></li><li class="half_rhythm"><div>Platyspondyly, hypodysplastic vertebrae, and cervical kyphosis. Ossification of the upper thoracic vertebrae and coronal clefts of the lumbar and lower thoracic vertebrae may be incomplete.</div></li><li class="half_rhythm"><div>Hypoplastic ilia with flat acetabulum. The pubic bones are often unossified.</div></li><li class="half_rhythm"><div>Shortened long bones with metaphyseal flaring. The distal humerus is sometimes bifid or V-shaped, sometimes pointed and hypoplastic; the femur is distally rounded; the radius and tibia are typically bowed.</div></li><li class="half_rhythm"><div>Note: (1) A distally pointed, triangular humerus had led <a class="bk_pop" href="#ao2.REF.slaney.1999.835">Slaney et al [1999]</a> to the suggestion of a new condition, but this finding is a typical feature of <a href="/books/n/gene/achon1b/"><i>SLC26A2</i>-related achondrogenesis</a> bordering on <i>SLC26A2</i>-related atelosteogenesis [<a class="bk_pop" href="#ao2.REF.unger.2001.893">Unger et al 2001</a>]. (2) The first individuals with de la Chapelle dysplasia described by <a class="bk_pop" href="#ao2.REF.de_la_chapelle.1972.759">de la Chapelle et al [1972]</a> and <a class="bk_pop" href="#ao2.REF.whitley.1986.29">Whitley et al [1986]</a> showed a triangular remnant of ulna and fibula. Those individuals were subsequently classified as having <i>SLC26A2</i>-related atelosteogenesis [<a class="bk_pop" href="#ao2.REF.bonaf_.2008.827">Bonafé et al 2008</a>].</div></li><li class="half_rhythm"><div>Characteristic hand findings of sulfate transporter-related dysplasia:</div><ul><li class="half_rhythm"><div>Hitchhiker thumb with ulnar deviation of the fingers (characteristic of <a href="/books/n/gene/diastrophic-d/"><i>SLC26A2</i>-related diastrophic dysplasia</a> [<i>SLC26A2</i>-DTD])</div></li><li class="half_rhythm"><div>Gap between the first and second toe (characteristic of <i>SLC26A2</i>-related achondrogenesis [when the phalanges are identifiable on x-ray] and <i>SLC26A2</i>-DTD)</div></li><li class="half_rhythm"><div>Hypoplasia of the first metacarpal bone (also present in <i>SLC26A2</i>-related achondrogenesis and <i>SLC26A2</i>-DTD)</div></li></ul></li></ul><p><b>Histopathology</b> (important when radiologic material is not available or is of poor quality)</p><ul><li class="half_rhythm"><div>Paucity of sulfated proteoglycans in cartilage matrix [<a class="bk_pop" href="#ao2.REF.supertifurga.1996a.195">Superti-Furga et al 1996a</a>, <a class="bk_pop" href="#ao2.REF.rossi.1997.741">Rossi et al 1997</a>] similar to that seen <i>SLC26A2</i>-DTD and <i>SLC26A2</i>-related achondrogenesis</div></li><li class="half_rhythm"><div>Abnormal extracellular matrix with threads of fibrillar material between cystic acellular areas and areas of normal cellularity</div></li><li class="half_rhythm"><div>Some chondrocytes appear surrounded by lamellar material forming concentric rings that are in some cases indistinguishable from the collagen rings typical of <i>SLC26A2</i>-related achondrogenesis.</div></li><li class="half_rhythm"><div>The growth plate shows disruption of column formation and hypertrophic zones with irregular invasion of the metaphyseal capillaries and fibrosis.</div></li><li class="half_rhythm"><div>These cartilage matrix abnormalities are present in long bones as well as in tracheal, laryngeal, and peribronchial cartilage, whereas intramembranous ossification shows no abnormalities.</div></li></ul></div><div id="ao2.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>SLC26A2</i>-related atelosteogenesis <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with <a href="#ao2.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/NBK1317/table/ao2.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobao2Tmoleculargenetictestingusedin">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="#ao2.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.</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 clinical and radiographic findings described in <a href="#ao2.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#ao2.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 inherited disorders with perinatal-lethal skeletal dysplasia are more likely to be diagnosed using genomic testing (see <a href="#ao2.Option_2">Option 2</a>).</p><div id="ao2.Option_1"><h4>Option 1</h4><p>When the phenotypic and radiographic findings suggest the diagnosis of <i>SLC26A2</i>-related atelosteogenesis, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> approaches can include <b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b> or use of a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of <i>SLC26A2</i> is performed first to detect 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. Note: Depending on the sequencing method used, single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a>, multiexon, or whole-gene deletions/duplications may not be detected. If 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 exon and whole-gene deletions or duplications. Note: To date such variants have not been identified as a cause of <i>SLC26A2</i>-related atelosteogenesis.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A skeletal dysplasia</b>
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<b><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="#ao2.Differential_Diagnosis">Differential Diagnosis</a>) can be considered 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.</div><div class="half_rhythm">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>.</div></li></ul></div><div id="ao2.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 many other inherited disorders characterized by perinatal-lethal skeletal dysplasia, <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, may be pursued. <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="ao2.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 Atelosteogenesis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1317/table/ao2.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ao2.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ao2.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_ao2.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_ao2.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_ao2.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_ao2.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_ao2.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>90% <sup>4</sup></td></tr><tr><td headers="hd_h_ao2.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>5</sup></td><td headers="hd_h_ao2.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="ao2.TF.1.1"><p class="no_margin">See <a href="/books/NBK1317/#ao2.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="ao2.TF.1.2"><p class="no_margin">See <a href="#ao2.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="ao2.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="ao2.TF.1.4"><p class="no_margin"><a class="bk_pop" href="#ao2.REF.rossi.2001.159">Rossi & Superti-Furga [2001]</a> and data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bk_pop" href="#ao2.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd><dt>5. </dt><dd><div id="ao2.TF.1.5"><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></dl></div></div></div></div></div></div><div id="ao2.Clinical_Characteristics"><h2 id="_ao2_Clinical_Characteristics_">Clinical Characteristics</h2><div id="ao2.Clinical_Description"><h3>Clinical Description</h3><p>To date, only a handful of individuals with <i>SLC26A2</i>-related atelosteogenesis have been reported [<a class="bk_pop" href="#ao2.REF.rossi.2001.159">Rossi & Superti-Furga 2001</a>]. The following description of the phenotypic features associated with this condition is based on these reports.</p><p>The diagnosis of <i>SLC26A2</i>-related atelosteogenesis should be made only if specific <i>SLC26A2</i> pathogenic variants that are associated with SLC26A2-related atelosteogenesis (see <a href="#ao2.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>) have been identified, and/or the clinical and radiographic severity lies somewhere between <a href="/books/n/gene/achon1b/"><i>SLC26A2</i>-related achondrogenesis</a> and <a href="/books/n/gene/diastrophic-d/"><i>SLC26A2</i>-related diastrophic dysplasia</a> (<i>SLC26A2</i>-DTD) (see <a href="#ao2.Genetically_Related_Allelic_Disorder">Genetically Related Disorders</a>). It follows, then, that the diagnosis of <i>SLC26A2</i>-related atelosteogenesis will only apply to a fetus/individual with severe prenatal-onset short stature. Almost all individuals will have club feet (adducted feet) and many will have lung hypoplasia (consequences of the generalized skeletal alterations). The <a class="def" href="/books/n/gene/glossary/def-item/dysmorphic/">dysmorphic</a> facial features are very consistent and cleft palate is frequent.</p><p><i>SLC26A2</i>-related atelosteogenesis is usually lethal in the neonatal period because of lung hypoplasia, tracheobronchomalacia, and laryngeal malformations. Pregnancy complication of polyhydramnios may occur.</p><p>Newborns with <i>SLC26A2</i>-related atelosteogenesis present with short limbs, adducted feet with wide space between the hallux and the second toe, hitchhiker thumb, cleft palate, and facial dysmorphism. <i>SLC26A2</i>-related atelosteogenesis is clinically very similar to <i>SLC26A2</i>-DTD [<a class="bk_pop" href="#ao2.REF.rossi.1996b.657">Rossi et al 1996b</a>].</p><p><b>Skeletal features.</b> Disproportion between the short skeleton and normal-sized skull is immediately evident; the limb shortening is mainly rhizomelic; the gap between the toes, ulnar deviation of the fingers, and adducted thumbs are typical of sulfate transporter-related dysplasias [<a class="bk_pop" href="#ao2.REF.newburyecob.1998.49">Newbury-Ecob 1998</a>, <a class="bk_pop" href="#ao2.REF.supertifurga.2001.282">Superti-Furga et al 2001</a>]. The neck is short, the thorax narrow, and the abdomen protuberant.</p><p><b>Craniofacial features.</b> Cleft palate is a constant feature, whereas the degree of facial dysmorphism is variable. Midface retrusion is usually present, together with a flat nasal bridge and micrognathia. Epicanthal folds, widely spaced eyes, and low-set ears can also be present.</p><p><b>Other.</b> Spinal scoliosis and dislocation of the elbows are reported [<a class="bk_pop" href="#ao2.REF.newburyecob.1998.49">Newbury-Ecob 1998</a>].</p></div><div id="ao2.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 [<a class="bk_pop" href="#ao2.REF.rossi.1997.741">Rossi et al 1997</a>] in a spectrum from lethal <a href="/books/n/gene/achon1b/"><i>SLC26A2</i>-related achondrogenesis</a> to mild <a href="/books/n/gene/edm/"><i>SLC26A2</i>-related multiple epiphyseal dysplasia</a> (<i>SLC26A2</i>-MED).</p><ul><li class="half_rhythm"><div>Homozygosity or compound heterozygosity for pathogenic variants predicting stop codons or structural variants in transmembrane domains of the sulfate transporter are associated with the more severe <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of <i>SLC26A2</i>-related achondrogenesis.</div></li><li class="half_rhythm"><div>The combination of a severe <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> (predicting stop codons or structural variants in transmembrane domains) with a pathogenic variant 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> results in the less severe phenotypes, i.e., <i>SLC26A2</i>-related atelosteogenesis and <i>SLC26A2</i>-<a href="/books/n/gene/diastrophic-d/">DTD</a> [<a class="bk_pop" href="#ao2.REF.h_stbacka.1996.255">Hästbacka et al 1996</a>, <a class="bk_pop" href="#ao2.REF.supertifurga.1996b.144">Superti-Furga et al 1996b</a>, <a class="bk_pop" href="#ao2.REF.rossi.1997.741">Rossi et al 1997</a>, <a class="bk_pop" href="#ao2.REF.karniski.2001.1485">Karniski 2001</a>, <a class="bk_pop" href="#ao2.REF.rossi.2001.159">Rossi & Superti-Furga 2001</a>, <a class="bk_pop" href="#ao2.REF.karniski.2004.2165">Karniski 2004</a>].</div></li></ul><p>The <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <a href="/books/NBK1317/table/ao2.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobao2Tnotableslc26a2pathogenicvariant">p.Arg279Trp</a>, the most common <i>SLC26A2</i> variant outside Finland (45% of alleles), results in a 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 the <i>SLC26A2-</i>DTD phenotype when in the <a class="def" href="/books/n/gene/glossary/def-item/compound-heterozygous/">compound heterozygous</a> state.</p><p>The <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <a href="/books/NBK1317/table/ao2.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobao2Tnotableslc26a2pathogenicvariant">p.Arg178Ter</a> is the second-most common variant (9% of alleles) and is associated with a more severe <i>SLC26A2-</i>DTD <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> or even the perinatal-lethal <i>SLC26A2</i>-related atelosteogenesis phenotype, particularly when combined in <a class="def" href="/books/n/gene/glossary/def-item/trans/"><i>trans</i></a> with the p.Arg279Trp variant. It has also been found in some individuals with more severe <i>SLC26A2</i>-MED and <i>SLC26A2</i>-related achondrogenesis, making it one of two pathogenic variants identified in all four <i>SLC26A2</i>-related dysplasias.</p><p>Pathogenic variants p.Cys653Ser and c.-26+2T>C are the third-most common variants (8% of alleles for each).</p><ul><li class="half_rhythm"><div><a href="/books/NBK1317/table/ao2.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobao2Tnotableslc26a2pathogenicvariant">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 <i>SLC26A2</i>-DTD when <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a>.</div></li><li class="half_rhythm"><div>Together with p.Arg178Ter, <a href="/books/NBK1317/table/ao2.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobao2Tnotableslc26a2pathogenicvariant">c.-26+2T>C</a> is the only <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> that has been identified in all four <i>SLC26A2</i>-related dysplasias, in compound heterozygosity with mild (<i>SLC26A2</i>-MED and <i>SLC26A2</i>-DTD) or severe (<i>SLC26A2</i>-related atelosteogenesis and <i>SLC26A2</i>-related achondrogenesis) alleles [<a class="bk_pop" href="#ao2.REF.dwyer.2010.3043">Dwyer et al 2010</a>; Bonafe, unpublished results].</div></li><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> p.Cys653Ser 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 <i>SLC26A2-</i>DTD when compounded with other pathogenic variants. It is not found in <i>SLC26A2</i>-related atelosteogenesis or <i>SLC26A2</i>-related achondrogenesis.</div></li></ul><p>Another <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> specific to the Finnish population is <a href="/books/NBK1317/table/ao2.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobao2Tnotableslc26a2pathogenicvariant">p.Thr512Lys</a>, which results in <i>SLC26A2</i>-related atelosteogenesis (de la Chapelle dysplasia) when <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> and in <i>SLC26A2-</i>DTD when in compound heterozygosity with a milder <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> [<a class="bk_pop" href="#ao2.REF.bonaf_.2008.827">Bonafé et al 2008</a>].</p><p>Most other pathogenic variants are rare.</p><p>The same pathogenic variants found in some individuals who have the <i>SLC26A2</i>-related atelosteogenesis <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> can also be found in individuals with a milder phenotype (<i>SLC26A2</i>-MED and <i>SLC26A2</i>-DTD) if the second <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> is a relatively mild variant. Indeed, pathogenic <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 a 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="#ao2.REF.rossi.2001.159">Rossi & Superti-Furga 2001</a>].</p></div><div id="ao2.Nomenclature"><h3>Nomenclature</h3><p>The name "atelosteogenesis" was coined by <a class="bk_pop" href="#ao2.REF.maroteaux.1982.15">Maroteaux et al [1982]</a> for a different condition.</p><p><a class="bk_pop" href="#ao2.REF.sillence.1987.112">Sillence et al [1987]</a> created the term "atelosteogenesis type 2" for a group of fetuses or stillborns who had all previously been diagnosed as having "severe diastrophic dysplasia." The reason was an apparent hypoplasia of the distal humerus and variable fibular hypoplasia (but not aplasia) that was slightly reminiscent of atelosteogenesis type 1 (AO1). The redefinition of this severe DTD variant as atelosteogenesis type 2 was unfortunate because it suggested a relationship with AO1 and at the same time denied the relationship with diastrophic dysplasia. Later biochemical and molecular studies brought this entity back to its origin – that is, in the diastrophic dysplasia-achondrogenesis group in which <i>SLC26A2</i>-related atelosteogenesis is considered to be a severe form of <i>SLC26A2</i>-DTD, and in which lethality distinguishes <i>SLC26A2</i>-related atelosteogenesis from <i>SLC26A2</i>-DTD.</p><p><a class="bk_pop" href="#ao2.REF.de_la_chapelle.1972.759">De la Chapelle et al [1972]</a> described two sibs with a novel condition very similar to <i>SLC26A2</i>-related atelosteogenesis, with very hypoplastic ulna and fibula; one additional sib and one more person with this condition (de la Chapelle dysplasia) were reported by <a class="bk_pop" href="#ao2.REF.whitley.1986.29">Whitley et al [1986]</a>. The histopathologic similarities with <i>SLC26A2</i>-related achondrogenesis suggested a relationship with the sulfate transporter-related dysplasias. The identity of de la Chapelle dysplasia with <i>SLC26A2</i>-related atelosteogenesis was subsequently confirmed by molecular testing, which revealed pathogenic variants in <i>SLC26A2</i> [<a class="bk_pop" href="#ao2.REF.bonaf_.2008.827">Bonafé et al 2008</a>].</p><p><i>SLC26A2</i>-related atelosteogenesis may also be referred to as <b>McAlister dysplasia</b>.</p><p><i>SLC26A2</i>-related atelosteogenesis is classified in the sulfation disorders group in the 2023 revision of the Nosology of Genetic Skeletal Disorders [<a class="bk_pop" href="#ao2.REF.unger.2023">Unger et al 2023</a>].</p></div><div id="ao2.Prevalence"><h3>Prevalence</h3><p>No data on the prevalence of <i>SLC26A2</i>-related atelosteogenesis are available. Among the sulfate transporter-related dysplasias, <i>SLC26A2</i>-related atelosteogenesis is the rarest <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p></div></div><div id="ao2.Genetically_Related_Allelic_Disorder"><h2 id="_ao2_Genetically_Related_Allelic_Disorder_">Genetically Related (Allelic) Disorders</h2><p>Three other phenotypes (all with an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>) – <i>SLC26A2</i>-related achondrogenesis, <i>SLC26A2</i>-related diastrophic dysplasia (<i>SLC26A2</i>-DTD), and <i>SLC26A2</i>-related multiple epiphyseal dysplasia (<i>SLC26A2</i>-MED) – are associated with pathogenic variants in <i>SLC26A2</i>. <i>SLC26A2</i>-related achondrogenesis and <i>SLC26A2</i>-DTD have phenotypic overlap with <i>SLC26A2</i>-related atelosteogenesis and should be considered in the differential diagnosis (see <a href="/books/NBK1317/table/ao2.T.slc26a2_allelic_disorders_in_the_d/?report=objectonly" target="object" rid-ob="figobao2Tslc26a2allelicdisordersinthed">Table 2</a>).</p><div id="ao2.T.slc26a2_allelic_disorders_in_the_d" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p><i>SLC26A2</i> Allelic Disorders in the Differential Diagnosis of <i>SLC26A2</i>-Related Atelosteogenesis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1317/table/ao2.T.slc26a2_allelic_disorders_in_the_d/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ao2.T.slc26a2_allelic_disorders_in_the_d_lrgtbl__"><table><thead><tr><th id="hd_h_ao2.T.slc26a2_allelic_disorders_in_the_d_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Allelic Disorder</th><th id="hd_h_ao2.T.slc26a2_allelic_disorders_in_the_d_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th><th id="hd_h_ao2.T.slc26a2_allelic_disorders_in_the_d_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Differentiating Features</th></tr></thead><tbody><tr><td headers="hd_h_ao2.T.slc26a2_allelic_disorders_in_the_d_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/"><i>SLC26A2</i>-related achondrogenesis</a>
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</td><td headers="hd_h_ao2.T.slc26a2_allelic_disorders_in_the_d_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Characterized by severe hypoplasia/dysplasia of spine, rib cage, & extremities, w/relatively preserved cranium</div></li><li class="half_rhythm"><div>Among most severe skeletal disorders in humans; invariably lethal in perinatal period.</div></li></ul>
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</td><td headers="hd_h_ao2.T.slc26a2_allelic_disorders_in_the_d_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>The radiologic differentiation of <i>SLC26A2</i>-related atelosteogenesis from <i>SLC26A2</i>-related achondrogenesis is based on more severe underossification of skeleton & extreme limb shortening seen in <i>SLC26A2</i>-related achondrogenesis.</div></li><li class="half_rhythm"><div>Histopathology is similar in <i>SLC26A2</i>-related atelosteogenesis & <i>SLC26A2</i>-related achondrogenesis.</div></li></ul>
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</td></tr><tr><td headers="hd_h_ao2.T.slc26a2_allelic_disorders_in_the_d_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/diastrophic-d/"><i>SLC26A2</i>-related diastrophic dysplasia</a> (<i>SLC26A2</i>-DTD)</td><td headers="hd_h_ao2.T.slc26a2_allelic_disorders_in_the_d_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>SLC26A2</i>-DTD, a skeletal dysplasia, is characterized by short stature, joint contractures, cleft palate, & characteristic clinical signs incl "hitchhiker" thumb, & cystic swelling of external ears.</td><td headers="hd_h_ao2.T.slc26a2_allelic_disorders_in_the_d_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><i>SLC26A2</i>-related atelosteogenesis, rather than <i>SLC26A2</i>-DTD, must be considered when distinct hypoplasia of ≥1 long bones (humerus, ulna, radius, or fibula) &/or pulmonary hypoplasia is present.</div></li><li class="half_rhythm"><div>Histopathology is very similar in <i>SLC26A2</i>-DTD & <i>SLC26A2</i>-related atelosteogenesis, but cartilage growth plate shows fewer disorganized hypertrophic & proliferative zones & columnar zones in <i>SLC26A2</i>-DTD.</div></li></ul>
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</td></tr></tbody></table></div></div><p><a href="/books/n/gene/edm/"><b><i>SLC26A2</i>-related multiple epiphyseal dysplasia</b></a> is characterized by joint pain (usually the hips and knees); malformations of the hands, feet, and knees; and scoliosis. Approximately 50% of individuals have an abnormal finding at birth, e.g., clubfoot, cleft palate, or cystic ear swelling. Median height in adulthood is in the tenth centile.</p></div><div id="ao2.Differential_Diagnosis"><h2 id="_ao2_Differential_Diagnosis_">Differential Diagnosis</h2><p><i>SLC26A2</i>-related achondrogenesis and <i>SLC26A2</i>-related diastrophic dysplasia have phenotypic overlap with <i>SLC26A2</i>-related atelosteogenesis (and should be considered in the differential diagnosis (see <a href="/books/NBK1317/table/ao2.T.slc26a2_allelic_disorders_in_the_d/?report=objectonly" target="object" rid-ob="figobao2Tslc26a2allelicdisordersinthed">Table 2</a>).</p><p>The differentiation of <i>SLC26A2</i>-related atelosteogenesis from other subtypes of atelosteogenesis ("incomplete bone formation"), and even from other lethal skeletal dysplasias, should be based on clinical examination as well as radiographic imaging.</p><div id="ao2.T.genes_of_interest_in_the_different" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of <i>SLC26A2</i>-Related Atelosteogenesis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1317/table/ao2.T.genes_of_interest_in_the_different/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ao2.T.genes_of_interest_in_the_different_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Differential Disorder</th><th id="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Differentiating Clinical & Radiographic Features</th></tr></thead><tbody><tr><td headers="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FLNB</i>
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</td><td headers="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>FLNB</i>-related AO1 (<i>FLNB</i>-AOI) (See <a href="/books/n/gene/flnb-dis/"><i>FLNB </i>Disorders</a>.)</td><td headers="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hitchhiker thumb & gap between toes are not present in <i>FLNB</i>-AO1 & cleft palate is rare.</div></li><li class="half_rhythm"><div><i>FLNB</i>-AO1 shows better development of long bones & better ossification of spine & pelvis.</div></li><li class="half_rhythm"><div>Absence of fibula may suggest <i>FLNB</i>-AO1; dysplasia of fibula is more typical of <i>SLC26A2</i>-related atelosteogenesis.</div></li><li class="half_rhythm"><div>Humerus may be completely absent in <i>FLNB</i>-AO1.</div></li></ul>
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</td></tr><tr><td headers="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multiple<br />genes <sup>1</sup> incl:<br /><i>DYNC2H1</i><br /><i>IFT80</i><br /><i>TTC21B</i></td><td headers="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lethal short-rib polydactyly<br />syndromes (w/o polydactyly)<br />(OMIM <a href="https://omim.org/entry/613091" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613091</a>, <a href="https://omim.org/entry/611263" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">611263</a>, <a href="https://omim.org/entry/613819" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613819</a>)</td><td headers="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Thoracic hypoplasia is more significant.</div></li><li class="half_rhythm"><div>There may be trident pelvis.</div></li></ul>
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</td></tr><tr><td headers="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FGFR3</i>
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</td><td headers="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/td/">Thanatophoric dysplasia</a> (TD)</td><td headers="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_ao2.T.genes_of_interest_in_the_different_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Typical "telephone receiver" femur is visible on x-ray in TD.</div></li><li class="half_rhythm"><div>Cloverleaf skull is common in TD type II.</div></li></ul>
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||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; AO1 = atelosteogenesis type 1; AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a></p></div></dd><dt>1. </dt><dd><div id="ao2.TF.3.1"><p class="no_margin">See OMIM <a href="https://omim.org/phenotypicSeries/PS208500" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Short-Rib Thoracic Dysplasia Phenotypic Series</a> for genes associated with this <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> in OMIM.</p></div></dd></dl></div></div></div></div><div id="ao2.Management"><h2 id="_ao2_Management_">Management</h2><p>There is no specific treatment available. Decisions regarding supportive therapy versus palliative treatment depend on the degree of respiratory compromise at birth.</p><div id="ao2.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 atelosteogenesis, the evaluations summarized in <a href="/books/NBK1317/table/ao2.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object" rid-ob="figobao2Tnotableslc26a2pathogenicvariant">Table 5</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="ao2.T.recommended_evaluations_following" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with <i>SLC26A2</i>-Related Atelosteogenesis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1317/table/ao2.T.recommended_evaluations_following/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ao2.T.recommended_evaluations_following_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ao2.T.recommended_evaluations_following_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_ao2.T.recommended_evaluations_following_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_ao2.T.recommended_evaluations_following_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_ao2.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal</b>
|
||
</td><td headers="hd_h_ao2.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Complete skeletal survey in viable newborn</td><td headers="hd_h_ao2.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ao2.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Pulmonary</b>
|
||
</td><td headers="hd_h_ao2.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval of respiratory status in viable newborn</td><td headers="hd_h_ao2.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ao2.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic</b>
|
||
<br />
|
||
<b>counseling</b>
|
||
</td><td headers="hd_h_ao2.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_ao2.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & their families re nature, MOI, & implications of <i>SLC26A2</i>-related atelosteogenesis to facilitate medical & personal decision making</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a></p></div></dd><dt>1. </dt><dd><div id="ao2.TF.4.1"><p class="no_margin">Medical geneticist, certified genetic counselor, or certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="ao2.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>For long-term survivors, care should include surgical repair of cleft palate.</p><p>Utility of surgery for club feet is unclear as this is quite complicated and the results limited.</p><p>Physiotherapy is useful for retaining range of motion.</p></div><div id="ao2.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#ao2.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="ao2.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="ao2.Genetic_Counseling"><h2 id="_ao2_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="ao2.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>SLC26A2</i>-related atelosteogenesis is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div><div id="ao2.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 child are obligate heterozygotes (i.e., presumed to be carriers of one <i>SLC26A2</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> based on family history).</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a <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. (Although a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> pathogenic variant has not been reported in <i>SLC26A2</i>-related atelosteogenesis to date, <i>de novo</i> variants are known occur at a low but appreciable rate in <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorders [<a class="bk_pop" href="#ao2.REF.j_nsson.2017.519">Jónsson et al 2017</a>].)</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease.</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 suggests that carriers are at increased risk of developing degenerative joint disease.</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b>
|
||
<i>SLC26A2</i>-related atelosteogenesis is usually perinatal lethal; affected individuals do not reproduce.</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="ao2.Carrier_Detection"><h3>Carrier Detection</h3><p><b>At-risk relatives.</b> Carrier testing for at-risk relatives requires prior identification of the <i>SLC26A2</i> pathogenic variants in the family.</p><p><b>Reproductive partners of known carriers.</b> Sequence analysis of <i>SLC26A2</i>. Caution should be used when interpreting the phenotypic outcome of various <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> combinations.</p></div><div id="ao2.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, clarification of <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> status, and discussion of the 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 carriers or are at risk of being carriers.</div></li></ul></div><div id="ao2.Prenatal_Testing_and_Preimplantation"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>
|
||
<b>High-risk pregnancies</b>
|
||
</p><ul><li class="half_rhythm"><div><b>Molecular genetic testing.</b> 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.</div></li><li class="half_rhythm"><div><b>Ultrasound examination.</b> Transvaginal ultrasound examination early in pregnancy is a reasonable alternative to molecular <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> because the testing is not invasive. However, the diagnosis can be made with confidence only at weeks 14-15, and reliability is highly operator dependent.</div></li></ul><p>
|
||
<b>Low-risk pregnancies</b>
|
||
</p><ul><li class="half_rhythm"><div>If one parent is 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> and the other parent does not have an <i>SLC26A2</i> pathogenic variant, routine prenatal care is recommended.</div></li><li class="half_rhythm"><div><b>Routine ultrasound examination.</b> Routine prenatal ultrasound examination may identify very short fetal limbs ± polyhydramnios ± small thorax, raising the possibility of <i>SLC26A2</i>-related atelosteogenesis in a fetus not known to be at risk. Subtle findings on ultrasound examination may be recognizable in the first trimester, but in low-risk pregnancies, the diagnosis of skeletal dysplasia is usually not made until the second trimester.</div></li><li class="half_rhythm"><div><b>Molecular genetic testing.</b> DNA extracted from cells obtained by amniocentesis can theoretically be analyzed to try to make a molecular diagnosis prenatally. However, the differential diagnosis in such a setting is very broad (see <a href="#ao2.Differential_Diagnosis">Differential Diagnosis</a>).</div></li></ul><p>Differences in perspective may exist among medical professionals and within 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="ao2.Resources"><h2 id="_ao2_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>National Library of Medicine Genetics Home Reference</b>
|
||
</div><div>
|
||
<a href="https://ghr.nlm.nih.gov/condition/atelosteogenesistype2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Atelosteogenesis, type 2</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Compassionate Friends</b>
|
||
</div><div>
|
||
<i>Supporting Family After a Child Dies</i>
|
||
</div><div><b>Phone:</b> 877-969-0010</div><div>
|
||
<a href="http://www.compassionatefriends.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">compassionatefriends.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Helping After Neonatal Death (HAND)</b>
|
||
</div><div>PO Box 341</div><div>Los Gatos CA 95031</div><div><b>Phone:</b> 888-908-HAND (4263)</div><div>
|
||
<a href="http://handonline.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.handonline.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="ao2.Molecular_Genetics"><h2 id="_ao2_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="ao2.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Atelosteogenesis Type 2: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1317/table/ao2.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ao2.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_ao2.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_ao2.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_ao2.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_ao2.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_ao2.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_ao2.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_ao2.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_ao2.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_ao2.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_ao2.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="ao2.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="ao2.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Atelosteogenesis Type 2 (<a href="/omim/256050,606718" 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/NBK1317/table/ao2.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ao2.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/256050" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">256050</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ATELOSTEOGENESIS, TYPE II; AO2</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="ao2.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>SLC26A2</i> encodes a sulfate transporter protein [<a class="bk_pop" href="#ao2.REF.h_stbacka.1994.1073">Hästbacka et al 1994</a>]. This protein transports sulfate into chondrocytes to maintain adequate sulfation of proteoglycans. The sulfate transporter protein belongs to the family of sulfate permeases. <i>SLC26A2</i> is expressed in developing cartilage in human fetuses but also in a wide variety of other tissues [<a class="bk_pop" href="#ao2.REF.haila.2001.973">Haila et al 2001</a>].</p><p>Impaired activity of the sulfate transporter in chondrocytes and fibroblasts results in the synthesis of proteoglycans, which are either not sulfated or insufficiently sulfated [<a class="bk_pop" href="#ao2.REF.rossi.1998.361">Rossi et al 1998</a>, <a class="bk_pop" href="#ao2.REF.satoh.1998.12307">Satoh et al 1998</a>], most probably because of intracellular sulfate depletion [<a class="bk_pop" href="#ao2.REF.rossi.1996a.18456">Rossi et al 1996a</a>]. Undersulfation of proteoglycans affects the composition of the extracellular matrix and leads to impairment of proteoglycan deposition, which is necessary for proper enchondral bone formation [<a class="bk_pop" href="#ao2.REF.corsi.2001.1375">Corsi et al 2001</a>, <a class="bk_pop" href="#ao2.REF.forlino.2005.859">Forlino et al 2005</a>].</p><p>Loss of SLC26A2 sulfate transporter activity is associated with several skeletal disorders (see <a href="#ao2.Genetically_Related_Allelic_Disorder">Genetically Related Disorders</a>) [<a class="bk_pop" href="#ao2.REF.rossi.2001.159">Rossi & Superti-Furga 2001</a>].</p><p><b>Mechanism of disease causation</b>. Loss of function. The predicted residual activity of the sulfate transporter correlates with phenotypic severity [<a class="bk_pop" href="#ao2.REF.rossi.1997.741">Rossi et al 1997</a>, <a class="bk_pop" href="#ao2.REF.cai.1998.58">Cai et al 1998</a>, <a class="bk_pop" href="#ao2.REF.rossi.2001.159">Rossi & Superti-Furga 2001</a>, <a class="bk_pop" href="#ao2.REF.karniski.2004.2165">Karniski 2004</a>, <a class="bk_pop" href="#ao2.REF.maeda.2006.1143">Maeda et al 2006</a>].</p><div id="ao2.T.notable_slc26a2_pathogenic_variant" class="table"><h3><span class="label">Table 5. </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/NBK1317/table/ao2.T.notable_slc26a2_pathogenic_variant/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ao2.T.notable_slc26a2_pathogenic_variant_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ao2.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_ao2.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</th><th id="hd_h_ao2.T.notable_slc26a2_pathogenic_variant_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted<br />Protein Change</th><th id="hd_h_ao2.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_ao2.T.notable_slc26a2_pathogenic_variant_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000112.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000112<wbr style="display:inline-block"></wbr>.4</a>
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</td><td headers="hd_h_ao2.T.notable_slc26a2_pathogenic_variant_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.-26+2T>C<br />(IVS1+2T>C <sup>1</sup>)</td><td headers="hd_h_ao2.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_ao2.T.notable_slc26a2_pathogenic_variant_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Founder variant in Finnish population <sup>2</sup></td></tr><tr><td headers="hd_h_ao2.T.notable_slc26a2_pathogenic_variant_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000112.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000112<wbr style="display:inline-block"></wbr>.4</a>
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<br />
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<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>
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</td><td headers="hd_h_ao2.T.notable_slc26a2_pathogenic_variant_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.532C>T</td><td headers="hd_h_ao2.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_ao2.T.notable_slc26a2_pathogenic_variant_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Common <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <sup>2</sup></td></tr><tr><td headers="hd_h_ao2.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</td><td headers="hd_h_ao2.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_ao2.T.notable_slc26a2_pathogenic_variant_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Most common <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> outside of Finland <sup>2</sup></td></tr><tr><td headers="hd_h_ao2.T.notable_slc26a2_pathogenic_variant_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1535C>A</td><td headers="hd_h_ao2.T.notable_slc26a2_pathogenic_variant_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Thr512Lys</td><td headers="hd_h_ao2.T.notable_slc26a2_pathogenic_variant_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Second-most common <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in the Finnish population [<a class="bk_pop" href="#ao2.REF.bonaf_.2008.827">Bonafé et al 2008</a>]</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin">GeneReviews 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="ao2.TF.5.1"><p class="no_margin">Variant designation that does not conform to current naming conventions</p></div></dd><dt>2. </dt><dd><div id="ao2.TF.5.2"><p class="no_margin">See <a href="#ao2.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a> for severity.</p></div></dd></dl></div></div></div></div></div><div id="ao2.Chapter_Notes"><h2 id="_ao2_Chapter_Notes_">Chapter Notes</h2><div id="ao2.Author_History"><h3>Author History</h3><p>Diana Ballhausen, MD; Lausanne University Hospital (2002-2020)<br />Luisa Bonafé, MD, PhD; Lausanne University Hospital (2002-2020)<br />Lauréane Mittaz-Crettol, PhD; Lausanne University Hospital (2002-2020)<br />Andrea Superti-Furga, MD (2002-present)<br />Sheila Unger, MD, FRCPC (2020-present)</p></div><div id="ao2.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>16 March 2023 (sw) Revision: chapter title updated to "<i>SLC26A2</i>-Related Atelosteogenesis"; terminology for <i>SLC26A2</i>-related dysplasias updated to reflect current nosology [<a class="bk_pop" href="#ao2.REF.unger.2023">Unger et al 2023</a>]</div></li><li class="half_rhythm"><div>24 September 2020 (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>1 October 2009 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>28 December 2006 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>21 July 2004 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>30 August 2002 (me) Review posted live</div></li><li class="half_rhythm"><div>1 March 2002 (lb) Original submission</div></li></ul></div></div><div id="ao2.References"><h2 id="_ao2_References_">References</h2><div id="ao2.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.bonaf_.2008.827">Bonafé L, Hästbacka J, de la Chapelle A, Campos-Xavier AB, Chiesa C, Forlino A, Superti-Furga A, Rossi A. A novel mutation in the sulfate transporter gene SLC26A2 (DTDST) specific to the Finnish population causes de la Chapelle dysplasia. <span><span class="ref-journal">J Med Genet. </span>2008;<span class="ref-vol">45</span>:827–31.</span> [<a href="/pmc/articles/PMC4361899/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4361899</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18708426" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18708426</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.cai.1998.58">Cai G, Nakayama M, Hiraki Y, Ozono K. Mutational analysis of the DTDST gene in a fetus with achondrogenesis type 1B. <span><span class="ref-journal">Am J Med Genet. </span>1998;<span class="ref-vol">78</span>:58–60.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9637425" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9637425</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.corsi.2001.1375">Corsi A, Riminucci M, Fisher LW, Bianco P. Achondrogenesis type IB: agenesis of cartilage interterritorial matrix as the link between gene defect and pathological skeletal phenotype. <span><span class="ref-journal">Arch Pathol Lab Med. </span>2001;<span class="ref-vol">125</span>:1375–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11570921" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11570921</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.de_la_chapelle.1972.759">de la Chapelle A, Maroteaux P, Havu N, Granroth G. <span><span class="ref-journal">Arch Fr Pediatr. </span>1972;<span class="ref-vol">29</span>:759–70.</span> [A rare lethal bone dysplasia with recessive autosomic transmission.] [<a href="https://pubmed.ncbi.nlm.nih.gov/4644462" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 4644462</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.dwyer.2010.3043">Dwyer E, Hyland J, Modaff P, Pauli RM. Genotype-phenotype correlation in DTDST dysplasias: Atelosteogenesis type II and diastrophic dysplasia variant in one family. <span><span class="ref-journal">Am J Med Genet A. </span>2010;<span class="ref-vol">152A</span>:3043–50.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21077202" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21077202</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.forlino.2005.859">Forlino A, Piazza R, Tiveron C, Della Torre S, Tatangelo L, Bonafe L, Gualeni B, Romano A, Pecora F, Superti-Furga A, Cetta G, Rossi A. A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype. <span><span class="ref-journal">Hum Mol Genet. </span>2005;<span class="ref-vol">14</span>:859–71.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15703192" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15703192</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.haila.2001.973">Haila S, Hästbacka J, Bohling T, Karjalainen-Lindsberg ML, Kere J, Saarialho-Kere U. SLC26A2 (diastrophic dysplasia sulfate transporter) is expressed in developing and mature cartilage but also in other tissues and cell types. <span><span class="ref-journal">J Histochem Cytochem. </span>2001;<span class="ref-vol">49</span>:973–82.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11457925" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11457925</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.h_stbacka.1994.1073">Hästbacka J, de la Chapelle A, Mahtani MM, Clines G, Reeve-Daly MP, Daly M, Hamilton BA, Kusumi K, Trivedi B, Weaver A, Coloma A, Lovett M, Buckler A, Kaitila I, Lander ES. The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. <span><span class="ref-journal">Cell. </span>1994;<span class="ref-vol">78</span>:1073–87.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7923357" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7923357</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.h_stbacka.1996.255">Hästbacka J, Superti-Furga A, Wilcox WR, Rimoin DL, Cohn DH, Lander ES. Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias. <span><span class="ref-journal">Am J Hum Genet. </span>1996;<span class="ref-vol">58</span>:255–62.</span> [<a href="/pmc/articles/PMC1914552/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1914552</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8571951" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8571951</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.j_nsson.2017.519">Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. <span><span class="ref-journal">Nature. </span>2017;<span class="ref-vol">549</span>:519–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28959963" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28959963</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.karniski.2001.1485">Karniski LP. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype. <span><span class="ref-journal">Hum Mol Genet. </span>2001;<span class="ref-vol">10</span>:1485–90.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11448940" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11448940</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.karniski.2004.2165">Karniski LP. Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells. <span><span class="ref-journal">Hum Mol Genet. </span>2004;<span class="ref-vol">13</span>:2165–71.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15294877" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15294877</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.maeda.2006.1143">Maeda K, Miyamoto Y, Sawai H, Karniski LP, Nakashima E, Nishimura G, Ikegawa S. A compound heterozygote harboring novel and recurrent DTDST mutations with intermediate phenotype between atelosteogenesis type II and diastrophic dysplasia. <span><span class="ref-journal">Am J Med Genet A. </span>2006;<span class="ref-vol">140</span>:1143–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16642506" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16642506</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.maroteaux.1982.15">Maroteaux P, Spranger J, Stanescu V, Le Marec B, Pfeiffer RA, Beighton P, Mattei JF. Atelosteogenesis. <span><span class="ref-journal">Am J Med Genet. </span>1982;<span class="ref-vol">13</span>:15–25.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7137218" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7137218</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.newburyecob.1998.49">Newbury-Ecob R. Atelosteogenesis type 2. <span><span class="ref-journal">J Med Genet. </span>1998;<span class="ref-vol">35</span>:49–53.</span> [<a href="/pmc/articles/PMC1051187/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1051187</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/9475095" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9475095</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.richards.2015.405">Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. <span><span class="ref-journal">Genet Med. </span>2015;<span class="ref-vol">17</span>:405–24.</span> [<a href="/pmc/articles/PMC4544753/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4544753</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25741868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25741868</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.rossi.1996a.18456">Rossi A, Bonaventure J, Delezoide AL, Cetta G, Superti-Furga A. Undersulfation of proteoglycans synthesized by chondrocytes from a patient with achondrogenesis type 1B homozygous for an L483P substitution in the diastrophic dysplasia sulfate transporter. <span><span class="ref-journal">J Biol Chem. </span>1996a;<span class="ref-vol">271</span>:18456–64.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8702490" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8702490</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.rossi.1997.741">Rossi A, Bonaventure J, Delezoide AL, Superti-Furga A, Cetta G. Undersulfation of cartilage proteoglycans ex vivo and increased contribution of amino acid sulfur to sulfation in vitro in McAlister dysplasia/atelosteogenesis type 2. <span><span class="ref-journal">Eur J Biochem. </span>1997;<span class="ref-vol">248</span>:741–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9342225" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9342225</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.rossi.1998.361">Rossi A, Kaitila I, Wilcox WR, Rimoin DL, Steinmann B, Cetta G, Superti-Furga A. Proteoglycan sulfation in cartilage and cell cultures from patients with sulfate transporter chondrodysplasias: relationship to clinical severity and indications on the role of intracellular sulfate production. <span><span class="ref-journal">Matrix Biol. </span>1998;<span class="ref-vol">17</span>:361–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9822202" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9822202</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.rossi.2001.159">Rossi A, Superti-Furga A. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. <span><span class="ref-journal">Hum Mutat. </span>2001;<span class="ref-vol">17</span>:159–71.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11241838" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11241838</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.rossi.1996b.657">Rossi A, van der Harten HJ, Beemer FA, Kleijer WJ, Gitzelmann R, Steinmann B, Superti-Furga A. Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia. <span><span class="ref-journal">Hum Genet. </span>1996b;<span class="ref-vol">98</span>:657–61.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8931695" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8931695</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.satoh.1998.12307">Satoh H, Susaki M, Shukunami C, Iyama K, Negoro T, Hiraki Y. Functional analysis of diastrophic dysplasia sulfate transporter. Its involvement in growth regulation of chondrocytes mediated by sulfated proteoglycans. <span><span class="ref-journal">J Biol Chem. </span>1998;<span class="ref-vol">273</span>:12307–15.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9575183" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9575183</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.sillence.1987.112">Sillence DO, Kozlowski K, Rogers JG, Sprague PL, Cullity GJ, Osborn RA. Atelosteogenesis: evidence for heterogeneity. <span><span class="ref-journal">Pediatr Radiol. </span>1987;<span class="ref-vol">17</span>:112–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3562108" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3562108</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.slaney.1999.835">Slaney SF, Sprigg A, Davies NP, Hall CM. Lethal micromelic short-rib skeletal dysplasia with triangular-shaped humerus. <span><span class="ref-journal">Pediatr Radiol. </span>1999;<span class="ref-vol">29</span>:835–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10552063" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10552063</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.stenson.2020.1197">Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. <span><span class="ref-journal">Hum Genet. </span>2020;<span class="ref-vol">139</span>:1197–207.</span> [<a href="/pmc/articles/PMC7497289/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7497289</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32596782" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32596782</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.supertifurga.2001.282">Superti-Furga A, Bonafe L, Rimoin DL. Molecular-pathogenetic classification of genetic disorders of the skeleton. <span><span class="ref-journal">Am J Med Genet. </span>2001;<span class="ref-vol">106</span>:282–93.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11891680" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11891680</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.supertifurga.1996a.195">Superti-Furga A, Hästbacka J, Rossi A, van der Harten JJ, Wilcox WR, Cohn DH, Rimoin DL, Steinmann B, Lander ES, Gitzelmann R. A family of chondrodysplasias caused by mutations in the diastrophic dysplasia sulfate transporter gene and associated with impaired sulfation of proteoglycans. <span><span class="ref-journal">Ann N Y Acad Sci. </span>1996a;<span class="ref-vol">785</span>:195–201.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8702127" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8702127</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.supertifurga.1996b.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>1996b;<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="ao2.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="ao2.REF.unger.2001.893">Unger S, Le Merrer M, Meinecke P, Chitayat D, Rossi A, Superti-Furga A. New dysplasia or achondrogenesis type 1B? The importance of histology and molecular biology in delineating skeletal dysplasias. <span><span class="ref-journal">Pediatr Radiol. </span>2001;<span class="ref-vol">31</span>:893–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11727031" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11727031</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="ao2.REF.whitley.1986.29">Whitley CB, Burke BA, Granroth G, Gorlin RJ. de la Chapelle dysplasia. <span><span class="ref-journal">Am J Med Genet. </span>1986;<span class="ref-vol">25</span>:29–39.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3799721" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3799721</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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