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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Schmid Metaphyseal Chondrodysplasia" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2024/05/09" /><meta name="citation_author" content="Christopher Mark Richmond" /><meta name="citation_author" content="Ravi Savarirayan" /><meta name="citation_pmid" content="31633898" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK547823/" /><meta name="citation_keywords" content="Metaphyseal Chondrodysplasia Type Schmid (MCDS)" /><meta name="citation_keywords" content="Metaphyseal Dysplasia Schmid (MCS), COL10A1-Related" /><meta name="citation_keywords" content="Metaphyseal Chondrodysplasia Type Schmid (MCDS)" /><meta name="citation_keywords" content="Metaphyseal Dysplasia Schmid (MCS), COL10A1-Related" /><meta name="citation_keywords" content="Collagen alpha-1(X) chain" /><meta name="citation_keywords" content="COL10A1" /><meta name="citation_keywords" content="Schmid Metaphyseal Chondrodysplasia" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Schmid Metaphyseal Chondrodysplasia" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Christopher Mark Richmond" /><meta name="DC.Contributor" content="Ravi Savarirayan" /><meta name="DC.Date" content="2024/05/09" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK547823/" /><meta name="description" content="Schmid metaphyseal chondrodysplasia (SMCD) is characterized by progressive short stature that develops by age two years. The clinical and radiographic features are usually not present at birth, but manifest in early childhood with short limbs, genu varum, and waddling gait. Facial features and head size are normal. Radiographs show metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping); shortening of the tubular bones; widened growth plates; coxa vara; and anterior cupping, sclerosis, and splaying of the ribs. Mild hand involvement often includes shortening of the tubular bones and metaphyseal cupping of the metacarpals and proximal phalanges. Platyspondyly and vertebral end plate irregularities are less common. Hand and vertebral involvement can resolve with age. Early motor milestones may be delayed due to orthopedic complications. Intelligence is normal. Joint pain in the knees and hips is common and may limit physical activity. Adult height is typically more than 3.5 standard deviations below the mean, although a wide spectrum that overlaps normal height has been reported. There are no extraskeletal manifestations." /><meta name="og:title" content="Schmid Metaphyseal Chondrodysplasia" /><meta name="og:type" content="book" /><meta name="og:description" content="Schmid metaphyseal chondrodysplasia (SMCD) is characterized by progressive short stature that develops by age two years. The clinical and radiographic features are usually not present at birth, but manifest in early childhood with short limbs, genu varum, and waddling gait. Facial features and head size are normal. Radiographs show metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping); shortening of the tubular bones; widened growth plates; coxa vara; and anterior cupping, sclerosis, and splaying of the ribs. Mild hand involvement often includes shortening of the tubular bones and metaphyseal cupping of the metacarpals and proximal phalanges. Platyspondyly and vertebral end plate irregularities are less common. Hand and vertebral involvement can resolve with age. Early motor milestones may be delayed due to orthopedic complications. Intelligence is normal. Joint pain in the knees and hips is common and may limit physical activity. Adult height is typically more than 3.5 standard deviations below the mean, although a wide spectrum that overlaps normal height has been reported. 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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="#__NBK547823_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK547823_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/schinzel-giedion/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/spr-def/" 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="_NBK547823_"><span class="title" itemprop="name">Schmid Metaphyseal Chondrodysplasia</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Metaphyseal Chondrodysplasia Type Schmid (MCDS); Metaphyseal Dysplasia Schmid (MCS), <i>COL10A1-</i>Related</div><p class="contrib-group"><span itemprop="author">Christopher Mark Richmond</span>, BBiomedSc, MBBS, FRACP and <span itemprop="author">Ravi Savarirayan</span>, MBBS, MD, FRACP, ARCPA (Hon).</p><a data-jig="ncbitoggler" href="#__NBK547823_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK547823_ai__"><div class="contrib half_rhythm"><span itemprop="author">Christopher Mark Richmond</span>, BBiomedSc, MBBS, FRACP<div class="affiliation small">Genetic Health Queensland<br />Royal Brisbane & Women's Hospital<br />Herston, Queensland, Australia</div><div class="affiliation small">School of Medicine<br />Griffith University<br />Southport, Queensland, Australia<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ua.vog.dlq.htlaeh@dnomhcir.sirhc" class="oemail">ua.vog.dlq.htlaeh@dnomhcir.sirhc</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Ravi Savarirayan</span>, MBBS, MD, FRACP, ARCPA (Hon)<div class="affiliation small">Victorian Clinical Genetics Service<br />Murdoch Children's Research Institute<br />Parkville, Victoria, Australia<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ua.gro.sgcv@nayariravas.ivar" class="oemail">ua.gro.sgcv@nayariravas.ivar</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">October 21, 2019</span>; Last Update: <span itemprop="dateModified">May 9, 2024</span>.</p><p><em>Estimated reading time: 23 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="schmid-mcd.Summary" itemprop="description"><h2 id="_schmid-mcd_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Schmid metaphyseal chondrodysplasia (SMCD) is characterized by progressive short stature that develops by age two years. The clinical and radiographic features are usually not present at birth, but manifest in early childhood with short limbs, genu varum, and waddling gait. Facial features and head size are normal. Radiographs show metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping); shortening of the tubular bones; widened growth plates; coxa vara; and anterior cupping, sclerosis, and splaying of the ribs. Mild hand involvement often includes shortening of the tubular bones and metaphyseal cupping of the metacarpals and proximal phalanges. Platyspondyly and vertebral end plate irregularities are less common. Hand and vertebral involvement can resolve with age. Early motor milestones may be delayed due to orthopedic complications. Intelligence is normal. Joint pain in the knees and hips is common and may limit physical activity. Adult height is typically more than 3.5 standard deviations below the mean, although a wide spectrum that overlaps normal height has been reported. There are no extraskeletal manifestations.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of SMCD is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with characteristic clinical and radiographic features and/or identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>COL10A1</i> 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> Management of orthopedic complications by an orthopedist, physiotherapist, occupational therapist, and pain specialist as indicated; joint-friendly exercise, weight management; mobility device as needed; corrective osteotomy by guided growth surgery or valgus osteotomy may be considered in late childhood / adolescence in those with progressive or symptomatic varus deformity, significant coxa vara, triangular fragment in the interior femoral neck, or poor or deteriorating function; exercise and support from nutritionist to maintain healthy weight; psychosocial support; environmental or occupational modifications as needed for short stature with recommendations from occupational therapist as needed.</p><p><i>Surveillance:</i> Annual growth assessment; clinical evaluation for orthopedic manifestations; psychosocial evaluation.</p><p><i>Agents/circumstances to avoid</i>: Obesity; physical activities that cause excessive joint strain.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>SMCD is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner. Approximately half of individuals diagnosed with SMCD have an affected parent (the <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parent almost always exhibits features of the condition; however, considerable intrafamilial phenotypic variability is observed). Approximately half of individuals diagnosed with SMCD have the disorder as the result of a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
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<i>COL10A1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. Each child of an individual with SMCD has a 50% chance of inheriting the <i>COL10A1</i> pathogenic variant. If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> becomes more complicated because of the risk of inheriting two dominantly inherited bone growth disorders. Once the <i>COL10A1</i> pathogenic variant has been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk for SMCD and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p></div></div><div id="schmid-mcd.Diagnosis"><h2 id="_schmid-mcd_Diagnosis_">Diagnosis</h2><p>No formal diagnostic criteria for Schmid metaphyseal chondrodysplasia (SMCD) have been established.</p><div id="schmid-mcd.Suggestive_Findings"><h3>Suggestive Findings</h3><p>SMCD <b>should be suspected</b> in individuals with the following clinical, laboratory, radiographic, and family history findings.</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Short-limbed short stature by age two years (in >60%)</div></li><li class="half_rhythm"><div>Genu varum (bowed legs) (>60%)</div></li><li class="half_rhythm"><div>Waddling gait (>80%)</div></li><li class="half_rhythm"><div>Lumbar lordosis by age three to five years</div></li><li class="half_rhythm"><div>Normal craniofacies and absence of extraskeletal manifestations</div></li></ul><p><b>Laboratory findings.</b> Normal serum calcium, phosphate, vitamin D, and alkaline phosphatase</p><p><b>Radiographic findings</b> (See <a class="figpopup" href="/books/NBK547823/figure/schmid-mcd.F1/?report=objectonly" target="object" rid-figpopup="figschmidmcdF1" rid-ob="figobschmidmcdF1">Figure 1</a>.)</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figschmidmcdF1" co-legend-rid="figlgndschmidmcdF1"><a href="/books/NBK547823/figure/schmid-mcd.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figschmidmcdF1" rid-ob="figobschmidmcdF1"><img class="small-thumb" src="/books/NBK547823/bin/schmid-mcd-Image001.gif" src-large="/books/NBK547823/bin/schmid-mcd-Image001.jpg" alt="Figure 1. . Standing lower-limb radiograph of a girl age four years with Schmid metaphyseal chondrodysplasia." /></a><div class="icnblk_cntnt" id="figlgndschmidmcdF1"><h4 id="schmid-mcd.F1"><a href="/books/NBK547823/figure/schmid-mcd.F1/?report=objectonly" target="object" rid-ob="figobschmidmcdF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">Standing lower-limb radiograph of a girl age four years with Schmid metaphyseal chondrodysplasia. Note severe bilateral coxa vara with marked metaphyseal widening at proximal femurs, and metaphyseal widening and irregularity of the distal femurs with <a href="/books/NBK547823/figure/schmid-mcd.F1/?report=objectonly" target="object" rid-ob="figobschmidmcdF1">(more...)</a></p></div></div><ul><li class="half_rhythm"><div>Shortening of the tubular bones (>60%)</div></li><li class="half_rhythm"><div>Metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping), especially the proximal and distal femora (~100%)</div></li><li class="half_rhythm"><div>Widening of the growth plates</div></li><li class="half_rhythm"><div>Coxa vara (>80%)</div></li><li class="half_rhythm"><div>Anterior cupping, sclerosis, and splaying of the ribs (>90%)</div></li><li class="half_rhythm"><div>Mild hand involvement including shortening of the tubular bones and metaphyseal cupping of the metacarpals and proximal phalanges (~50%). Radiographic phalangeal and metacarpal findings may resolve with age.</div></li><li class="half_rhythm"><div>Vertebral involvement including platyspondyly and end plate irregularities (~10%)</div></li></ul><p><b>Family history</b> is consistent with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis, as approximately half of individuals have a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, and in those with an inherited pathogenic variant, considerable <a class="def" href="/books/n/gene/glossary/def-item/intrafamilial-variability/">intrafamilial variability</a> can be present.</p></div><div id="schmid-mcd.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of SMCD is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with characteristic clinical and radiographic features (see <a href="#schmid-mcd.Suggestive_Findings">Suggestive Findings</a>) and/or a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variant in <i>COL10A1</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK547823/table/schmid-mcd.T.molecular_genetic_testing_u/?report=objectonly" target="object" rid-ob="figobschmidmcdTmoleculargenetictestingu">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "<a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bk_pop" href="#schmid-mcd.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>COL10A1</i> variant of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> 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>). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see <a href="#schmid-mcd.Option_1">Option 1</a>), whereas comprehensive genomic testing does not (see <a href="#schmid-mcd.Option_2">Option 2</a>).</p><div id="schmid-mcd.Option_1"><h4>Option 1</h4><p>When the phenotypic and radiographic findings suggest a diagnosis of SMCD, <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> Perform <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> of <i>COL10A1</i> to detect <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 and small intragenic deletions/insertions; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-gene deletions/duplications are not detected. Note: All pathogenic variants reported to date are missense or truncating variants (including small intragenic deletions) in <i>COL10A1</i>; thus, testing for larger deletions or duplications is expected to be of low yield.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>COL10A1</i> and other genes of interest (see <a href="#schmid-mcd.Differential_Diagnosis">Differential Diagnosis</a>) may 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> or genome 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="schmid-mcd.Option_2"><h4>Option 2</h4><p>When the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> overlaps other inherited disorders characterized by metaphyseal dysplasia, <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> is the best option. <b>Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="schmid-mcd.T.molecular_genetic_testing_u" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Schmid Metaphyseal Chondrodysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547823/table/schmid-mcd.T.molecular_genetic_testing_u/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__schmid-mcd.T.molecular_genetic_testing_u_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_schmid-mcd.T.molecular_genetic_testing_u_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_schmid-mcd.T.molecular_genetic_testing_u_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_schmid-mcd.T.molecular_genetic_testing_u_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_schmid-mcd.T.molecular_genetic_testing_u_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL10A1</i>
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</td><td headers="hd_h_schmid-mcd.T.molecular_genetic_testing_u_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_schmid-mcd.T.molecular_genetic_testing_u_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~100% <sup>4</sup></td></tr><tr><td headers="hd_h_schmid-mcd.T.molecular_genetic_testing_u_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_schmid-mcd.T.molecular_genetic_testing_u_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported <sup>6</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="schmid-mcd.TF.1.1"><p class="no_margin">See <a href="/books/NBK547823/#schmid-mcd.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="schmid-mcd.TF.1.2"><p class="no_margin">See <a href="#schmid-mcd.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="schmid-mcd.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 <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 and small intragenic deletions/insertions; 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="schmid-mcd.TF.1.4"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bk_pop" href="#schmid-mcd.REF.stenson.2020.1197">Stenson et al 2020</a>] and ClinVar [<a class="bk_pop" href="#schmid-mcd.REF.landrum.2014.d980">Landrum et al 2014</a>]. All reported SMCD-related <i>COL10A1</i> pathogenic varinats were <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, frameshift, or <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a> variants or small intragenic deletions, duplications, or <a class="def" href="/books/n/gene/glossary/def-item/insertion/">insertion</a>-deletions.</p></div></dd><dt>5. </dt><dd><div id="schmid-mcd.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><dt>6. </dt><dd><div id="schmid-mcd.TF.1.6"><p class="no_margin">Review of all published reports, ClinVar [<a class="bk_pop" href="#schmid-mcd.REF.landrum.2014.d980">Landrum et al 2014</a>], and HGMD [<a class="bk_pop" href="#schmid-mcd.REF.stenson.2020.1197">Stenson et al 2020</a>] revealed no reports of large deletions or duplications causing SMCD to date [C Richmond, personal observation].</p></div></dd></dl></div></div></div></div></div></div><div id="schmid-mcd.Clinical_Characteristics"><h2 id="_schmid-mcd_Clinical_Characteristics_">Clinical Characteristics</h2><div id="schmid-mcd.Clinical_Description"><h3>Clinical Description</h3><p>Schmid metaphyseal chondrodysplasia (SMCD) is typically diagnosed in early childhood and is the most common and least severe metaphyseal chondrodysplasia [<a class="bk_pop" href="#schmid-mcd.REF.al_kaissi.2018.241">Al Kaissi et al 2018</a>]. It results from disrupted calcification of metaphyseal cartilage and consequent restricted longitudinal growth of bones with preservation of the epiphyses. The clinical and radiographic features are usually not present at birth, but manifest in early childhood with limb shortening, genu varum, and a waddling gait [<a class="bk_pop" href="#schmid-mcd.REF.bateman.2005.525">Bateman et al 2005</a>]. The pattern of radiographic features is generally similar across individuals with SMCD, but clinical severity varies considerably [<a class="bk_pop" href="#schmid-mcd.REF.m_kitie.2005.241">Mäkitie et al 2005</a>]. There are no extraskeletal manifestations.</p><p>A comprehensive review of the published reports and clinical databases identified at least 150 published unrelated individuals with SMCD and a confirmed <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>COL10A1</i>. The following description of the phenotypic features associated with this condition is based on these reports and author observations in a multidisciplinary skeletal dysplasia clinic.</p><div id="schmid-mcd.T.schmid_metaphyseal_chondrod" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Schmid Metaphyseal Chondrodysplasia: Frequency of Select Clinical and Radiographic Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547823/table/schmid-mcd.T.schmid_metaphyseal_chondrod/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__schmid-mcd.T.schmid_metaphyseal_chondrod_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Features</th><th id="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons<br />w/Feature</th><th id="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_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_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Clinical</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Waddling gait</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>80%</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Genu varum</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>80% <sup>1</sup></td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Genu valgum less commonly reported</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Short stature</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>60%</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Typically apparent by age 2 yrs</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Lumbar lordosis</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>60% <sup>1</sup></td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Scoliosis less commonly reported</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1" rowspan="6" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Radiographic</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Metaphyseal dysplasia of proximal/distal femora, proximal tibiae</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~100%</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Splaying, flaring, widening, cupping</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Cupped &/or sclerotic anterior rib ends</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>90%</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Coxa vara</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">50%-80% <sup>1, 2</sup></td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Angle head & shaft of femur <120 degrees</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Short long bones</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>60%</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Typically apparent by age 2 yrs</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Metaphyseal dysplasia of hands</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">33%-47% <sup>1, 3</sup></td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Metaphyseal cupping, short proximal phalanges/metacarpals</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Vertebral dysplasia</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">9% <sup>2</sup></td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Usually mild; platyspondyly, anterior rounding, indentations, & posterior wedging</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="schmid-mcd.TF.2.1"><p class="no_margin">
|
||
<a class="bk_pop" href="#schmid-mcd.REF.t_ys_z.2023.116614">Tüysüz et al [2023)</a>
|
||
</p></div></dd><dt>2. </dt><dd><div id="schmid-mcd.TF.2.2"><p class="no_margin">
|
||
<a class="bk_pop" href="#schmid-mcd.REF.savarirayan.2000.460">Savarirayan et al [2000]</a>
|
||
</p></div></dd><dt>3. </dt><dd><div id="schmid-mcd.TF.2.3"><p class="no_margin">
|
||
<a class="bk_pop" href="#schmid-mcd.REF.elliott.2005.191">Elliott et al [2005]</a>
|
||
</p></div></dd></dl></div></div></div><p><b>Growth.</b> Most neonates with SMCD have normal growth parameters. Progressive growth failure typically begins in the second year of life, with individuals coming to medical attention after age two years with short-limbed short stature and bowed legs [<a class="bk_pop" href="#schmid-mcd.REF.m_kitie.2005.241">Mäkitie et al 2005</a>]. Adult height is typically more than 3.5 standard deviations (SD) below the mean, although a wide spectrum that overlaps normal height has been reported [<a class="bk_pop" href="#schmid-mcd.REF.m_kitie.2005.241">Mäkitie et al 2005</a>]. No standardized growth curves for SMCD are available.</p><p><b>Musculoskeletal.</b> Most individuals with SMCD have genu varum (outward bowing at the knees), although valgus deformity has been reported. Waddling gait due to coxa vara is common by age two years and may require surgical correction. Joint pain in the knees and hips is common in children and adults with SMCD and may limit physical activity. Chronic joint pain may develop and limit mobility for some individuals. Lumbar lordosis is common, with typical onset by age three to five years. Scoliosis is less commonly reported [<a class="bk_pop" href="#schmid-mcd.REF.park.2015.175">Park et al 2015</a>, <a class="bk_pop" href="#schmid-mcd.REF.cammaratascalisi.2019.167">Cammarata-Scalisi et al 2019</a>].</p><p><b>Radiographic findings.</b> The metaphyses of the long bones become flared or widened. The proximal and distal femoral and proximal tibial metaphyses are consistently affected (ragged, cupped, sclerotic, or splayed) with widening of the growth plates. Enlarged capital femoral epiphyses are commonly reported and typically resolve between age 11 and 14 years [<a class="bk_pop" href="#schmid-mcd.REF.t_ys_z.2023.116614">Tüysüz et al 2023</a>]. Coxa vara (reduced angle to <120 degrees between the head and the shaft of the femur) is seen in a majority of individuals and is more prominent after age five years [<a class="bk_pop" href="#schmid-mcd.REF.t_ys_z.2023.116614">Tüysüz et al 2023</a>]. Coxa vara distinguishes SMCD from other forms of metaphyseal chondrodysplasia. Tibial and femoral bowing is typical. Metaphyseal irregularities of the distal ulnae and radii, and proximal and distal humeral metaphyses are less commonly reported [<a class="bk_pop" href="#schmid-mcd.REF.lachman.1988.93">Lachman et al 1988</a>, <a class="bk_pop" href="#schmid-mcd.REF.al_kaissi.2018.241">Al Kaissi et al 2018</a>, <a class="bk_pop" href="#schmid-mcd.REF.de_fran_a.2020.2554">de França et al 2020</a>]. The anterior rib ends are often cupped or sclerotic [<a class="bk_pop" href="#schmid-mcd.REF.bateman.2005.525">Bateman et al 2005</a>].</p><p>Hand involvement is present in fewer than half of individuals and is usually mild. Metaphyseal cupping of the distal metacarpals and proximal phalanges and shortening of the phalanges may be seen and are more pronounced in the fifth ray. Hand features may become less apparent with age [<a class="bk_pop" href="#schmid-mcd.REF.elliott.2005.191">Elliott et al 2005</a>].</p><p>Vertebral involvement is less common and, when present, is usually mild. Reported findings include platyspondyly and vertebral end plate anomalies (e.g., rounding of the anterior aspects of the vertebral bodies, superior and inferior indentations of the vertebral bodies, posterior wedging of the vertebrae) [<a class="bk_pop" href="#schmid-mcd.REF.hasegawa.1994.194">Hasegawa et al 1994</a>, <a class="bk_pop" href="#schmid-mcd.REF.savarirayan.2000.460">Savarirayan et al 2000</a>]. Vertebral changes may become less apparent with age.</p><p><b>Obesity.</b> Limited mobility due to chronic joint pain may contribute to the development of obesity and associated comorbidities.</p><p><b>Craniofacial.</b> The craniofacial bones and facial appearance are normal [<a class="bk_pop" href="#schmid-mcd.REF.bateman.2005.525">Bateman et al 2005</a>].</p><p><b>Neurodevelopment.</b> Intelligence is normal. Attainment of early motor milestones is usually preserved in infancy; however, mild gross and fine motor delays may accompany orthopedic complications in early childhood.</p><p><b>Other.</b> Hypothyroidism, growth hormone deficiency, celiac disease, hypospadias, and mild microcephaly have been rarely reported [<a class="bk_pop" href="#schmid-mcd.REF.de_fran_a.2020.2554">de França et al 2020</a>, <a class="bk_pop" href="#schmid-mcd.REF.chreitah.2023.4045">Chreitah et al 2023</a>]; however, these may represent coincidental occurrences and may be unrelated to SMCD.</p><p><b>Homozygotes.</b> Biallelic pathogenic variants in <i>COL10A1</i> have been associated with a more severe <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> [<a class="bk_pop" href="#schmid-mcd.REF.ain.2018.403">Ain et al 2018</a>, <a class="bk_pop" href="#schmid-mcd.REF.t_ys_z.2023.116614">Tüysüz et al 2023</a>] and in some instances embryonic lethality [<a class="bk_pop" href="#schmid-mcd.REF.zhang.2018.83">Zhang et al 2018</a>].</p></div><div id="schmid-mcd.GenotypePhenotype_Correlation"><h3>Genotype-Phenotype Correlations</h3><p>A more severe <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> has been observed in individuals with <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> pathogenic variants in the signal peptide <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a> at the N-terminal end of the protein and in the NC1 domain compared to truncating pathogenic variants [<a class="bk_pop" href="#schmid-mcd.REF.t_ys_z.2023.116614">Tüysüz et al 2023</a>]; however, no established <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a> have been identified.</p></div><div id="schmid-mcd.Penetrance"><h3>Penetrance</h3><p>Penetrance approaches 100%; however, there is wide inter- and intrafamilial phenotypic variation [<a class="bk_pop" href="#schmid-mcd.REF.kong.2019.200">Kong et al 2019</a>]. Males and females are equally represented in published reports. Normal stature has been reported, but radiographic features are usually still present. Age-dependent phenotypic manifestations are suggested by apparent reduction in hand and spine features [<a class="bk_pop" href="#schmid-mcd.REF.savarirayan.2000.460">Savarirayan et al 2000</a>, <a class="bk_pop" href="#schmid-mcd.REF.elliott.2005.191">Elliott et al 2005</a>] and resolution of enlarged capital femoral epiphyses with age [<a class="bk_pop" href="#schmid-mcd.REF.t_ys_z.2023.116614">Tüysüz et al 2023</a>].</p></div><div id="schmid-mcd.Nomenclature"><h3>Nomenclature</h3><p>In the 2023 revision of the Nosology of Genetic Skeletal Disorders [<a class="bk_pop" href="#schmid-mcd.REF.unger.2023.1164">Unger et al 2023</a>], SMCD is referred to as metaphyseal dysplasia Schmid (MCS), <i>COL10A1-</i>related.</p><p><b>Spondylometaphyseal dysplasia (SMD) Japanese type.</b> Affected individuals from one reported family had bowed legs, short stature, coxa vara, metaphyseal changes, and mild platyspondyly [<a class="bk_pop" href="#schmid-mcd.REF.hasegawa.1994.194">Hasegawa et al 1994</a>]. A <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>COL10A1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> was identified in affected individuals [<a class="bk_pop" href="#schmid-mcd.REF.ikegawa.1998.1659">Ikegawa et al 1998</a>]. Expansion of the clinical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of SMCD to include spinal changes led to the conclusion that SMD Japanese type and SMCD are the same disorder [<a class="bk_pop" href="#schmid-mcd.REF.savarirayan.2000.460">Savarirayan et al 2000</a>].</p></div><div id="schmid-mcd.Prevalence"><h3>Prevalence</h3><p>The exact prevalence of SMCD is unknown. Incidence has historically been estimated at between three and six individuals per million [<a class="bk_pop" href="#schmid-mcd.REF.gokhale.2005.1252">Gokhale & Mehta 2005</a>]; however, these figures may be an underestimate [<a class="bk_pop" href="#schmid-mcd.REF.al_kaissi.2018.241">Al Kaissi et al 2018</a>]. More than 150 unrelated individuals with SMCD and a confirmed <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>COL10A1</i> have been reported.</p></div></div><div id="schmid-mcd.Genetically_Related_Allelic_D"><h2 id="_schmid-mcd_Genetically_Related_Allelic_D_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than SMCD are known to be associated with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> pathogenic variants in <i>COL10A1</i>.</p></div><div id="schmid-mcd.Differential_Diagnosis"><h2 id="_schmid-mcd_Differential_Diagnosis_">Differential Diagnosis</h2><div id="schmid-mcd.T.genes_of_interest_in_the_di" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of Schmid Metaphyseal Chondrodysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547823/table/schmid-mcd.T.genes_of_interest_in_the_di/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__schmid-mcd.T.genes_of_interest_in_the_di_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_2" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Clinical Features of Disorder</th></tr><tr><th headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4" id="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/SMCD</th><th headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4" id="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from SMCD</th></tr></thead><tbody><tr><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>DNAJC21</i>
|
||
<br />
|
||
<i>EFL1</i>
|
||
<br />
|
||
<i>SBDS</i>
|
||
<br />
|
||
<i>SRP54</i>
|
||
</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/sds/">Shwachman-Diamond syndrome</a>
|
||
</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD<br />AR <sup>1</sup></td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4 hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Short stature</div></li><li class="half_rhythm"><div>Metaphyseal widening & irregularities</div></li></ul>
|
||
</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4 hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Skeletal changes usually milder</div></li><li class="half_rhythm"><div>Metaphyseal changes usually greatest in ribs</div></li><li class="half_rhythm"><div>Extraskeletal features: exocrine pancreatic insufficiency, neutropenia, ↑ infections, anemia</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>MMP9</i>
|
||
</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Metaphyseal anadysplasia, <i>MMP9-</i>related <sup>2</sup> (OMIM <a href="https://omim.org/entry/613073" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613073</a>)</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4 hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Genu varum</div></li><li class="half_rhythm"><div>Metaphyseal dysplasia</div></li><li class="half_rhythm"><div>Short limbs, limb disproportion</div></li></ul>
|
||
</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4 hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Apparent in 1st few mos of life but resolves spontaneously w/age</div></li><li class="half_rhythm"><div>Epiphyseal dysplasia</div></li><li class="half_rhythm"><div>Generalized osteopenia</div></li><li class="half_rhythm"><div>Normal stature by adolescence</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>MMP13</i>
|
||
</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Metaphyseal anadysplasia, <i>MMP13-</i>related <sup>2</sup> (OMIM <a href="https://omim.org/entry/602111" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">602111</a>)</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4 hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Genu varum</div></li><li class="half_rhythm"><div>Short limbs, limb disproportion</div></li><li class="half_rhythm"><div>Severe metaphyseal changes in long bones (irregularities, widening, marginal blurring)</div></li></ul>
|
||
</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4 hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Apparent in 1st few mos of life but resolves spontaneously w/age</div></li><li class="half_rhythm"><div>Epiphyseal dysplasia</div></li><li class="half_rhythm"><div>Generalized osteopenia</div></li><li class="half_rhythm"><div>Normal stature by adolescence</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Metaphyseal dysplasia Spahr, <i>MMP13-</i>related <sup>2</sup> (OMIM <a href="https://omim.org/entry/250400" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">250400</a>)</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4 hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Genu varum</div></li><li class="half_rhythm"><div>Metaphyseal dysplasia</div></li><li class="half_rhythm"><div>Moderate short stature</div></li></ul>
|
||
</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4 hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Abnormal ribs</div></li><li class="half_rhythm"><div>Carpal bone hypoplasia</div></li><li class="half_rhythm"><div>Iliac crest irregularity in childhood</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PTH1R</i><br />(<i>PTHR1</i>)</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Metaphyseal dysplasia, Jansen type, <i>PTH1R-</i>related <sup>2</sup> (OMIM <a href="https://omim.org/entry/156400" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">156400</a>)</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4 hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Genu varum</div></li><li class="half_rhythm"><div>Short stature</div></li><li class="half_rhythm"><div>Metaphyseal dysplasia</div></li><li class="half_rhythm"><div>Waddling gait</div></li></ul>
|
||
</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4 hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>± <a class="def" href="/books/n/gene/glossary/def-item/dysmorphic/">dysmorphic</a> features: prominent superciliary arches, exophthalmos</div></li><li class="half_rhythm"><div>Hypercalcemia, hypercalciuria</div></li><li class="half_rhythm"><div>Metaphyseal changes more severe</div></li><li class="half_rhythm"><div>Sclerosis of skull in late adulthood</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>RMRP</i>
|
||
</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cartilage-hair hypoplasia (CHH; metaphyseal dysplasia, McKusick type), <i>RMRP-</i>related <sup>2</sup> (OMIM <a href="https://omim.org/entry/250250" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">250250</a>)</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4 hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Genu varum</div></li><li class="half_rhythm"><div>Short-limbed short stature</div></li><li class="half_rhythm"><div>Variable metaphyseal dysplasia</div></li></ul>
|
||
</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4 hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Coxa vara rarely seen</div></li><li class="half_rhythm"><div>Extraskeletal features: fine/sparse hair, immune dysfunction, transient macrocytic anemia, Hirschsprung disease</div></li><li class="half_rhythm"><div>Ligament laxity</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>RUNX2</i>
|
||
</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Metaphyseal dysplasia w/maxillary hypoplasia, <i>RUNX2-</i>related <sup>2</sup> (OMIM <a href="https://omim.org/entry/156510" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">156510</a>)</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4 hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Metaphyseal flaring of long bones</div></li><li class="half_rhythm"><div>Short stature</div></li></ul>
|
||
</td><td headers="hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_1_4 hd_h_schmid-mcd.T.genes_of_interest_in_the_di_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Broad clavicles</div></li><li class="half_rhythm"><div>Maxillary hypoplasia</div></li><li class="half_rhythm"><div>Variable brachydactyly</div></li></ul>
|
||
</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>; AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; SMCD = Schmid metaphyseal chondrodysplasia; 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="schmid-mcd.TF.3.1"><p class="no_margin">Shwachman-Diamond syndrome (SDS) caused by pathogenic variants in <i>DNAJC21</i>, <i>EFL1</i>, or <i>SBDS</i> is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner. SDS caused by pathogenic variants in <i>SRP54</i> is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p></div></dd><dt>2. </dt><dd><div id="schmid-mcd.TF.3.2"><p class="no_margin">Terminology per 2023 revision of the Nosology of Genetic Skeletal Disorders [<a class="bk_pop" href="#schmid-mcd.REF.unger.2023.1164">Unger et al 2023</a>]</p></div></dd></dl></div></div></div><p><b>Rickets.</b> Many individuals with SMCD receive an initial diagnosis of vitamin D-deficient rickets, due to a similar age of onset and overlapping clinical features, including genu varum or valgum, waddling gait, and nonspecific metaphyseal and epiphyseal irregularities. In rickets, coxa vara is usually absent and the distal femoral metaphyses are typically more affected. SMCD is distinguished from vitamin D-deficient rickets and metabolic bone disease on the basis of nutritional history and biochemical investigations (see <a href="/books/NBK547823/table/schmid-mcd.T.biochemical_findings_in_sch/?report=objectonly" target="object" rid-ob="figobschmidmcdTbiochemicalfindingsinsch">Table 4</a>).</p><div id="schmid-mcd.T.biochemical_findings_in_sch" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Biochemical Findings in Schmid Metaphyseal Chondrodysplasia Compared with Vitamin D-Deficient Rickets and Metabolic Bone Diseases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547823/table/schmid-mcd.T.biochemical_findings_in_sch/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__schmid-mcd.T.biochemical_findings_in_sch_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Serum Calcium</th><th id="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Serum Phosphate</th><th id="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Serum PTH</th><th id="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Serum 25-OH<br />Cholecalciferol</th><th id="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_6" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Serum 1,25(OH)<sub>2</sub><br />Cholecalciferol</th></tr></thead><tbody><tr><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>SMCD</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal</td></tr><tr><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Vitamin D-deficient rickets</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↓</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↓</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal or ↑</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↓</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal or ↑</td></tr><tr><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hypophosphatemic rickets</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↓ <sup>1</sup></td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal or ↑</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal or ↓</td></tr><tr><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Vitamin D-dependent rickets <sup>2</sup></b>
|
||
</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal or ↓</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↓</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal or ↑</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal</td><td headers="hd_h_schmid-mcd.T.biochemical_findings_in_sch_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↓</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">SMCD = Schmid metaphyseal chondrodysplasia; PTH = parathyroid stimulating hormone</p></div></dd><dt>1. </dt><dd><div id="schmid-mcd.TF.4.1"><p class="no_margin">Urinary phosphates may be increased.</p></div></dd><dt>2. </dt><dd><div id="schmid-mcd.TF.4.2"><p class="no_margin">Caused by deficient 25-OHD-1-α-hydroxylase activity</p></div></dd></dl></div></div></div></div><div id="schmid-mcd.Management"><h2 id="_schmid-mcd_Management_">Management</h2><p>No clinical practice management guidelines for Schmid metaphyseal chondrodysplasia (SMCD) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder. Management should emphasize multidisciplinary care and a considered approach to surgical intervention when appropriate.</p><div id="schmid-mcd.Evaluations_Following_Initial"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with SMCD, the evaluations summarized in <a href="/books/NBK547823/table/schmid-mcd.T.schmid_metaphyseal_chondrod_1/?report=objectonly" target="object" rid-ob="figobschmidmcdTschmidmetaphysealchondrod1">Table 5</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="schmid-mcd.T.schmid_metaphyseal_chondrod_1" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Schmid Metaphyseal Chondrodysplasia: Recommended Evaluations Following Initial Diagnosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547823/table/schmid-mcd.T.schmid_metaphyseal_chondrod_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__schmid-mcd.T.schmid_metaphyseal_chondrod_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_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_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Constitutional</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Growth assessment</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to nutritionist if needed for weight mgmt.</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Complete radiographic skeletal survey incl lateral spine radiographs</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess extent of skeletal malformations & evaluate for lumbar lordosis & scoliosis</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Orthopedic consultation</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval by specialist experienced in skeletal dysplasia if possible</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Functional & pain assessment</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider:
|
||
<ul><li class="half_rhythm"><div>Qualification of functional limitations / activities of daily living;</div></li><li class="half_rhythm"><div>Referral to PT &/or OT.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Psychosocial</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assessment for adaptive needs due to short stature</div></li><li class="half_rhythm"><div>Referral to support resources</div></li></ul>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Environmental modifications to accommodate short stature may be needed, such as:
|
||
<ul><li class="half_rhythm"><div>In school: step stools, lowered light switches, appropriate-height toilets or other means to make them accessible, lower desks, & foot support in front of chairs. All children need to be able to independently escape the building in an emergency.</div></li><li class="half_rhythm"><div>In adults: pedal extenders for driving, workplace modification (e.g., lower desks, smaller keyboards, step stools, & toilet access)</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic counseling</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_1_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_schmid-mcd.T.schmid_metaphyseal_chondrod_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To obtain a <a class="def" href="/books/n/gene/glossary/def-item/pedigree/">pedigree</a> & inform affected persons & their families re nature, MOI, & implications of SMCD 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>; OT = occupational therapist; PT = physical therapist; SMCD = Schmid metaphyseal chondrodysplasia</p></div></dd><dt>1. </dt><dd><div id="schmid-mcd.TF.5.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="schmid-mcd.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see <a href="/books/NBK547823/table/schmid-mcd.T.schmid_metaphyseal_chondrod_2/?report=objectonly" target="object" rid-ob="figobschmidmcdTschmidmetaphysealchondrod2">Table 6</a>).</p><div id="schmid-mcd.T.schmid_metaphyseal_chondrod_2" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Schmid Metaphyseal Chondrodysplasia: Treatment of Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547823/table/schmid-mcd.T.schmid_metaphyseal_chondrod_2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__schmid-mcd.T.schmid_metaphyseal_chondrod_2_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/<br />Concern</th><th id="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Joint pain,</b>
|
||
<br />
|
||
<b>functional</b>
|
||
<br />
|
||
<b>limitation</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Referral to orthopedic surgeon for eval</div></li><li class="half_rhythm"><div>Referral to PT</div></li><li class="half_rhythm"><div>Referral to OT if indicated</div></li><li class="half_rhythm"><div>Analgesics, pain specialist referral if appropriate</div></li></ul>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Advice on joint-friendly activities (e.g., swimming, cycling)</div></li><li class="half_rhythm"><div>Counseling re weight optimization where appropriate</div></li><li class="half_rhythm"><div>Consider need for a mobility device.</div></li><li class="half_rhythm"><div>Avoidance of physical activities that strain joints, when possible</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Lower-limb</b>
|
||
<br />
|
||
<b>malalignment,</b>
|
||
<br />
|
||
<b>coxa vara,</b>
|
||
<br />
|
||
<b>varus</b>
|
||
<br />
|
||
<b>deformity <sup>1</sup></b>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Referral to orthopedic surgeon</div></li><li class="half_rhythm"><div>Guided growth surgery</div></li><li class="half_rhythm"><div>Valgus osteotomy</div></li></ul>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Varus deformity alone, w/o symptoms, does not usually warrant surgical correction. Corrective osteotomy may be considered in late childhood / adolescence w/indications of:
|
||
<ul><li class="half_rhythm"><div>Progressive or symptomatic varus deformity (e.g., varus angulation >120 degrees) or significant coxa vara;</div></li><li class="half_rhythm"><div>Triangular fragment in the inferior femoral neck;</div></li><li class="half_rhythm"><div>Poor or deteriorating function.</div></li></ul>
|
||
Surgical options incl:
|
||
<ul><li class="half_rhythm"><div>Guided growth using 8-plates, hemiepiphysiodesis, stapling;</div></li><li class="half_rhythm"><div>Valgus-producing & derotational osteotomies.</div></li></ul>
|
||
No controlled studies comparing outcomes of treatment options have been completed.</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Obesity</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to nutritionist</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Anticipatory guidance for maintenance of healthy weight</div></li><li class="half_rhythm"><div>Advice re regular low-impact exercise</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Psychosocial</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Referral to support resources</div></li><li class="half_rhythm"><div>Referral to psychologist</div></li></ul>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Short stature</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Environmental or occupational modifications may be needed (e.g., step stools, lower desks).</div></li><li class="half_rhythm"><div>Consultation w/OT may be beneficial.</div></li></ul>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evidence for treatment w/recombinant growth hormone has not been evaluated in children w/SMCD.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">OT = occupational therapist; PT = physical therapist; SMCD = Schmid metaphyseal chondrodysplasia</p></div></dd><dt>1. </dt><dd><div id="schmid-mcd.TF.6.1"><p class="no_margin">Adapted from <a class="bk_pop" href="#schmid-mcd.REF.al_kaissi.2018.241">Al Kaissi et al [2018]</a></p></div></dd></dl></div></div></div></div><div id="schmid-mcd.Surveillance"><h3>Surveillance</h3><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in <a href="/books/NBK547823/table/schmid-mcd.T.schmid_metaphyseal_chondrod_3/?report=objectonly" target="object" rid-ob="figobschmidmcdTschmidmetaphysealchondrod3">Table 7</a> are recommended.</p><div id="schmid-mcd.T.schmid_metaphyseal_chondrod_3" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Schmid Metaphyseal Chondrodysplasia: Recommended Surveillance</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547823/table/schmid-mcd.T.schmid_metaphyseal_chondrod_3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__schmid-mcd.T.schmid_metaphyseal_chondrod_3_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_3_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_3_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_3_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_3_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Constitutional</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of linear growth, proportions, & weight</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_3_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Annually or as indicated</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_3_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_schmid-mcd.T.schmid_metaphyseal_chondrod_3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Clinical exam</div></li><li class="half_rhythm"><div>Referral for orthopedic assessment if indicated</div></li><li class="half_rhythm"><div>Referral to PT if indicated</div></li><li class="half_rhythm"><div>Monitoring for surgical complications if indicated</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_3_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Psychosocial</b>
|
||
<br />
|
||
<b>concerns</b>
|
||
</td><td headers="hd_h_schmid-mcd.T.schmid_metaphyseal_chondrod_3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Specific attention to mood, affect, & psychosocial stressors when taking history & during physical exam</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">PT = physical therapist</p></div></dd></dl></div></div></div></div><div id="schmid-mcd.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Individuals with SMCD should maintain an appropriate weight for height, as obesity increases stress on the joints and may exacerbate joint pain and worsen the impact of genu varum and waddling gait on mobility. Education should include advice regarding weight loss (when appropriate), maintenance of a healthy diet, and regular low-impact exercise.</p><p>High-impact exercise or exercise that causes repetitive strain on affected joints should be avoided in favor of joint-friendly low-impact activities, including swimming and biking.</p></div><div id="schmid-mcd.Evaluation_of_Relatives_at_Ri"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#schmid-mcd.Related_Genetic_Counseling_Is">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="schmid-mcd.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Carbamazepine is an FDA-approved medication for use in epilepsy and bipolar affective disorder. Its additional action as a stimulator of autophagy and proteasomal degradation pathways have led to its repurposing as a candidate therapy for conditions caused by retention of misfolded mutated structural proteins, such as SMCD [<a class="bk_pop" href="#schmid-mcd.REF.hidvegi.2010.229">Hidvegi et al 2010</a>]. In preclinical studies, carbamazepine alleviates endoplasmic reticulum stress (unfolded protein response) caused by the presence of structurally abnormal and misfolded type X collagen in prehypertrophic chondrocytes, restoring growth and improving coxa vara in a validated mouse model of SMCD [<a class="bk_pop" href="#schmid-mcd.REF.hidvegi.2010.229">Hidvegi et al 2010</a>]. Carbamazepine received orphan drug designation by the European Commission for the treatment of SMCD in September 2016 (EMA/OD/148/16 and EMA/COMP/513538/2016).</p><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.</p></div></div><div id="schmid-mcd.Genetic_Counseling"><h2 id="_schmid-mcd_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="schmid-mcd.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Schmid metaphyseal chondrodysplasia (SMCD) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p></div><div id="schmid-mcd.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>Approximately half (45%-57%) of individuals diagnosed with SMCD inherited the condition from a parent. The <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parent almost always exhibits features of the condition; however, considerable intrafamilial phenotypic variability is observed in SMCD, and the heterozygous parent may only have mild features [<a class="bk_pop" href="#schmid-mcd.REF.wu.2021.e1668">Wu et al 2021</a>, <a class="bk_pop" href="#schmid-mcd.REF.t_ys_z.2023.116614">Tüysüz et al 2023</a>].</div></li><li class="half_rhythm"><div>Approximately half (43%-55%) of individuals diagnosed with SMCD represent <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases (i.e., a single occurrence in a family) and have the disorder as the result of a <i>de novo COL10A1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> appears to be the only affected family member, recommendations for the parents of the proband include physical examination and measurement of proportions. Recommendations may also include radiographs (as isolated asymptomatic individuals have been reported with radiographic changes only) and, if a molecular diagnosis has been established in the proband, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</div></li><li class="half_rhythm"><div>If a molecular diagnosis has been established in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>, the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> inherited a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> from a parent with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> (or somatic and germline) <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a>. Note: Testing of parental leukocyte DNA may not detect all instances of <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a> and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.</div></li></ul></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with SMCD may appear to be negative because of failure to recognize the disorder in family members, reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> (reported in rare, isolated cases), or mild radiographic features in an affected parent that have not previously come to medical attention. Therefore, an apparently negative family history cannot be confirmed unless <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> has established that neither parent is <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li></ul><p><b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is affected and/or is known to have the <i>COL10A1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband, the risk to the sibs is 50%. Because considerable intrafamilial phenotypic variability is observed in SMCD, a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> sib may have milder or more severe manifestations of SMCD.</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a known SMCD-causing variant that cannot be detected in the leukocyte DNA of either parent, the <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> to sibs is estimated to be 1% because of the possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> [<a class="bk_pop" href="#schmid-mcd.REF.rahbari.2016.126">Rahbari et al 2016</a>]. (Note: Recurrence of SMCD in sibs of a proband with an apparently <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
|
||
<i>COL10A1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has not been reported to date.)</div></li><li class="half_rhythm"><div>If the parents are clinically unaffected (based on physical examination, measurement of proportions, and radiographs) but their genetic status is unknown, the risk to the sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for SMCD because of the possibility of reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> in a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parent or the possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>.</div></li></ul><p>
|
||
<b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>Each child of an individual with SMCD has a 50% chance of inheriting the <i>COL10A1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with SMCD may be at risk of having <a class="def" href="/books/n/gene/glossary/def-item/double-heterozygosity/">double heterozygosity</a> for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals have serious sequelae and poor outcomes [<a class="bk_pop" href="#schmid-mcd.REF.flynn.2003.193">Flynn & Pauli 2003</a>].</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> and the proband's reproductive partner are both affected with SMCD, each child has a 25% likelihood of average stature (unaffected), a 50% likelihood of having SMCD due to a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, and a 25% likelihood of having a more severe SMCD <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> due to inheritance of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants.</div><ul><li class="half_rhythm"><div>Two individuals with <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> SMCD-causing pathogenic variants and more severe presentations have been reported [<a class="bk_pop" href="#schmid-mcd.REF.ain.2018.403">Ain et al 2018</a>, <a class="bk_pop" href="#schmid-mcd.REF.t_ys_z.2023.116614">Tüysüz et al 2023</a>].</div></li><li class="half_rhythm"><div>Multiple miscarriages have been reported in a large <a class="def" href="/books/n/gene/glossary/def-item/consanguineous/">consanguineous</a> family segregating SMCD, suggesting that some <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> <i>COL10A1</i> pathogenic variants may result in early fetal demise [<a class="bk_pop" href="#schmid-mcd.REF.zhang.2018.83">Zhang et al 2018</a>].</div></li></ul></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child has at conception a 25% likelihood of average stature, a 25% likelihood of having the same skeletal dysplasia as the father, a 25% likelihood of having the same skeletal dysplasia as the mother, and a 25% likelihood of inheriting a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> from both parents and being at risk for a more severe blended skeletal <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>, including fetal demise.</div></li></ul><p><b>Other family members.</b> The risk to other family members depends on the status of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents: if a parent has the <i>COL10A1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the parent's family members may be at risk.</p></div><div id="schmid-mcd.Related_Genetic_Counseling_Is"><h3>Related Genetic Counseling Issues</h3><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of 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 affected.</div></li></ul></div><div id="schmid-mcd.Prenatal_Testing_and_Preimpla"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>COL10A1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a>. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="schmid-mcd.Resources"><h2 id="_schmid-mcd_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>Genetic and Rare Diseases Information Center (GARD)</b>
|
||
</div><div>
|
||
<a href="https://rarediseases.info.nih.gov/diseases/7029/index" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Metaphyseal chondrodysplasia, Schmid type</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Little People UK</b>
|
||
</div><div>
|
||
<a href="https://littlepeopleuk.org/information-about-dwarfism-conditions/types-of-dwarfism/metaphyseal-chondrodysplasia/metaphyseal-chordrodysplasia-schmid-type" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Metaphyseal Chondrodysplasia Schmid Type</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Short Statured People of Australasia</b>
|
||
</div><div>
|
||
<a href="https://sspa.org.au/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">sspa.org.au</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="schmid-mcd.Molecular_Genetics"><h2 id="_schmid-mcd_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="schmid-mcd.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Schmid Metaphyseal Chondrodysplasia: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547823/table/schmid-mcd.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__schmid-mcd.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_schmid-mcd.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_schmid-mcd.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_schmid-mcd.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_schmid-mcd.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_schmid-mcd.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_schmid-mcd.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_schmid-mcd.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/1300" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>COL10A1</i>
|
||
</a>
|
||
</td><td headers="hd_b_schmid-mcd.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=1300" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">6q22<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td><td headers="hd_b_schmid-mcd.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q03692" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Collagen alpha-1(X) chain</a>
|
||
</td><td headers="hd_b_schmid-mcd.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://databases.lovd.nl/shared/genes/COL10A1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL10A1 @ LOVD</a>
|
||
</td><td headers="hd_b_schmid-mcd.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=COL10A1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL10A1</a>
|
||
</td><td headers="hd_b_schmid-mcd.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=COL10A1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL10A1</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="schmid-mcd.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="schmid-mcd.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Schmid Metaphyseal Chondrodysplasia (<a href="/omim/120110,156500" 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/NBK547823/table/schmid-mcd.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__schmid-mcd.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/120110" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">120110</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">COLLAGEN, TYPE X, ALPHA-1; COL10A1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/156500" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">156500</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">METAPHYSEAL CHONDRODYSPLASIA, SCHMID TYPE; MCDS</td></tr></tbody></table></div></div><div id="schmid-mcd.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>Type X collagen, encoded by <i>COL10A1</i>, is a homotrimer non-fibrillar collagen protein consisting of three α-1(X) chains. Type X collagen is present in the extracellular matrix and expressed exclusively by hypertrophic chondrocytes in the cartilage growth plates of growing bones undergoing endochondral ossification.</p><p>Pathogenic variants in <i>COL10A1</i> are clustered in the C-terminal non-collagenous (NC1) <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a>, which contains motifs required for normal assembly of the collagen trimer. Both <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> and truncating (frameshift and <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>) variants in <i>COL10A1</i> cause collagen X protein misfolding during protein synthesis, resulting in a failure of trimerization and aggregation within the endoplasmic reticulum (ER) of hypertrophic chondrocytes. Resultant ER stress, activation of the unfolded protein response, and reduced levels of functional type X collagen in the growth plate cause chondrodysplasia and development of the SMCD <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> [<a class="bk_pop" href="#schmid-mcd.REF.rajpar.2009.e1000691">Rajpar et al 2009</a>].</p><p><b>Mechanism of disease causation.</b> Both <a class="def" href="/books/n/gene/glossary/def-item/haploinsufficiency/">haploinsufficiency</a> [<a class="bk_pop" href="#schmid-mcd.REF.bateman.2003.217">Bateman et al 2003</a>] and <a class="def" href="/books/n/gene/glossary/def-item/dominant-negative/">dominant-negative</a> [<a class="bk_pop" href="#schmid-mcd.REF.chan.1998.1490">Chan et al 1998</a>, <a class="bk_pop" href="#schmid-mcd.REF.wilson.2005.15544">Wilson et al 2005</a>] mechanisms have been proposed. Recognition of the central role of the unfolded protein response in molecular pathogenesis suggests a neomorphic, dominant-negative model in which the misfolding and accumulation of mutated type X collagen is responsible for the SMCD <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p></div></div><div id="schmid-mcd.Chapter_Notes"><h2 id="_schmid-mcd_Chapter_Notes_">Chapter Notes</h2><div id="schmid-mcd.Author_Notes"><h3>Author Notes</h3><p>Dr Richmond and Prof Savarirayan are actively involved in clinical research regarding individuals with SMCD. They would be happy to communicate with persons who have any questions regarding diagnosis of SMCD or other considerations.</p></div><div id="schmid-mcd.Acknowledgments"><h3>Acknowledgments</h3><p>The authors wish to acknowledge the patients, their families, and the clinicians of the multidisciplinary bone dysplasia clinics at the Victorian Clinical Genetics Services, Royal Children's Hospital, Genetic Health Queensland, and Queensland Children's Hospital.</p></div><div id="schmid-mcd.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>9 May 2024 (sw) Comprehensive updated posted live</div></li><li class="half_rhythm"><div>21 October 2019 (sw) Review posted live</div></li><li class="half_rhythm"><div>5 July 2019 (rs) Original submission</div></li></ul></div></div><div id="schmid-mcd.References"><h2 id="_schmid-mcd_References_">References</h2><div id="schmid-mcd.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="schmid-mcd.REF.ain.2018.403">Ain
|
||
NU, Mäkitie
|
||
O, Naz
|
||
S. Autosomal recessive chondrodysplasia with severe short stature caused by a biallelic COL10A1 variant.
|
||
J Med Genet.
|
||
2018;55:403-7.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/28830906" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28830906</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="schmid-mcd.REF.al_kaissi.2018.241">Al Kaissi
|
||
A, Ghachem
|
||
MB, Nabil
|
||
NM, Kenis
|
||
V, Melchenko
|
||
E, Morenko
|
||
E, Grill
|
||
F, Ganger
|
||
R, Kircher
|
||
SG. Schmid's type of metaphyseal chondrodysplasia: diagnosis and management.
|
||
Orthop Surg.
|
||
2018;10:241-6.
|
||
[<a href="/pmc/articles/PMC6594483/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6594483</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30027601" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30027601</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="schmid-mcd.REF.bateman.2003.217">Bateman
|
||
JF, Freddi
|
||
S, Nattrass
|
||
G, Savarirayan
|
||
R. Tissue-specific RNA surveillance? Nonsense-mediated mRNA decay causes collagen X haploinsufficiency in Schmid metaphyseal chondrodysplasia cartilage.
|
||
Hum Mol Genet.
|
||
2003;12:217-25.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/12554676" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12554676</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="schmid-mcd.REF.bateman.2005.525">Bateman
|
||
JF, Wilson
|
||
R, Freddi
|
||
S, Lamandé
|
||
SR, Savarirayan
|
||
R. Mutations of COL10A1 in Schmid metaphyseal chondrodysplasia.
|
||
Hum Mutat.
|
||
2005;25:525-34.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/15880705" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15880705</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="schmid-mcd.REF.cammaratascalisi.2019.167">Cammarata-Scalisi
|
||
F, Matysiak
|
||
U, Velten
|
||
T, Callea
|
||
M, Araque
|
||
D, Willoughby
|
||
CE, Galeotti
|
||
A, Avendaño
|
||
A. A Venezuelan case of Schmid-type metaphyseal chondrodysplasia with a novel mutation in COL10A1.
|
||
Mol Syndromol.
|
||
2019;10:167-70.
|
||
[<a href="/pmc/articles/PMC6528095/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6528095</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31191206" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31191206</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="schmid-mcd.REF.chan.1998.1490">Chan
|
||
D, Weng
|
||
YM, Graham
|
||
HK, Sillence
|
||
DO, Bateman
|
||
JF. A nonsense mutation in the carboxyl-terminal domain of type X collagen causes haploinsufficiency in chmid metaphyseal chondrodysplasia.
|
||
J Clin Invest.
|
||
1998;101:1490-9.
|
||
[<a href="/pmc/articles/PMC508727/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC508727</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/9525992" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9525992</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="schmid-mcd.REF.chreitah.2023.4045">Chreitah
|
||
A, Bress
|
||
F, Aljanati
|
||
O, Alkilany
|
||
Z, Mohammed
|
||
A, Kherbek
|
||
F.
|
||
A rare case of SCHMID metaphyseal chondrodysplasia associated with hypothyroidism, growth hormone deficiency and celiac disease: case report.
|
||
Ann Med Surg (Lond). 2023;85:4045-9.
|
||
[<a href="/pmc/articles/PMC10406062/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10406062</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/37554853" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 37554853</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="schmid-mcd.REF.de_fran_a.2020.2554">de França
|
||
M, de Faria Soares
|
||
MF, Luce
|
||
ALP, Perrone
|
||
E. Schmid metaphyseal chondrodysplasia: an example of radiology guidance to molecular diagnosis.
|
||
Radiol Case Rep.
|
||
2020;15:2554-6.
|
||
[<a href="/pmc/articles/PMC7553887/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7553887</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33082897" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33082897</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="schmid-mcd.REF.elliott.2005.191">Elliott
|
||
AM, Field
|
||
FM, Rimoin
|
||
DL, Lachman
|
||
RS. Hand involvement in Schmid metaphyseal chondrodysplasia.
|
||
Am J Med Genet A.
|
||
2005;132A:191-3.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/15578582" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15578582</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="schmid-mcd.REF.flynn.2003.193">Flynn
|
||
MA, Pauli
|
||
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK547823/?report=reader">PubReader</a></li><li><a href="/books/NBK547823/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK547823" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK547823" style="display:none" title="Cite this Page"><div class="bk_tt">Richmond CM, Savarirayan R. Schmid Metaphyseal Chondrodysplasia. 2019 Oct 21 [Updated 2024 May 9]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK547823/pdf/Bookshelf_NBK547823.pdf">PDF version of this page</a> (804K)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this GeneReview</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#schmid-mcd.Summary" ref="log$=inpage&link_id=inpage">Summary</a></li><li><a href="#schmid-mcd.Diagnosis" ref="log$=inpage&link_id=inpage">Diagnosis</a></li><li><a href="#schmid-mcd.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#schmid-mcd.Genetically_Related_Allelic_D" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#schmid-mcd.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#schmid-mcd.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#schmid-mcd.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#schmid-mcd.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#schmid-mcd.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#schmid-mcd.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li><li><a href="#schmid-mcd.References" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/ca/84/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download GeneReviews data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>GeneReviews Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/gene/advanced/"><i>GeneReviews</i> Advanced Search</a></li><li><a href="/books/n/gene/glossary/"><i>GeneReviews</i> Glossary</a></li><li><a href="/books/n/gene/resource_mats/">Resource Materials</a> <span class="bk_hlight1">NEW FEATURE</span></li><li><a href="/books/n/gene/updates/">New in <i>GeneReviews</i></a></li><li><a href="/books/n/gene/authors/">Author List</a></li><li><a href="/books/n/gene/prospective_authors/">For Current/Prospective Authors</a></li><li><a href="/books/n/gene/GRpersonnel/"><i>GeneReviews</i> Personnel</a></li><li><a href="/books/n/gene/howto_linkin/">Download/Link to <i>GeneReviews</i></a></li><li><a href="/books/n/gene/contact_us/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Tests in GTR by Gene</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
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<p class="address_footer text-white">National Library of Medicine<br />
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<a href="https://www.google.com/maps/place/8600+Rockville+Pike,+Bethesda,+MD+20894/@38.9959508,-77.101021,17z/data=!3m1!4b1!4m5!3m4!1s0x89b7c95e25765ddb:0x19156f88b27635b8!8m2!3d38.9959508!4d-77.0988323" class="text-white" target="_blank" rel="noopener noreferrer">8600 Rockville Pike<br />
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<p><a href="https://www.nlm.nih.gov/web_policies.html" class="text-white">Web Policies</a><br />
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<a href="https://www.hhs.gov/vulnerability-disclosure-policy/index.html" class="text-white" id="vdp">HHS Vulnerability Disclosure</a></p>
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<p><a class="supportLink text-white" href="https://support.nlm.nih.gov/">Help</a><br />
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<a href="https://www.nlm.nih.gov/accessibility.html" class="text-white">Accessibility</a><br />
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<a href="https://www.nlm.nih.gov/careers/careers.html" class="text-white">Careers</a></p>
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<a class="text-white" href="https://www.nih.gov/">NIH</a>
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