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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Craniometaphyseal Dysplasia, Autosomal Dominant" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2020/06/11" /><meta name="citation_author" content="Ernst Reichenberger" /><meta name="citation_author" content="I-Ping Chen" /><meta name="citation_pmid" content="20301634" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1461/" /><meta name="citation_keywords" content="Mineralization regulator ANKH" /><meta name="citation_keywords" content="ANKH" /><meta name="citation_keywords" content="Craniometaphyseal Dysplasia, Autosomal Dominant" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Craniometaphyseal Dysplasia, Autosomal Dominant" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Ernst Reichenberger" /><meta name="DC.Contributor" content="I-Ping Chen" /><meta name="DC.Date" content="2020/06/11" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1461/" /><meta name="description" content="Autosomal dominant craniometaphyseal dysplasia (designated AD-CMD in this review) is characterized by progressive diffuse hyperostosis of cranial bones evident clinically as wide nasal bridge, paranasal bossing, widely spaced eyes with an increase in bizygomatic width, and prominent mandible. Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone. Progressive thickening of craniofacial bones continues throughout life, often resulting in narrowing of the cranial foramina, including the foramen magnum. If untreated, compression of cranial nerves can lead to disabling conditions such as facial palsy, blindness, or deafness (conductive and/or sensorineural hearing loss). In individuals with typical uncomplicated AD-CMD life expectancy is normal; in those with severe AD-CMD life expectancy can be reduced as a result of compression of the foramen magnum." /><meta name="og:title" content="Craniometaphyseal Dysplasia, Autosomal Dominant" /><meta name="og:type" content="book" /><meta name="og:description" content="Autosomal dominant craniometaphyseal dysplasia (designated AD-CMD in this review) is characterized by progressive diffuse hyperostosis of cranial bones evident clinically as wide nasal bridge, paranasal bossing, widely spaced eyes with an increase in bizygomatic width, and prominent mandible. Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone. Progressive thickening of craniofacial bones continues throughout life, often resulting in narrowing of the cranial foramina, including the foramen magnum. If untreated, compression of cranial nerves can lead to disabling conditions such as facial palsy, blindness, or deafness (conductive and/or sensorineural hearing loss). In individuals with typical uncomplicated AD-CMD life expectancy is normal; in those with severe AD-CMD life expectancy can be reduced as a result of compression of the foramen magnum." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK1461/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/gene/cranio-md/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK1461/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} </style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script>
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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></div>
<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK1461_"><span class="title" itemprop="name">Craniometaphyseal Dysplasia, Autosomal Dominant</span></h1><div class="contrib half_rhythm"><span itemprop="author">Ernst Reichenberger</span>, PhD<div class="affiliation small">Professor, Department of Reconstructive Sciences<br />Center for Regenerative Medicine and Skeletal Development<br />UConn Health (UCH)<br />Farmington, Connecticut<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.chcu@regrebnehcier" class="oemail">ude.chcu@regrebnehcier</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">I-Ping Chen</span>, DDS, MS, PhD<div class="affiliation small">Associate Professor, Department of Oral Health and Diagnostic Sciences<br />UConn Health (UCH)<br />Farmington, Connecticut<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.chcu@nehcpi" class="oemail">ude.chcu@nehcpi</a></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">August 27, 2007</span>; Last Update: <span itemprop="dateModified">June 11, 2020</span>.</p><p><em>Estimated reading time: 17 minutes</em></p></div><div class="body-content whole_rhythm" itemprop="text"><div id="cranio-md.Summary" itemprop="description"><h2 id="_cranio-md_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Autosomal dominant craniometaphyseal dysplasia (designated AD-CMD in this review) is characterized by progressive diffuse hyperostosis of cranial bones evident clinically as wide nasal bridge, paranasal bossing, widely spaced eyes with an increase in bizygomatic width, and prominent mandible. Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone. Progressive thickening of craniofacial bones continues throughout life, often resulting in narrowing of the cranial foramina, including the foramen magnum. If untreated, compression of cranial nerves can lead to disabling conditions such as facial palsy, blindness, or deafness (conductive and/or sensorineural hearing loss). In individuals with typical uncomplicated AD-CMD life expectancy is normal; in those with severe AD-CMD life expectancy can be reduced as a result of compression of the foramen magnum.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>Diagnosis is based on clinical and radiographic findings that include diffuse hyperostosis of the cranial base, cranial vault, facial bones, and mandible as well as widening and radiolucency of metaphyses in long bones. Identification of a heterozygous pathogenic variant in <i>ANKH</i> by molecular genetic testing can confirm the diagnosis if clinical features are inconclusive.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Treatment for feeding and respiratory issues per craniofacial team; surgical intervention to reduce compression of cranial nerves and the brain stem / spinal cord at the level of the foramen magnum. Severely overgrown facial bones can be contoured; however, surgical procedures can be technically difficult and bone regrowth is common. Hearing aids; vision aids and surgical treatment for optic nerve impaction; speech therapy; surgical intervention for malocclusion.</p><p><i>Surveillance:</i> Evaluation for feeding and respiratory issues at least annually. Neurologic evaluation for signs and symptoms of narrowing of the cranial foramina including the foramen magnum at least annually. Hearing and ophthalmologic assessment at least annually.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>By definition, AD-CMD is inherited in an autosomal dominant manner. Most individuals diagnosed with AD-CMD have an affected parent; the proportion of individuals with AD-CMD caused by a <i>de novo</i> pathogenic variant is thought to be very low. Each child of an individual with AD-CMD has a 50% chance of inheriting the pathogenic variant. Once the AD-CMD-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.</p></div></div><div id="cranio-md.Diagnosis"><h2 id="_cranio-md_Diagnosis_">Diagnosis</h2><p>Formal diagnostic criteria for autosomal dominant craniometaphyseal dysplasia (AD-CMD) have not been established.</p><div id="cranio-md.Suggestive_Findings"><h3>Suggestive Findings</h3><p>AD-CMD <b>should be suspected</b> in individuals with the following clinical, radiographic, and laboratory features.</p><p>
<b>Clinical features</b>
</p><ul><li class="half_rhythm"><div>Obstruction of the nasal sinuses</div></li><li class="half_rhythm"><div>Characteristic facial features. Wide nasal bridge, paranasal bossing, hypertelorism with an increase in bizygomatic width, and prominent mandible (see <a class="figpopup" href="/books/NBK1461/figure/cranio-md.F1/?report=objectonly" target="object" rid-figpopup="figcraniomdF1" rid-ob="figobcraniomdF1">Figure 1</a>)</div></li><li class="half_rhythm"><div>Dolichocephaly due to fronto-occipital hyperostosis</div></li></ul><p>
<b>Radiographic features</b>
</p><ul><li class="half_rhythm"><div><b>Cranial base.</b> Sclerosis may begin in infancy (see <a class="figpopup" href="/books/NBK1461/figure/cranio-md.F2/?report=objectonly" target="object" rid-figpopup="figcraniomdF2" rid-ob="figobcraniomdF2">Figure 2</a>). Increasing diffuse hyperostosis of the cranial base leads to narrowing of the foramen magnum.</div></li><li class="half_rhythm"><div><b>Skull.</b> Diffuse hyperostosis of cranial vault, facial bones, and mandible increases as the condition progresses [<a class="bk_pop" href="#cranio-md.REF.lamazza.2009.e23">Lamazza et al 2009</a>] with obstruction of the cranial foramina.</div></li><li class="half_rhythm"><div><b>Long bones.</b> Metaphyseal widening (described as Erlenmeyer flask- or club-shaped) with thinned cortex and decreased bony density in the metaphyses can be detected early in life. Metaphyseal changes typically develop during early childhood. The flaring is most prominent in the distal femur and tibia (see <a class="figpopup" href="/books/NBK1461/figure/cranio-md.F3/?report=objectonly" target="object" rid-figpopup="figcraniomdF3" rid-ob="figobcraniomdF3">Figure 3</a>). Diaphyseal sclerosis/hyperostosis can be present in infancy but disappears with age. Bone density of the diaphyses is normal in children and adults; cortical thickness can be increased.</div></li><li class="half_rhythm"><div><b>Ribs</b>
<b>and clavicles</b> (medial portion [i.e., endochondral]) can be sclerotic in younger children but show normal bone density by age five years [<a class="bk_pop" href="#cranio-md.REF.richards.1996.328">Richards et al 1996</a>].</div></li></ul><p>
<b>Laboratory features</b>
</p><ul><li class="half_rhythm"><div><b>Blood calcium and phosphate concentrations</b> are within normal limits [<a class="bk_pop" href="#cranio-md.REF.cheung.1997.241">Cheung et al 1997</a>] or decreased [<a class="bk_pop" href="#cranio-md.REF.sheppard.2003.71">Sheppard et al 2003</a>].</div></li><li class="half_rhythm"><div><b>Serum alkaline phosphatase activity</b> can be elevated [<a class="bk_pop" href="#cranio-md.REF.sheppard.2003.71">Sheppard et al 2003</a>, <a class="bk_pop" href="#cranio-md.REF.wu.2016.122">Wu et al 2016</a>].</div></li><li class="half_rhythm"><div><b>Parathyroid hormone level</b> is normal or can be slightly/transiently elevated [<a class="bk_pop" href="#cranio-md.REF.fanconi.1988.587">Fanconi et al 1988</a>, <a class="bk_pop" href="#cranio-md.REF.cheung.1997.241">Cheung et al 1997</a>, <a class="bk_pop" href="#cranio-md.REF.sheppard.2003.71">Sheppard et al 2003</a>, <a class="bk_pop" href="#cranio-md.REF.wu.2016.122">Wu et al 2016</a>].</div></li><li class="half_rhythm"><div><b>Osteocalcin</b> is decreased [<a class="bk_pop" href="#cranio-md.REF.yamamoto.1993.362">Yamamoto et al 1993</a>].</div></li></ul><p>Note: Findings are based on very limited data. Variability of the described parameters can be expected. Abnormal parameters may be transient.</p></div><div id="cranio-md.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of AD-CMD <b>is established</b> in a proband with characteristic craniofacial hyperostosis and flaring and undertrabeculation of long bone metaphyses and/or a heterozygous pathogenic variant in <i>ANKH</i> identified by molecular genetic testing (see <a href="/books/NBK1461/table/cranio-md.T.molecular_genetic_testing_us/?report=objectonly" target="object" rid-ob="figobcraniomdTmoleculargenetictestingus">Table 1</a>).</p><p>Note: Identification of a heterozygous <i>ANKH</i> variant of uncertain significance does not establish or rule out the diagnosis of this disorder.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single-gene testing and multigene panel) and <b>comprehensive</b>
<b>genomic testing</b> (exome sequencing, exome array, genome sequencing) depending on the phenotype.</p><p>Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of AD-CMD is broad, individuals with the distinctive findings described in <a href="#cranio-md.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#cranio-md.Option_1">Option 1</a>), whereas those with a phenotype indistinguishable from many other inherited disorders with hyperostosis are more likely to be diagnosed using genomic testing (see <a href="#cranio-md.Option_2">Option 2</a>).</p><div id="cranio-md.Option_1"><h4>Option 1</h4><p>When the phenotypic and laboratory findings suggest the diagnosis of AD-CMD, molecular genetic testing approaches can include <b>single-gene testing</b> or use of a <b>multigene panel</b>:</p><ul><li class="half_rhythm"><div><b>Single-gene testing.</b> Sequence analysis of <i>ANKH</i> is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. Note: To date such variants have not been identified as a cause of this disorder.</div></li><li class="half_rhythm"><div><b>A multigene panel</b> that includes <i>ANKH</i> and other genes of interest (see <a href="#cranio-md.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene 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 exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</div></li></ul><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</p></div><div id="cranio-md.Option_2"><h4>Option 2</h4><p>When the phenotype is indistinguishable from many other inherited disorders characterized by hyperostosis, <b>comprehensive</b>
<b>genomic testing</b>, which does not require the clinician to determine which gene is likely involved, is most likely to establish the diagnosis. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</p><p>If exome sequencing is not diagnostic &#x02013; and particularly when evidence supports autosomal dominant inheritance &#x02013; <b>exome array</b> (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date such variants have not been identified as a cause of this disorder.</p><p>For an introduction to comprehensive genomic 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="cranio-md.T.molecular_genetic_testing_us" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Autosomal Dominant Craniometaphyseal Dysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1461/table/cranio-md.T.molecular_genetic_testing_us/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cranio-md.T.molecular_genetic_testing_us_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cranio-md.T.molecular_genetic_testing_us_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene&#x000a0;<sup>1</sup></th><th id="hd_h_cranio-md.T.molecular_genetic_testing_us_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_cranio-md.T.molecular_genetic_testing_us_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant&#x000a0;<sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_cranio-md.T.molecular_genetic_testing_us_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<i>ANKH</i>
</td><td headers="hd_h_cranio-md.T.molecular_genetic_testing_us_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis&#x000a0;<sup>3</sup></td><td headers="hd_h_cranio-md.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~90%&#x000a0;<sup>4</sup></td></tr><tr><td headers="hd_h_cranio-md.T.molecular_genetic_testing_us_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis&#x000a0;<sup>5</sup></td><td headers="hd_h_cranio-md.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported&#x000a0;<sup>6</sup></td></tr><tr><td headers="hd_h_cranio-md.T.molecular_genetic_testing_us_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown&#x000a0;<sup>7</sup></td><td headers="hd_h_cranio-md.T.molecular_genetic_testing_us_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NA</td><td headers="hd_h_cranio-md.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~10%</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="cranio-md.TF.1.1"><p class="no_margin">See <a href="/books/NBK1461/#cranio-md.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd><dt>2. </dt><dd><div id="cranio-md.TF.1.2"><p class="no_margin">See <a href="#cranio-md.Molecular_Genetics">Molecular Genetics</a> for information on allelic variants detected in this gene.</p></div></dd><dt>3. </dt><dd><div id="cranio-md.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="cranio-md.TF.1.4"><p class="no_margin"><a class="bk_pop" href="#cranio-md.REF.n_rnberg.2001.37">N&#x000fc;rnberg et al [2001]</a>, <a class="bk_pop" href="#cranio-md.REF.reichenberger.2001.1321">Reichenberger et al [2001]</a></p></div></dd><dt>5. </dt><dd><div id="cranio-md.TF.1.5"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd><dt>6. </dt><dd><div id="cranio-md.TF.1.6"><p class="no_margin">Since AD-CMD occurs through a gain-of-function/dominant negative mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.</p></div></dd><dt>7. </dt><dd><div id="cranio-md.TF.1.7"><p class="no_margin">Some simplex cases of CMD did not have identifiable pathogenic variants in <i>ANKH</i>, suggesting possible locus heterogeneity.</p></div></dd></dl></div></div></div></div></div></div><div id="cranio-md.Clinical_Characteristics"><h2 id="_cranio-md_Clinical_Characteristics_">Clinical Characteristics</h2><div id="cranio-md.Clinical_Description"><h3>Clinical Description</h3><p>Autosomal dominant craniometaphyseal dysplasia (AD-CMD) is often detected within the first few weeks of life because of breathing or feeding problems resulting from choanal stenosis (narrowing of nasal sinus) [<a class="bk_pop" href="#cranio-md.REF.haverkamp.1996.159">Haverkamp et al 1996</a>, <a class="bk_pop" href="#cranio-md.REF.cheung.1997.241">Cheung et al 1997</a>, <a class="bk_pop" href="#cranio-md.REF.taggart.2014.983">Taggart et al 2014</a>].</p><p>Early stages of AD-CMD can be radiographically recognized as sclerosis of the cranial base. Hyperostosis of the cranial base, cranial vault, facial bones, and mandible occurs gradually. Overgrowth of the lower jaw (mandibular hyperostosis) and recessed midface (midface retrusion) are often seen [<a class="bk_pop" href="#cranio-md.REF.hayashibara.2000.460">Hayashibara et al 2000</a>].</p><p>Progressive thickening of craniofacial bones continues throughout life, often resulting in narrowing of the cranial foramina, including the foramen magnum. If untreated, compression of cranial nerves can lead to disabling conditions such as facial palsy, blindness, or deafness (conductive and/or sensorineural hearing loss) as cranial hyperostosis and sclerosis progress [<a class="bk_pop" href="#cranio-md.REF.beighton.1979.252">Beighton et al 1979</a>, <a class="bk_pop" href="#cranio-md.REF.richards.1996.328">Richards et al 1996</a>]. Nasal obstruction and mandibular hyperostosis affect speech modulation.</p><p>Associated Chiari I malformation can lead to severe headaches [<a class="bk_pop" href="#cranio-md.REF.tanaka.2013.385">Tanaka et al 2013</a>].</p><p>Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone [<a class="bk_pop" href="#cranio-md.REF.chen.2014.553">Chen et al 2014</a>].</p><p>Malocclusion and anterior cross-bite can be caused by jaw overgrowth [<a class="bk_pop" href="#cranio-md.REF.hayashibara.2000.460">Hayashibara et al 2000</a>].</p><p><b>Life expectancy.</b> Individuals with typical uncomplicated AD-CMD have normal life expectancy. Expressivity in simplex cases (i.e., single occurrence in a family) of CMD is highly variable.</p></div><div id="cranio-md.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No genotype-phenotype correlation has been reported.</p><p>The phenotypic severity (expressivity) in AD-CMD is variable even among affected members of the same family.</p></div><div id="cranio-md.Penetrance"><h3>Penetrance</h3><p>Penetrance is 100%. Males and females are equally affected.</p></div><div id="cranio-md.Nomenclature"><h3>Nomenclature</h3><p>AD-CMD was previously referred to as "craniometaphyseal dysplasia-Jackson type."</p></div><div id="cranio-md.Prevalence"><h3>Prevalence</h3><p>CMD is very rare. No epidemiology has been established.</p></div></div><div id="cranio-md.Genetically_Related_Allelic_Di"><h2 id="_cranio-md_Genetically_Related_Allelic_Di_">Genetically Related (Allelic) Disorders</h2><div id="cranio-md.T.ankh_allelic_disorders" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p><i>ANKH</i> Allelic Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1461/table/cranio-md.T.ankh_allelic_disorders/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cranio-md.T.ankh_allelic_disorders_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cranio-md.T.ankh_allelic_disorders_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_cranio-md.T.ankh_allelic_disorders_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_cranio-md.T.ankh_allelic_disorders_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_cranio-md.T.ankh_allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Chondrocalcinosis 2 (OMIM <a href="https://omim.org/entry/118600" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">118600</a>)</td><td headers="hd_h_cranio-md.T.ankh_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_cranio-md.T.ankh_allelic_disorders_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1 family described w/cosegregating AD-CMD &#x00026; chondrocalcinosis&#x000a0;<sup>1</sup></td></tr><tr><td headers="hd_h_cranio-md.T.ankh_allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intellectual disability, deafness, &#x00026; ankylosis syndrome</td><td headers="hd_h_cranio-md.T.ankh_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_cranio-md.T.ankh_allelic_disorders_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In 1 family, hearing loss, intellectual disability, spinal ankylosis, &#x00026; periarticular calcification of small joints described in individuals w/biallelic pathogenic variants (mild arthropathy described in individuals w/heterozygous pathogenic variants)&#x000a0;<sup>2</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AD-CMD = autosomal dominant craniometaphyseal dysplasia; AR = autosomal recessive; MOI = mode of inheritance</p></div></dd><dt>1. </dt><dd><div id="cranio-md.TF.2.1"><p class="no_margin">
<a class="bk_pop" href="#cranio-md.REF.baynam.2009.1331">Baynam et al [2009]</a>
</p></div></dd><dt>2. </dt><dd><div id="cranio-md.TF.2.2"><p class="no_margin">
<a class="bk_pop" href="#cranio-md.REF.morava.2011.e189">Morava et al [2011]</a>
</p></div></dd></dl></div></div></div></div><div id="cranio-md.Differential_Diagnosis"><h2 id="_cranio-md_Differential_Diagnosis_">Differential Diagnosis</h2><div id="cranio-md.T.genes_of_interest_in_the_dif" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of Autosomal Dominant Craniometaphyseal Dysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1461/table/cranio-md.T.genes_of_interest_in_the_dif/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cranio-md.T.genes_of_interest_in_the_dif_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Characteristics</th><th id="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing Features</th></tr></thead><tbody><tr><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>AMER1</i>
</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="/books/n/gene/os-cs/">Osteopathia striata with cranial sclerosis</a>
</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Longitudinal striations of sclerotic long bones in combination w/osteosclerosis of cranial &#x00026; facial bones</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Short stature, delayed closure of anterior fontanelle, micrognathia, linear striations in long bones of females</td></tr><tr><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>FLNA</i>
</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frontometaphyseal dysplasia type 1 (See <a href="/books/n/gene/opd/">Otopalatodigital Spectrum Disorders</a>.)</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Skeletal findings are frontal bone hyperostosis &#x00026; metaphyseal dysplasia (similar to those seen in Pyle disease).</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Urogenital defects, contractures in hands, elbows, knees, &#x00026; ankles</td></tr><tr><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>GJA1</i>
</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Autosomal recessive craniometaphyseal dysplasia (AR-CMD) (OMIM <a href="http://omim.org/entry/218400" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">218400</a>)</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hyperostosis of cranial base &#x00026; cranial vault w/metaphyseal flaring similar to AD-CMD</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Skeletal phenotype may be less severe than in typical AD-CMD.</td></tr><tr><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>LRP5</i>
</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Autosomal dominant osteopetrosis type 1 (OMIM <a href="http://omim.org/entry/607634" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">607634</a>)</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cranial sclerosis &#x00026; high bone mass w/o &#x02191; fragility</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Diffuse osteosclerosis, no metaphyseal flaring</td></tr><tr><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>SFRP4</i>
</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pyle disease (OMIM <a href="http://omim.org/entry/265900" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">265900</a>)</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Metaphyseal dysplasia</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Little or no involvement of cranial bones in Pyle disease</td></tr><tr><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<i>SOST</i>
</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Craniodiaphyseal dysplasia (CDD) (OMIM <a href="http://omim.org/entry/218300" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">218300</a>)</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Progressive overgrowth of craniofacial bones w/deafness, facial palsy, &#x00026; visual disturbance due to nerve entrapment</div></li><li class="half_rhythm"><div>Choanal stenosis is a clinically significant complication.</div></li><li class="half_rhythm"><div>Radiologically, cranial &#x00026; facial bones are hyperostotic while diaphyses of limb bones are expanded, w/thin cortices.</div></li></ul>
</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cranial &#x00026; facial thickening are generally more severe in CDD than in CMD.</td></tr><tr><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Sclerosteosis (See <a href="/books/n/gene/sost/"><i>SOST</i> Sclerosing Bone Dysplasias</a>.)</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Progressive skeletal overgrowth (most pronounced in skull &#x00026; mandible) &#x00026; variable syndactyly</div></li><li class="half_rhythm"><div>Facial distortion due to bossing of forehead &#x00026; mandibular overgrowth becomes apparent in early childhood w/progression into adulthood.</div></li><li class="half_rhythm"><div>Hyperostosis of skull &#x02192; narrowing of foramina &#x00026; entrapment of 7th cranial nerve (&#x02192; facial palsy) w/other, less common nerve entrapment syndromes.</div></li><li class="half_rhythm"><div>Hyperostosis of calvarium &#x02193; intracranial volume, &#x02191; risk for potentially lethal elevation of intracranial pressure.</div></li><li class="half_rhythm"><div>Survival into old age is unusual but not unprecedented.</div></li></ul>
</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sclerosis in spine &#x00026; pelvis, 2-3 finger syndactyly, nail dysplasia, no metaphyseal flaring, gigantism</td></tr><tr><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Van Buchem disease (See <a href="/books/n/gene/sost/"><i>SOST</i> Sclerosing Bone Dysplasias</a>.)</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Progressive skeletal overgrowth</div></li><li class="half_rhythm"><div>Van Buchem disease is generally milder than sclerosteosis; no syndactyly.</div></li><li class="half_rhythm"><div>Life span appears normal.</div></li></ul>
</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Osteosclerosis incl clavicles &#x00026; ribs; hyperphosphatasemia.</td></tr><tr><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>TGFB1</i>
</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Progressive diaphyseal dysplasia</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hyperostosis of skull results in narrowing of foramina, causing facial palsy &#x00026; deafness.</td><td headers="hd_h_cranio-md.T.genes_of_interest_in_the_dif_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Diaphyseal hyperostosis of long bones is pronounced.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AD-CMD = autosomal dominant craniometaphyseal dysplasia; AR = autosomal recessive; CMD = craniometaphyseal dysplasia; MOI = mode of inheritance; XL = X-linked</p></div></dd></dl></div></div></div><p><b>Braun-Tinschert type of metaphyseal dysplasia</b> (OMIM <a href="http://omim.org/entry/605946" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">605946</a>) is inherited in an autosomal dominant manner. The gene(s) in which mutation is causative are unknown [<a class="bk_pop" href="#cranio-md.REF.braun.2001.74">Braun et al 2001</a>].</p></div><div id="cranio-md.Management"><h2 id="_cranio-md_Management_">Management</h2><div id="cranio-md.Evaluations_Following_Initial"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with autosomal dominant craniometaphyseal dysplasia (AD-CMD), the evaluations summarized in <a href="/books/NBK1461/table/cranio-md.T.recommended_evaluations_foll/?report=objectonly" target="object" rid-ob="figobcraniomdTrecommendedevaluationsfoll">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="cranio-md.T.recommended_evaluations_foll" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Autosomal Dominant Craniometaphyseal Dysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1461/table/cranio-md.T.recommended_evaluations_foll/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cranio-md.T.recommended_evaluations_foll_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_cranio-md.T.recommended_evaluations_foll_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_cranio-md.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Respiratory &#x00026; feeding</b>
<br />
<b>problems in infancy</b>
</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral for craniofacial team eval incl otolaryngologic eval</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl eval for choanal stenosis</td></tr><tr><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Skeletal hyperostosis</b>
</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>X-rays of skull, hands, knees</div></li><li class="half_rhythm"><div>CT to evaluate involvement of foramina &#x00026; foramen magnum</div></li></ul>
</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Cranial nerve</b>
<br />
<b>compression</b>
</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic exam</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Otolaryngologic eval</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate auditory system</td></tr><tr><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Audiologic assessment</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for hearing loss</td></tr><tr><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic exam</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for vision loss</td></tr><tr><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Endocrine / Bone</b>
<br />
<b>metabolism</b>
</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Alkaline phosphatase</div></li><li class="half_rhythm"><div>P1NP</div></li><li class="half_rhythm"><div>CTX</div></li></ul>
</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate bone turnover</td></tr><tr><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Speech</b>
</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval by speech therapist</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In early childhood; progressive hearing loss, facial palsy, &#x00026; hyperostosis can &#x02192; speech issues.</td></tr><tr><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Delayed eruption &#x00026;</b>
<br />
<b>malocclusion</b>
</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval by dentist</td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">From the time of primary tooth eruption to identify tooth impaction or delay in tooth eruption</td></tr><tr><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_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_cranio-md.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals&#x000a0;<sup>1</sup></td><td headers="hd_h_cranio-md.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons &#x00026; families re nature, MOI, &#x00026; implications of AD-CMD to facilitate medical &#x00026; personal decision making</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD-CMD = autosomal dominant craniometaphyseal dysplasia; CTX = carboxy-terminal collagen crosslinks; MOI = mode of inheritance; P1NP = procollagen type 1 N-terminal propeptide</p></div></dd><dt>1. </dt><dd><div id="cranio-md.TF.4.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="cranio-md.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div id="cranio-md.T.treatment_of_manifestations" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Autosomal Dominant Craniometaphyseal Dysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1461/table/cranio-md.T.treatment_of_manifestations/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cranio-md.T.treatment_of_manifestations_lrgtbl__"><table><thead><tr><th id="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_cranio-md.T.treatment_of_manifestations_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_cranio-md.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Feeding &#x00026; respiratory issues in newborns &#x00026; infants</b>
</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per craniofacial team</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Cranial nerve compression</b>
</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Surgical intervention</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To relieve severe symptoms caused by cranial nerve compression</td></tr><tr><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Narrowed foramen magnum</b>
</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Surgical intervention</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To relieve headaches &#x00026; risks assoc w/Chiari malformation</td></tr><tr><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Hyperostosis of facial bones</b>
</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe bony overgrowth of facial bones &#x00026; nasal, forehead, &#x00026; cranial regions can be contoured.</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Surgical procedures can be technically difficult &#x00026; bone regrowth is common.</div></li><li class="half_rhythm"><div>As severe complications have occurred, surgery is considered for conservative purposes to relieve severe symptoms caused by cranial nerve compression.</div></li></ul>
</td></tr><tr><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Hearing loss</b>
</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing aids</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cochlear implant may be possible.</td></tr><tr><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Vison loss</b>
</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Surgery for optic nerve impaction</div></li><li class="half_rhythm"><div>Vision aids</div></li></ul>
</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In anticipation of progressive vision loss, children may learn Braille.</td></tr><tr><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Speech issues</b>
</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider speech therapy.</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Malocclusion</b>
</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Surgical intervention for severe malocclusion</td><td headers="hd_h_cranio-md.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Delayed tooth eruption should be considered when planning orthodontic treatment [<a class="bk_pop" href="#cranio-md.REF.chen.2014.553">Chen et al 2014</a>].</td></tr></tbody></table></div></div></div><div id="cranio-md.Surveillance"><h3>Surveillance</h3><div id="cranio-md.T.recommended_surveillance_for" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Autosomal Dominant Craniometaphyseal Dysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1461/table/cranio-md.T.recommended_surveillance_for/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cranio-md.T.recommended_surveillance_for_lrgtbl__"><table><thead><tr><th id="hd_h_cranio-md.T.recommended_surveillance_for_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_cranio-md.T.recommended_surveillance_for_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_cranio-md.T.recommended_surveillance_for_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_cranio-md.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Feeding &#x00026; respiratory issues in newborns &#x00026; infants</b>
</td><td headers="hd_h_cranio-md.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Craniofacial team</td><td headers="hd_h_cranio-md.T.recommended_surveillance_for_1_1_1_3" rowspan="4" colspan="1" style="text-align:left;vertical-align:middle;">Annually, or more frequently if needed</td></tr><tr><td headers="hd_h_cranio-md.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Narrowing cranial foramina, incl foramen magnum</b>
</td><td headers="hd_h_cranio-md.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td></tr><tr><td headers="hd_h_cranio-md.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Hearing loss</b>
</td><td headers="hd_h_cranio-md.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing assessment</td></tr><tr><td headers="hd_h_cranio-md.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Vision loss</b>
</td><td headers="hd_h_cranio-md.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic exam</td></tr></tbody></table></div></div></div><div id="cranio-md.Evaluation_of_Relatives_at_Ris"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Early diagnosis of at-risk relatives may be beneficial for management of complications from progressive hyperostosis.</p><p>Evaluations can include:</p><ul><li class="half_rhythm"><div>Molecular genetic testing if the pathogenic variant in the family is known;</div></li><li class="half_rhythm"><div>Clinical evaluation and cranial and long bone radiographs if the pathogenic variant in the family is not known.</div></li></ul><p>See <a href="#cranio-md.Related_Genetic_Counseling_Iss">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="cranio-md.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="http://clinicaltrials.gov/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">ClinicalTrials.gov</a> in the US and <a href="http://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div><div id="cranio-md.Other"><h3>Other</h3><p>Calcitonin has been thought to be effective because of its inhibitory effect on bone turnover. However, previous case reports found calcitonin therapy to be ineffective in treating hyperplasia of craniofacial bones in persons with CMD [<a class="bk_pop" href="#cranio-md.REF.fanconi.1988.587">Fanconi et al 1988</a>, <a class="bk_pop" href="#cranio-md.REF.haverkamp.1996.159">Haverkamp et al 1996</a>].</p><p>Calcitriol with a low-calcium diet to stimulate bone resorption by promoting osteoclast formation had been reported to improve facial paralysis but has no effect on metaphyseal deformity [<a class="bk_pop" href="#cranio-md.REF.key.1988.583">Key et al 1988</a>, <a class="bk_pop" href="#cranio-md.REF.wu.2016.122">Wu et al 2016</a>].</p><p>Acetazolamide has been suggested for treatment of disorders with increased bone mineral density. <a class="bk_pop" href="#cranio-md.REF.gonz_lezrodr_guez.2016.284">Gonz&#x000e1;lez-Rodr&#x000ed;guez et al [2016]</a> reported acetazolamide use in an individual with a phenotype similar to CMD, but diagnosis of AD-CMD was not confirmed.</p></div></div><div id="cranio-md.Genetic_Counseling"><h2 id="_cranio-md_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>. &#x02014;ED.</p><div id="cranio-md.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>By definition, autosomal dominant craniometaphyseal dysplasia (AD-CMD) is inherited in an autosomal dominant manner.</p></div><div id="cranio-md.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
<b>Parents of a proband</b>
</p><ul><li class="half_rhythm"><div>Most individuals diagnosed with AD-CMD have an affected parent.</div></li><li class="half_rhythm"><div>Some individuals diagnosed with AD-CMD have the disorder as the result of a <i>de novo</i> pathogenic variant. The proportion of individuals with AD-CMD caused by a <i>de novo</i> pathogenic variant is thought to be very low; however statistical data are not available.</div></li></ul><ul><li class="half_rhythm"><div class="half_rhythm">If the proband appears to be the only affected family member (i.e., a simplex case) and has a known <i>ANKH</i> pathogenic variant, molecular genetic testing is recommended for the parents of a proband.</div></li><li class="half_rhythm"><div class="half_rhythm">If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a <i>de novo</i> pathogenic variant in the proband or germline mosaicism in a parent.* Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported.</div><div class="half_rhythm">* Misattributed parentage can also be explored as an alternative explanation for an apparent <i>de novo</i> pathogenic variant.</div></li><li class="half_rhythm"><div class="half_rhythm">The family history of some individuals diagnosed with AD-CMD may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).</div></li></ul><p><b>Sibs of a proband.</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 proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Because penetrance of AD-CMD is 100%, sibs who inherit a pathogenic variant will develop the phenotype although the severity of the phenotype may vary.</div></li><li class="half_rhythm"><div>If the proband has a known <i>ANKH</i> pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [<a class="bk_pop" href="#cranio-md.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low but still increased over that of the general population because of the theoretic possibility of parental germline mosaicism.</div></li></ul><p><b>Offspring of a proband.</b> Each child of an individual with AD-CMD has a 50% chance of inheriting the causative pathogenic variant.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the proband's parents: If a parent is affected, his or her family members may be at risk.</p></div><div id="cranio-md.Related_Genetic_Counseling_Iss"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#cranio-md.Evaluation_of_Relatives_at_Ris">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><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/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.</div></li></ul></div><div id="cranio-md.Prenatal_Testing_and_Preimplan"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the AD-CMD-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="cranio-md.Resources"><h2 id="_cranio-md_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>American Society for Deaf Children</b>
</div><div><b>Phone:</b> 800-942-2732 (ASDC)</div><div><b>Email:</b> info@deafchildren.org</div><div>
<a href="https://deafchildren.org/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">deafchildren.org</a>
</div></li><li class="half_rhythm"><div>
<b>Children's Craniofacial Association</b>
</div><div><b>Phone:</b> 800-535-3643</div><div><b>Email:</b> contactCCA@ccakids.com</div><div>
<a href="https://ccakids.org/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">ccakids.org</a>
</div></li><li class="half_rhythm"><div>
<b>Face Equality International</b>
</div><div>United Kingdom</div><div>
<a href="https://faceequalityinternational.org/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">faceequalityinternational.org</a>
</div></li><li class="half_rhythm"><div>
<b>National Association of the Deaf</b>
</div><div><b>Phone:</b> 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)</div><div><b>Fax:</b> 301-587-1791</div><div><b>Email:</b> nad.info@nad.org</div><div>
<a href="https://www.nad.org" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">nad.org</a>
</div></li><li class="half_rhythm"><div>
<b>UCLA International Skeletal Dysplasia Registry (ISDR)</b>
</div><div><b>Phone:</b> 310-825-8998</div><div>
<a href="https://www.uclahealth.org/ortho/isdr" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">International Skeletal Dysplasia Registry</a>
</div></li></ul>
</div><div id="cranio-md.Molecular_Genetics"><h2 id="_cranio-md_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. &#x02014;</i>ED.</p><div id="cranio-md.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Craniometaphyseal Dysplasia, Autosomal Dominant: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1461/table/cranio-md.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cranio-md.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_cranio-md.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_cranio-md.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_cranio-md.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_cranio-md.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_cranio-md.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_cranio-md.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_cranio-md.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
<a href="/gene/56172" ref="pagearea=body&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=gene">
<i>ANKH</i>
</a>
</td><td headers="hd_b_cranio-md.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&#x00026;acc=56172" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">5p15<wbr style="display:inline-block"></wbr>​.2</a>
</td><td headers="hd_b_cranio-md.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
<a href="http://www.uniprot.org/uniprot/Q9HCJ1" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">Mineralization regulator ANKH</a>
</td><td headers="hd_b_cranio-md.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
<a href="http://www.LOVD.nl/ANKH" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">ANKH @ LOVD</a>
</td><td headers="hd_b_cranio-md.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=ANKH" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">ANKH</a>
</td><td headers="hd_b_cranio-md.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=ANKH[gene]" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">ANKH</a>
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="cranio-md.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
<a href="http://www.genenames.org/index.html" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">HGNC</a>;
chromosome locus from
<a href="http://www.omim.org/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">OMIM</a>;
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;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="cranio-md.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Craniometaphyseal Dysplasia, Autosomal Dominant (<a href="/omim/123000,605145" ref="pagearea=body&amp;targetsite=entrez&amp;targetcat=term&amp;targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1461/table/cranio-md.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cranio-md.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
<a href="/omim/123000" ref="pagearea=body&amp;targetsite=entrez&amp;targetcat=term&amp;targettype=omim">123000</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CRANIOMETAPHYSEAL DYSPLASIA, AUTOSOMAL DOMINANT; CMDD</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
<a href="/omim/605145" ref="pagearea=body&amp;targetsite=entrez&amp;targetcat=term&amp;targettype=omim">605145</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ANKH INORGANIC PYROPHOSPHATE TRANSPORT REGULATOR; ANKH</td></tr></tbody></table></div></div><div id="cranio-md.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>ANKH</i> encodes the progressive ankylosis protein homolog, a multispan transmembrane protein located at the outer cell membrane that transports intracellular pyrophosphate into the extracellular matrix. Pyrophosphate is a regulator of matrix (bone) mineralization. The protein sequence of the progressive ankylosis protein homolog is highly conserved among vertebrate animals.</p><p>Progressive ankylosis protein homolog expressing a craniometaphyseal dysplasia-associated variant most likely has a reduced ability to transport intracellular pyrophosphate from osteoblasts to the bone matrix [<a class="bk_pop" href="#cranio-md.REF.ho.2000.265">Ho et al 2000</a>].</p><p><b>Mechanism of disease causation.</b> Most common pathogenic variants result in one-amino acid deletions, while others are missense or small in-frame deletions and insertions [<a class="bk_pop" href="#cranio-md.REF.n_rnberg.2001.37">N&#x000fc;rnberg et al 2001</a>, <a class="bk_pop" href="#cranio-md.REF.reichenberger.2001.1321">Reichenberger et al 2001</a>, <a class="bk_pop" href="#cranio-md.REF.kornak.2010.870">Kornak et al 2010</a>, <a class="bk_pop" href="#cranio-md.REF.zajac.2010.770">Zajac et al 2010</a>, <a class="bk_pop" href="#cranio-md.REF.dutra.2012.93">Dutra et al 2012</a>]. Most pathogenic variants occur in the nucleotide region encoding presumed intracellular domains of the transmembrane loop structure. Based on findings in knockout and knock-in mice studies, <i>ANKH</i> pathogenic variants are thought to result in a dominant negative gain of function as well as loss of function of pyrophosphate transport. The shared phenotype between these murine models is explained by the rapid degradation of pathogenic ANK protein [<a class="bk_pop" href="#cranio-md.REF.kanaujiya.2018.15710">Kanaujiya et al 2018</a>]. To date, no other information on mechanism is available.</p></div></div><div id="cranio-md.References"><h2 id="_cranio-md_References_">References</h2><div id="cranio-md.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.baynam.2009.1331">Baynam G, Goldblatt J, Schofield L. Craniometaphyseal dysplasia and chondrocalcinosis cosegregating in a family with an ANKH mutation. <span><span class="ref-journal">Am J Med Genet A. </span>2009;<span class="ref-vol">149A</span>:1331–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19449425" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 19449425</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.beighton.1979.252">Beighton P, Hamersma H, Horan F. Craniometaphyseal dysplasia--variability of expression within a large family. <span><span class="ref-journal">Clin Genet. </span>1979;<span class="ref-vol">15</span>:252–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/421364" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 421364</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.braun.2001.74">Braun HS, Nurnberg P, Tinschert S. Metaphyseal dysplasia: a new autosomal dominant type in a large German kindred. <span><span class="ref-journal">Am J Med Genet. </span>2001;<span class="ref-vol">101</span>:74–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11343343" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 11343343</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.chen.2014.553">Chen IP, Tadinada A, Dutra EH, Utrja A, Uribe F, Reichenberger EJ. Dental anomalies associated with craniometaphyseal dysplasia. <span><span class="ref-journal">J Dent Res. </span>2014;<span class="ref-vol">93</span>:553–8.</span> [<a href="/pmc/articles/PMC4023465/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC4023465</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24663682" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 24663682</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.cheung.1997.241">Cheung VG, Boechat MI, Barrett CT. Bilateral choanal narrowing as a presentation of craniometaphyseal dysplasia. <span><span class="ref-journal">J Perinatol. </span>1997;<span class="ref-vol">17</span>:241–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9210083" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 9210083</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.dutra.2012.93">Dutra EH, Chen I-P, McGregor TL, Ranells JD, Reichenberger EJ. Two novel large <em>ANKH</em> deletion mutations in sporadic cases with craniometaphyseal dysplasia. <span><span class="ref-journal">Clin Genet. </span>2012;<span class="ref-vol">81</span>:93–5.</span> [<a href="/pmc/articles/PMC3417334/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC3417334</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22150416" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 22150416</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.fanconi.1988.587">Fanconi S, Fischer JA, Wieland P, Giedion A, Boltshauser E, Olah AJ, Landolt AM, Prader A. Craniometaphyseal dysplasia with increased bone turnover and secondary hyperparathyroidism: therapeutic effect of calcitonin. <span><span class="ref-journal">J Pediatr. </span>1988;<span class="ref-vol">112</span>:587–91.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3351685" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 3351685</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.gonz_lezrodr_guez.2016.284">Gonz&#x000e1;lez-Rodr&#x000ed;guez JD, Luis-Yanes MI, Ingles-Torres E, Arango-Sancho P, Cabrera-Sevilla JE, Duque-Fernandez MR, Gil-Sanchez S, Garcia-Nieto VM. Can acetazolamide be used to treat diseases involving increased bone mineral density? <span><span class="ref-journal">Intractable Rare Dis Res. </span>2016;<span class="ref-vol">5</span>:284–9.</span> [<a href="/pmc/articles/PMC5116865/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC5116865</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27904825" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 27904825</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.haverkamp.1996.159">Haverkamp F, Emons D, Straehler-Pohl HJ, Zerres K. Craniometaphyseal dysplasia as a rare cause of a severe neonatal nasal obstruction. <span><span class="ref-journal">Int J Pediatr Otorhinolaryngol. </span>1996;<span class="ref-vol">34</span>:159–64.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8770684" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 8770684</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.hayashibara.2000.460">Hayashibara T, Komura T, Sobue S, Ooshima T. Tooth eruption in a patient with craniometaphyseal dysplasia: case report. <span><span class="ref-journal">J Oral Pathol Med. </span>2000;<span class="ref-vol">29</span>:460–2.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11016689" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 11016689</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.ho.2000.265">Ho AM, Johnson MD, Kingsley DM. Role of the mouse ank gene in control of tissue calcification and arthritis. <span><span class="ref-journal">Science. </span>2000;<span class="ref-vol">289</span>:265–70.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10894769" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 10894769</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.kanaujiya.2018.15710">Kanaujiya J, Bastow E, Luxmi R, Hao Z, Zattas D, Hochstrasser M, Reichenberger EJ, Chen IP. Rapid degradation of progressive ankylosis protein (ANKH) in craniometaphyseal dysplasia. <span><span class="ref-journal">Scientific Reports. </span>2018;<span class="ref-vol">8</span>:15710.</span> [<a href="/pmc/articles/PMC6200807/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC6200807</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30356088" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 30356088</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.key.1988.583">Key LL Jr, Volberg F, Baron R, Anast CS. Treatment of craniometaphyseal dysplasia with calcitriol. <span><span class="ref-journal">J Pediatr. </span>1988;<span class="ref-vol">112</span>:583–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3351684" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 3351684</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.kornak.2010.870">Kornak U, Brancati F, Le Merrer M, Lichtenbelt K, Hohne W, Tinschert S, Garaci FG, Dallapiccola B, Nurnberg P. Three novel mutations in the ANK membrane protein cause craniometaphyseal dysplasia with variable conductive hearing loss. <span><span class="ref-journal">Am J Med Genet A. </span>2010;<span class="ref-vol">152A</span>:870–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20358596" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 20358596</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.lamazza.2009.e23">Lamazza L, Messina A, D'Ambrosio F, Spink M, De Biase A. Craniometaphyseal dysplasia: a case report. <span><span class="ref-journal">Oral Surg Oral Med Oral Pathol Oral Radiol Endod. </span>2009;<span class="ref-vol">107</span>:e23–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19426903" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 19426903</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.morava.2011.e189">Morava E, K&#x000fc;hnisch J, Drijvers JM, Robben JH, Cremers C, van Setten P, Branten A, Stumpp S, de Jong A, Voesenek K, Vermeer S, Heister A, Claahsen-van der Grinten HL, O'Neill CW, Willemsen MA, Lefeber D, Deen PM, Kornak U, Kremer H, Wevers RA. Autosomal recessive mental retardation, deafness, ankylosis, and mild hypophosphatemia associated with a novel ANKH mutation in a consanguineous family. <span><span class="ref-journal">J Clin Endocrinol Metab. </span>2011;<span class="ref-vol">96</span>:E189–98.</span> [<a href="/pmc/articles/PMC5393418/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC5393418</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20943778" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 20943778</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.n_rnberg.2001.37">N&#x000fc;rnberg P, Thiele H, Chandler D, H&#x000f6;hne W, Cunningham ML, Ritter H, Leschik G, Uhlmann K, Mischung C, Harrop K, Goldblatt J, Borochowitz ZU, Kotzot D, Westermann F, Mundlos S, Braun HS, Laing N, Tinschert S. Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. <span><span class="ref-journal">Nat Genet. </span>2001;<span class="ref-vol">28</span>:37–41.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11326272" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 11326272</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.rahbari.2016.126">Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. <span><span class="ref-journal">Nat Genet. </span>2016;<span class="ref-vol">48</span>:126–33.</span> [<a href="/pmc/articles/PMC4731925/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC4731925</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26656846" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 26656846</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.reichenberger.2001.1321">Reichenberger E, Tiziani V, Watanabe S, Park L, Ueki Y, Santanna C, Baur ST, Shiang R, Grange DK, Beighton P, Gardner J, Hamersma H, Sellars S, Ramesar R, Lidral AC, Sommer A, Raposo do Amaral CM, Gorlin RJ, Mulliken JB, Olsen BR. 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Craniometaphyseal dysplasia: a case report and review of medical and surgical management. <span><span class="ref-journal">Int J Pediatr Otorhinolaryngol. </span>2003;<span class="ref-vol">67</span>:71–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12560153" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 12560153</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.taggart.2014.983">Taggart MG, Crockett DJ, Meier JD, Wiggins RH. Infant with persistent nasal obstruction. <span><span class="ref-journal">JAMA Otolaryngol Head Neck Surg. </span>2014;<span class="ref-vol">140</span>:983–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25188335" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 25188335</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.tanaka.2013.385">Tanaka M, Arataki S, Sugimoto Y, Takigawa T, Tetsunaga T, Ozaki T. Chiari type I malformation caused by craniometaphyseal dysplasia. <span><span class="ref-journal">Acta Med Okayama. </span>2013;<span class="ref-vol">67</span>:385–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24356723" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 24356723</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.wu.2016.122">Wu B, Jiang Y, Wang O, Li M, Xing XP, Xia WB. Craniometaphyseal dysplasia with obvious biochemical abnormality and rickets-like features. <span><span class="ref-journal">Clin Chim Acta. </span>2016;<span class="ref-vol">456</span>:122–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/26820766" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 26820766</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.yamamoto.1993.362">Yamamoto T, Kurihara N, Yamaoka K, Ozono K, Okada M, Yamamoto K, Matsumoto S, Michigami T, Ono J, Okada S. Bone marrow-derived osteoclast-like cells from a patient with craniometaphyseal dysplasia lack expression of osteoclast-reactive vacuolar proton pump. <span><span class="ref-journal">J Clin Invest. </span>1993;<span class="ref-vol">91</span>:362–7.</span> [<a href="/pmc/articles/PMC330035/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC330035</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/7678608" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 7678608</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="cranio-md.REF.zajac.2010.770">Zajac A, Baek SH, Salhab I, Radecki MA, Kim S, Hakonarson H, Nah HD. Novel ANKH mutation in a patient with sporadic craniometaphyseal dysplasia. <span><span class="ref-journal">Am J Med Genet A. </span>2010;<span class="ref-vol">152A</span>:770–6.</span> [<a href="/pmc/articles/PMC2944898/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC2944898</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20186813" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 20186813</span></a>]</div></li></ul></div></div><div id="cranio-md.Chapter_Notes"><h2 id="_cranio-md_Chapter_Notes_">Chapter Notes</h2><div id="cranio-md.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>11 June 2020 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>15 January 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>2 November 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>27 August 2007 (me) Review posted live</div></li><li class="half_rhythm"><div>25 May 2007 (er) Original submission</div></li></ul></div></div><div class="bk_prnt_sctn"><h2>Figures</h2><div class="whole_rhythm bk_prnt_obj bk_first_prnt_obj"><div id="cranio-md.F1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK1461/bin/cranio-md-Image001.jpg" alt="Figure 1. " /></div><h3><span class="label">Figure 1. </span></h3><div class="caption"><p>Facial features of a girl age 13 years with AD-CMD</p><p>Reprinted from <a class="bk_pop" href="#cranio-md.REF.reichenberger.2001.1321">Reichenberger et al [2001]</a> with permission from Elsevier</p></div></div></div><div class="whole_rhythm bk_prnt_obj"><div id="cranio-md.F2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK1461/bin/cranio-md-Image002.jpg" alt="Figure 2. " /></div><h3><span class="label">Figure 2. </span></h3><div class="caption"><p>Increased thickness of craniofacial bones in a child age three years with AD-CMD</p></div></div></div><div class="whole_rhythm bk_prnt_obj"><div id="cranio-md.F3" class="figure bk_fig"><div class="graphic"><img src="/books/NBK1461/bin/cranio-md-Image003.jpg" alt="Figure 3. " /></div><h3><span class="label">Figure 3. </span></h3><div class="caption"><p>Metaphyseal widening of long bones, specifically prominent at the knee joint</p></div></div></div></div><div id="bk_toc_contnr"></div></div></div>
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