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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
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<meta name="citation_title" content="PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2024/06/13">
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<meta name="citation_author" content="Marianne Rohrbach">
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<meta name="citation_author" content="Cecilia Giunta">
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<meta name="citation_pmid" content="20301635">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1462/">
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<meta name="citation_keywords" content="Ehlers-Danlos Syndrome Type VIA (EDS VIA)">
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<meta name="citation_keywords" content="Lysyl-Hydroxylase 1 Deficiency">
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<meta name="citation_keywords" content="PLOD1-kEDS">
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<meta name="citation_keywords" content="Ehlers-Danlos Syndrome Type VIA (EDS VIA),">
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<meta name="citation_keywords" content="Lysyl-Hydroxylase 1 Deficiency">
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<meta name="citation_keywords" content="PLOD1-kEDS">
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<meta name="citation_keywords" content="Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1">
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<meta name="citation_keywords" content="PLOD1">
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<meta name="citation_keywords" content="PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome">
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<meta name="DC.Title" content="PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome">
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<meta name="DC.Contributor" content="Marianne Rohrbach">
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<meta name="DC.Contributor" content="Cecilia Giunta">
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<meta name="DC.Date" content="2024/06/13">
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<meta name="description" content="PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality. Intelligence is normal. Life span may be normal, but affected individuals are at risk of life-threatening arterial ruptures and spontaneous dissections of medium-sized arteries. Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure.">
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<meta name="og:description" content="PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality. Intelligence is normal. Life span may be normal, but affected individuals are at risk of life-threatening arterial ruptures and spontaneous dissections of medium-sized arteries. Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure.">
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yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK1462_"><span class="title" itemprop="name"><i>PLOD1</i>-Related Kyphoscoliotic Ehlers-Danlos Syndrome</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Ehlers-Danlos Syndrome Type VIA (EDS VIA), Lysyl-Hydroxylase 1 Deficiency, <i>PLOD1-</i>kEDS</div><p class="contribs">Rohrbach M, Giunta C.</p><p class="fm-aai"><a href="#_NBK1462_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 23 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="eds6.Summary" itemprop="description"><h2 id="_eds6_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>PLOD1</i>-related kyphoscoliotic Ehlers-Danlos syndrome (<i>PLOD1</i>-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality. Intelligence is normal. Life span may be normal, but affected individuals are at risk of life-threatening arterial ruptures and spontaneous dissections of medium-sized arteries. Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>PLOD1</i>-kEDS is established in a proband with characteristic clinical features and biallelic pathogenic variants in <i>PLOD1</i> identified by molecular genetic testing. If only one pathogenic variant and/or variants of uncertain significance are identified, testing for a markedly increased ratio of deoxypyridinoline to pyridinoline cross-links in urine measured by high-performance liquid chromatography (a highly sensitive, specific, and inexpensive test) may be necessary for confirmation of the diagnosis.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Physical therapy to strengthen large muscle groups; swimming; management of kyphoscoliosis by an orthopedic surgeon, including surgery as needed; bracing to support unstable joints; protective pads and helmets during active sports; dermal wounds should be closed without tension, preferably in two layers; deep stitches should be applied generously; cutaneous stitches should be left in place twice as long as usual, and additional fixation of adjacent skin with adhesive tape can help prevent stretching of the scar; treatment of cardiovascular manifestations per a cardiologist; control of blood pressure to reduce the risk of arterial rupture; treatment with beta-blockers as needed to prevent aortic dilatation; standard American Heart Association guidelines for antimicrobial prophylaxis for mitral valve prolapse; corrective lenses for myopia and/or astigmatism; laser treatment of the retina for those with imminent detachment; careful stitching for hernia repair.</p><p><i>Surveillance:</i> Annual physical therapy assessment for weakness and motor issues and orthopedic assessment for management of kyphoscoliosis and recurrent dislocations; assessment for osteopenia as needed beginning at age ten to 12 years; assessment for respiratory complications as needed; echocardiogram at five-year intervals beginning at age five years; consider intermittent surveillance of the entire aorta with CT or MRA beginning in young adulthood and at least annually in anyone with aortic or arterial dilatation; annual ophthalmology examination; annual examination for inguinal hernia.</p><p><i>Agents/circumstances to avoid:</i> Sports that stress the joints, such as gymnastics or long-distance running; high-impact sports (collision sports); heavy lifting and weight training with extreme lifting; arteriography should be discouraged and used only to identify life-threatening sources of bleeding prior to surgical intervention because of the risk of vascular injury.</p><p><i>Evaluation of relatives at risk:</i> Clarify the genetic status of apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.</p><p><i>Pregnancy management</i>: Affected pregnant women may be at increased risk for miscarriage, premature rupture of membranes, and rupture of arteries. Monitoring aortic root measurement during pregnancy by echocardiogram is recommended. Delivery should be performed in a medical center with a high-risk perinatologist in attendance.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>PLOD1</i>-kEDS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a <i>PLOD1</i> pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If both <i>PLOD1</i> pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.</p></div></div><div id="eds6.Diagnosis"><h2 id="_eds6_Diagnosis_">Diagnosis</h2><div id="eds6.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>PLOD1</i>-related kyphoscoliotic Ehlers-Danlos syndrome (<i>PLOD1</i>-kEDS) <b>should be suspected</b> in individuals with minimal criteria suggestive of <i>PLOD1</i>-kEDS.</p><div id="eds6.Clinical_Features"><h4>Clinical Features</h4><p>
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<b>Major criteria</b>
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</p><ul><li class="half_rhythm"><div>Congenital muscular hypotonia</div></li><li class="half_rhythm"><div>Congenital or early-onset kyphoscoliosis (progressive or nonprogressive)</div></li><li class="half_rhythm"><div>Generalized joint hypermobility with dislocations/subluxations (shoulders, hips, and knees in particular)</div></li></ul><p>
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<b>Minor criteria</b>
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</p><ul><li class="half_rhythm"><div>Skin hyperextensibility</div></li><li class="half_rhythm"><div>Skin fragility (easy bruising, friable skin, poor wound healing, widened atrophic scarring)</div></li><li class="half_rhythm"><div>Rupture/aneurysm of a medium-sized artery</div></li><li class="half_rhythm"><div>Osteopenia/osteoporosis</div></li><li class="half_rhythm"><div>Blue sclerae, scleral and ocular fragility/rupture</div></li><li class="half_rhythm"><div>Hernia (umbilical or inguinal)</div></li><li class="half_rhythm"><div>Pectus deformity</div></li><li class="half_rhythm"><div>Marfanoid habitus</div></li><li class="half_rhythm"><div>Talipes equinovarus</div></li><li class="half_rhythm"><div>Refractive errors (myopia, hypermetropia)</div></li><li class="half_rhythm"><div>Microcornea</div></li></ul><p>
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<b>Minimal criteria suggestive of <i>PLOD1</i>-kEDS</b>
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</p><ul><li class="half_rhythm"><div>Congenital muscular hypotonia AND congenital or early-onset kyphoscoliosis; PLUS</div></li><li class="half_rhythm"><div>Either of the following:</div><ul><li class="half_rhythm"><div>Generalized joint hypermobility</div></li><li class="half_rhythm"><div>Three minor criteria</div></li></ul></li></ul></div><div id="eds6.Family_History"><h4>Family History</h4><p>Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.</p></div></div><div id="eds6.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>PLOD1-</i>kEDS <b>is established</b> in a proband with <a href="#eds6.Suggestive_Findings">suggestive findings</a> and biallelic pathogenic (or likely pathogenic) variants in <i>PLOD1</i> identified by molecular genetic testing (see <a href="/books/NBK1462/table/eds6.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobeds6Tmoleculargenetictestingusedin">Table 1</a>). If only one pathogenic variant and/or variants of uncertain significance are identified, <a href="#eds6.Additional_Confirmatory_Testing">additional confirmatory testing</a> (e.g., measuring urinary pyridinolines) may be necessary.</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bibr" href="#eds6.REF.richards.2015.405" rid="eds6.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of biallelic <i>PLOD1</i> variants of uncertain significance (or of one known <i>PLOD1</i> pathogenic variant and one <i>PLOD1</i> variant of uncertain significance) does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single-gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see <a href="#eds6.Option_1">Option 1</a>), whereas comprehensive genomic testing does not (see <a href="#eds6.Option_2">Option 2</a>).</p><div id="eds6.Option_1"><h4>Option 1</h4><p>When the phenotypic and laboratory findings suggest the diagnosis of <i>PLOD1-</i>kEDS, 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 class="half_rhythm"><b>Single-gene testing.</b> Sequence analysis of <i>PLOD1</i> is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or 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.</div><div class="half_rhythm"><b>Note:</b> A common intragenic duplication caused by an Alu-Alu recombination in introns 9 and 16 accounts for approximately 30% of pathogenic variants [<a class="bibr" href="#eds6.REF.brady.2017.70" rid="eds6.REF.brady.2017.70">Brady et al 2017</a>]. First-tier analysis of <i>PLOD1</i>, typically sequencing, should include analysis for this duplication. If this analysis does not identify one or both pathogenic variants in an individual, gene-targeted deletion/duplication analysis is performed.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A multigene panel</b> that includes <i>PLOD1</i> and other genes of interest (see <a href="#eds6.Differential_Diagnosis">Differential Diagnosis</a>) may be considered to identify the genetic cause of the condition 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><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul></div><div id="eds6.Option_2"><h4>Option 2</h4><p>When the phenotype is indistinguishable from many other inherited generalized connective tissue disorders, <b>comprehensive</b>
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<b>genomic testing</b> does not require the clinician to determine which gene is likely involved. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figeds6Tmoleculargenetictestingusedin"><a href="/books/NBK1462/table/eds6.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobeds6Tmoleculargenetictestingusedin"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="eds6.T.molecular_genetic_testing_used_in"><a href="/books/NBK1462/table/eds6.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobeds6Tmoleculargenetictestingusedin">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in <i>PLOD1</i>-Related Kyphoscoliotic Ehlers-Danlos Syndrome </p></div></div></div><div id="eds6.Additional_Confirmatory_Testing"><h4>Additional Confirmatory Testing</h4><p><b>Biochemical testing.</b> Deficiency of the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1; also called lysyl hydroxylase, or LH1) results in a deficiency in hydroxylysine-based pyridinoline cross-links in collagens. Detection of an increased ratio of deoxypyridinoline (Dpyr) to pyridinoline (Pyr) cross-links in urine quantitated by high-performance liquid chromatography is a highly sensitive and specific test for <i>PLOD1</i>-kEDS. The normal ratio of Dpyr:Pyr cross-links is approximately 0.2, whereas in <i>PLOD1</i>-kEDS the ratio is approximately 6.0 [<a class="bibr" href="#eds6.REF.steinmann.1995.1505" rid="eds6.REF.steinmann.1995.1505">Steinmann et al 1995</a>, <a class="bibr" href="#eds6.REF.rohrbach.2011.46" rid="eds6.REF.rohrbach.2011.46">Rohrbach et al 2011</a>, <a class="bibr" href="#eds6.REF.abdalla.2015.105" rid="eds6.REF.abdalla.2015.105">Abdalla et al 2015</a>]. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) can be used to detect faster migration of underhydroxylated collagen chains and their derivatives.</p></div></div></div><div id="eds6.Clinical_Characteristics"><h2 id="_eds6_Clinical_Characteristics_">Clinical Characteristics</h2><div id="eds6.Clinical_Description"><h3>Clinical Description</h3><p><i>PLOD1</i>-related kyphoscoliotic Ehlers-Danlos syndrome (<i>PLOD1</i>-kEDS) is characterized by hypotonia, early-onset kyphoscoliosis, and generalized joint hypermobility in association with skin fragility and ocular abnormality. To date, 94 individuals have been identified with biallelic pathogenic variants in <i>PLOD1</i> [<a class="bibr" href="#eds6.REF.yeowell.2000.90" rid="eds6.REF.yeowell.2000.90">Yeowell et al 2000</a>, <a class="bibr" href="#eds6.REF.brunk.2004.214" rid="eds6.REF.brunk.2004.214">Brunk et al 2004</a>, <a class="bibr" href="#eds6.REF.walker.2004.155" rid="eds6.REF.walker.2004.155">Walker et al 2004</a>, <a class="bibr" href="#eds6.REF.giunta.2005b.269" rid="eds6.REF.giunta.2005b.269">Giunta et al 2005b</a>, <a class="bibr" href="#eds6.REF.walker.2005.914" rid="eds6.REF.walker.2005.914">Walker et al 2005</a>, <a class="bibr" href="#eds6.REF.yeowell.2005.353" rid="eds6.REF.yeowell.2005.353">Yeowell et al 2005</a>, <a class="bibr" href="#eds6.REF.yi_.2008.210" rid="eds6.REF.yi_.2008.210">Yiş et al 2008</a>, <a class="bibr" href="#eds6.REF.esaka.2009.515" rid="eds6.REF.esaka.2009.515">Esaka et al 2009</a>, <a class="bibr" href="#eds6.REF.voermans.2009.2311" rid="eds6.REF.voermans.2009.2311">Voermans et al 2009</a>, <a class="bibr" href="#eds6.REF.kariminejad.2010.358" rid="eds6.REF.kariminejad.2010.358">Kariminejad et al 2010</a>, <a class="bibr" href="#eds6.REF.gok.2012.482" rid="eds6.REF.gok.2012.482">Gok et al 2012</a>, <a class="bibr" href="#eds6.REF.busch.2014.216" rid="eds6.REF.busch.2014.216">Busch et al 2014</a>, <a class="bibr" href="#eds6.REF.tosun.2014.566" rid="eds6.REF.tosun.2014.566">Tosun et al 2014</a>, <a class="bibr" href="#eds6.REF.brady.2017.70" rid="eds6.REF.brady.2017.70">Brady et al 2017</a>, <a class="bibr" href="#eds6.REF.quade.2017.92" rid="eds6.REF.quade.2017.92">Quade et al 2017</a>, <a class="bibr" href="#eds6.REF.henneton.2018.bcr2018224423" rid="eds6.REF.henneton.2018.bcr2018224423">Henneton et al 2018</a>, <a class="bibr" href="#eds6.REF.ni.2020.214" rid="eds6.REF.ni.2020.214">Ni et al 2020</a>, <a class="bibr" href="#eds6.REF.shin.2020.e96" rid="eds6.REF.shin.2020.e96">Shin et al 2020</a>, <a class="bibr" href="#eds6.REF.conti.2021.28" rid="eds6.REF.conti.2021.28">Conti et al 2021</a>, <a class="bibr" href="#eds6.REF.zhao.2021.104269" rid="eds6.REF.zhao.2021.104269">Zhao et al 2021</a>, <a class="bibr" href="#eds6.REF.colman.2022.1994" rid="eds6.REF.colman.2022.1994">Colman et al 2022</a>, <a class="bibr" href="#eds6.REF.yan.2022.813758" rid="eds6.REF.yan.2022.813758">Yan et al 2022</a>]. The following description of the phenotypic features associated with this condition is based on these reports.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figeds6Tplod1relatedkyphoscolioticehler"><a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobeds6Tplod1relatedkyphoscolioticehler"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="eds6.T.plod1related_kyphoscoliotic_ehler"><a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler/?report=objectonly" target="object" rid-ob="figobeds6Tplod1relatedkyphoscolioticehler">Table 2. </a></h4><p class="float-caption no_bottom_margin"><i>PLOD1</i>-Related Kyphoscoliotic Ehlers-Danlos Syndrome: Frequency of Select Features </p></div></div><p><b>Prenatal.</b> Pregnancy involving an affected fetus may be complicated by premature rupture of membranes.</p><p><b>Neurologic manifestations / development.</b> Muscular hypotonia with muscular weakness is common; weakness may be severe with wrist drop and may lead to upper brachial plexus palsy.</p><p>Mild-to-moderate gross motor delay is common. Walking nearly always occurs before age two years. Loss of motor milestones does not occur. Fine motor skills can be affected as well due to weakness and/or joint laxity. Intellect is unaffected.</p><p><b>Musculoskeletal manifestations.</b> Generalized joint hypermobility is present in neonates. Recurrent joint dislocations are a common serious problem. The joints most affected include hips, shoulders, knees, and wrists.</p><p>Thoracic (kypho)scoliosis is also common in the neonate. Kyphoscoliosis appears during infancy and becomes moderate to severe in childhood.</p><p>Clubfoot (talipes equinovarus) deformities are present at birth in approximately 25% of affected individuals. Pectus deformity is also present with similar frequency.</p><p>Osteopenia/osteoporosis occurs in 25% of affected individuals, but its clinical significance is currently unknown.</p><p>A marfanoid habitus is often striking, including pectus deformity (~25%), long limbs, and arachnodactyly.</p><p><b>Skin.</b> All individuals with <i>PLOD1</i>-kEDS have hyperelastic and easily stretched skin with velvety texture. The skin is friable with poor wound healing. An estimated 60% of individuals have widened atrophic scarring. Bruising occurs easily in all individuals, and severe bruising occurs in approximately 50%.</p><p><b>Cardiovascular.</b> Both aortic dilatation/dissection and rupture of medium-sized arteries may occur. The rate of progression of aortic root dilatation in <i>PLOD1</i>-kEDS is not known. Mitral valve prolapse is common. Venous ectasia following use of intravenous catheters has been reported [<a class="bibr" href="#eds6.REF.heim.1998.708" rid="eds6.REF.heim.1998.708">Heim et al 1998</a>]. Antenatal/neonatal brain hemorrhage has been described [<a class="bibr" href="#eds6.REF.giunta.2005b.269" rid="eds6.REF.giunta.2005b.269">Giunta et al 2005b</a>, <a class="bibr" href="#eds6.REF.rohrbach.2011.46" rid="eds6.REF.rohrbach.2011.46">Rohrbach et al 2011</a>, <a class="bibr" href="#eds6.REF.tosun.2014.566" rid="eds6.REF.tosun.2014.566">Tosun et al 2014</a>, <a class="bibr" href="#eds6.REF.quade.2017.92" rid="eds6.REF.quade.2017.92">Quade et al 2017</a>, <a class="bibr" href="#eds6.REF.ni.2020.214" rid="eds6.REF.ni.2020.214">Ni et al 2020</a>, <a class="bibr" href="#eds6.REF.shin.2020.e96" rid="eds6.REF.shin.2020.e96">Shin et al 2020</a>, <a class="bibr" href="#eds6.REF.yan.2022.813758" rid="eds6.REF.yan.2022.813758">Yan et al 2022</a>].</p><p><b>Eyes.</b> Bluish sclerae and refractive errors (high myopia, hypermetropia) are common. Many individuals have microcornea, although its clinical significance is unclear. Ocular fragility (scleral as opposed to corneal), which was observed in the original reports of individuals with procollagen lysyl hydroxylase deficiency [<a class="bibr" href="#eds6.REF.pinnell.1972.1013" rid="eds6.REF.pinnell.1972.1013">Pinnell et al 1972</a>], is found in a minority of individuals.</p><p><b>Hernias.</b> An equal distribution of umbilical and inguinal hernias is reported.</p><p><b>Other.</b> High palate is also reported.</p><p><b>Prognosis.</b> Life span may be normal. Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure. Vascular rupture is the major life-threatening complication in this disorder.</p></div><div id="eds6.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No genotype-phenotype correlations have been reported to date.</p></div><div id="eds6.Penetrance"><h3>Penetrance</h3><p>Penetrance for <i>PLOD1</i>-kEDS is 100%.</p></div><div id="eds6.Nomenclature"><h3>Nomenclature</h3><p>Kyphoscoliotic EDS (or EDS, kyphoscoliotic form) was initially referred to as EDS, oculoscoliotic form after its first description by <a class="bibr" href="#eds6.REF.pinnell.1972.1013" rid="eds6.REF.pinnell.1972.1013">Pinnell et al [1972]</a>.</p><p>Prior to the development of the 1998 Villefranche classification, kEDS was known as Ehlers-Danlos syndrome type VI (EDS VI) or Ehlers-Danlos syndrome type VIA (EDS VIA).</p><p><a class="bibr" href="#eds6.REF.giunta.2005a.158" rid="eds6.REF.giunta.2005a.158">Giunta et al [2005a]</a> convincingly demonstrated that Nevo syndrome is part of the spectrum of EDS VI; thus, the term "Nevo syndrome" does not refer to a distinct disorder but is now incorporated into kEDS.</p><p>In 2017, the International EDS Consortium proposed a revised EDS classification system. The new nomenclature for EDS, kyphoscoliotic form is kyphoscoliotic EDS, or kEDS [<a class="bibr" href="#eds6.REF.malfait.2017.8" rid="eds6.REF.malfait.2017.8">Malfait et al 2017</a>].</p></div><div id="eds6.Prevalence"><h3>Prevalence</h3><p><i>PLOD1</i>-kEDS is rare; the exact prevalence is unknown. A disease incidence of approximately 1:100,000 live births is a reasonable estimate.</p><p>Prevalence does not vary by race or ethnicity, although many of the reported and unreported individuals originated from Turkey, the Middle East, and Greece [<a class="bibr" href="#eds6.REF.giunta.2005a.158" rid="eds6.REF.giunta.2005a.158">Giunta et al 2005a</a>, <a class="bibr" href="#eds6.REF.giunta.2005b.269" rid="eds6.REF.giunta.2005b.269">Giunta et al 2005b</a>].</p></div></div><div id="eds6.Genetically_Related_Allelic_Disorde"><h2 id="_eds6_Genetically_Related_Allelic_Disorde_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with germline pathogenic variants in <i>PLOD1</i>.</p></div><div id="eds6.Differential_Diagnosis"><h2 id="_eds6_Differential_Diagnosis_">Differential Diagnosis</h2><p><i>PLOD1</i>-related kyphoscoliotic Ehlers-Danlos syndrome (<i>PLOD1</i>-kEDS) has some overlapping clinical features with other forms of Ehlers-Danlos syndrome (EDS), particularly <a href="/books/n/gene/eds/?report=reader">classic EDS</a> and <a href="/books/n/gene/eds4/?report=reader">vascular EDS</a>. Abnormal wound healing and joint laxity are present in many EDS types. Although all types of EDS involve a relatively high risk for scoliosis compared to the general population, scoliosis in <i>PLOD1</i>-kEDS is usually more severe and of earlier onset than that seen in other EDS types.</p><p><a href="/books/NBK1462/table/eds6.T.selected_genes_of_interest_in_the/?report=objectonly" target="object" rid-ob="figobeds6Tselectedgenesofinterestinthe">Table 3</a> lists selected EDS-related genes and other genes of interest in the differential diagnosis of <i>PLOD1</i>-kEDS. Of note, all of the disorders in <a href="/books/NBK1462/table/eds6.T.selected_genes_of_interest_in_the/?report=objectonly" target="object" rid-ob="figobeds6Tselectedgenesofinterestinthe">Table 3</a> can be biochemically distinguished from <i>PLOD1</i>-kEDS by normal lysyl hydroxylase enzyme activity as indicated by the absence of a markedly increased ratio of deoxypyridinoline to pyridinoline cross-links in urine.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figeds6Tselectedgenesofinterestinthe"><a href="/books/NBK1462/table/eds6.T.selected_genes_of_interest_in_the/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobeds6Tselectedgenesofinterestinthe"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="eds6.T.selected_genes_of_interest_in_the"><a href="/books/NBK1462/table/eds6.T.selected_genes_of_interest_in_the/?report=objectonly" target="object" rid-ob="figobeds6Tselectedgenesofinterestinthe">Table 3. </a></h4><p class="float-caption no_bottom_margin">Selected Genes of Interest in the Differential Diagnosis of <i>PLOD1</i>-Related Kyphoscoliotic Ehlers-Danlos Syndrome </p></div></div><p><b>Congenital myopathies.</b> Most congenital myopathies present with poor muscle tone and increased range of motion of small and large joints. Joint laxity can be difficult to distinguish from muscular hypotonia, particularly in infants and children. In <i>PLOD1</i>-kEDS, in which both hypotonia and joint laxity are present, the increased range of motion is often striking. Velvety skin texture may help distinguish <i>PLOD1</i>-kEDS from congenital myopathies such as <a href="/books/n/gene/mtm/?report=reader">X-linked myotubular myopathy</a>. Unlike <a href="/books/n/gene/sma/?report=reader">spinal muscular atrophy</a>, <i>PLOD1</i>-kEDS is characterized by normal deep tendon reflexes.</p><p><b>Disorders with early-onset hypotonia.</b> Many syndromic and metabolic disorders include early-onset hypotonia. In these disorders, however, the other manifestations of <i>PLOD1</i>-kEDS are generally absent, and additional features are usually present.</p></div><div id="eds6.Management"><h2 id="_eds6_Management_">Management</h2><p>No clinical practice guidelines for <i>PLOD1</i>-related kyphoscoliotic Ehlers-Danlos syndrome (<i>PLOD1</i>-kEDS) have been published.</p><div id="eds6.Evaluations_Following_Initial_Diagn"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <i>PLOD1</i>-kEDS, the evaluations summarized in <a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler_1/?report=objectonly" target="object" rid-ob="figobeds6Tplod1relatedkyphoscolioticehler1">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figeds6Tplod1relatedkyphoscolioticehler1"><a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler_1/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobeds6Tplod1relatedkyphoscolioticehler1"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="eds6.T.plod1related_kyphoscoliotic_ehler_1"><a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler_1/?report=objectonly" target="object" rid-ob="figobeds6Tplod1relatedkyphoscolioticehler1">Table 4. </a></h4><p class="float-caption no_bottom_margin"><i>PLOD1</i>-Related Kyphoscoliotic Ehlers-Danlos Syndrome: Recommended Evaluations Following Initial Diagnosis </p></div></div></div><div id="eds6.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>There is no cure for <i>PLOD1</i>-kEDS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see <a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler_2/?report=objectonly" target="object" rid-ob="figobeds6Tplod1relatedkyphoscolioticehler2">Table 5</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figeds6Tplod1relatedkyphoscolioticehler2"><a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler_2/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobeds6Tplod1relatedkyphoscolioticehler2"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="eds6.T.plod1related_kyphoscoliotic_ehler_2"><a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler_2/?report=objectonly" target="object" rid-ob="figobeds6Tplod1relatedkyphoscolioticehler2">Table 5. </a></h4><p class="float-caption no_bottom_margin"><i>PLOD1</i>-Related Kyphoscoliotic Ehlers-Danlos Syndrome: Treatment of Manifestations </p></div></div></div><div id="eds6.Surveillance"><h3>Surveillance</h3><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in <a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler_3/?report=objectonly" target="object" rid-ob="figobeds6Tplod1relatedkyphoscolioticehler3">Table 6</a> are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figeds6Tplod1relatedkyphoscolioticehler3"><a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler_3/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobeds6Tplod1relatedkyphoscolioticehler3"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="eds6.T.plod1related_kyphoscoliotic_ehler_3"><a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler_3/?report=objectonly" target="object" rid-ob="figobeds6Tplod1relatedkyphoscolioticehler3">Table 6. </a></h4><p class="float-caption no_bottom_margin"><i>PLOD1</i>-Related Kyphoscoliotic Ehlers-Danlos Syndrome: Recommended Surveillance </p></div></div></div><div id="eds6.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>In children with significant joint hyperextensibility, sports that place stress on the joints (e.g., gymnastics, long-distance running) should be avoided.</p><p>High-impact sports (collision sports), heavy lifting, and weight training with extreme lifting should be avoided.</p><p>Arteriography should be discouraged and used only to identify life-threatening sources of bleeding prior to surgical intervention because of the risk of vascular injury.</p></div><div id="eds6.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include:</p><ul><li class="half_rhythm"><div>Molecular genetic testing if both <i>PLOD1</i> pathogenic variants have been identified in the proband;</div></li><li class="half_rhythm"><div>Measurement of cross-links in urine for markedly increased ratio of deoxypyridinoline to pyridinoline by high-performance liquid chromatography if only one or no pathogenic variant in <i>PLOD1</i> has been identified in the proband and the diagnosis in the proband was established with biochemical testing. (Note: Carrier status cannot be reliably ascertained by biochemical testing or by enzyme assay.)</div></li></ul><p>See <a href="#eds6.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="eds6.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Affected pregnant women may be at increased risk for miscarriage, premature rupture of membranes, and rupture of arteries [<a class="bibr" href="#eds6.REF.esaka.2009.515" rid="eds6.REF.esaka.2009.515">Esaka et al 2009</a>]. Two affected women had a total of seven pregnancies resulting in three miscarriages and four healthy children, three of whom were born vaginally at term and one of whom was born at 24 weeks; there were no maternal complications [B Steinmann, unpublished data]. Monitoring aortic root measurement during pregnancy by echocardiogram is recommended. Delivery should be performed in a medical center with a high-risk perinatologist in attendance.</p></div><div id="eds6.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="eds6.Genetic_Counseling"><h2 id="_eds6_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="eds6.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>PLOD1</i>-related kyphoscoliotic Ehlers-Danlos syndrome (<i>PLOD1</i>-kEDS) is inherited in an autosomal recessive manner.</p></div><div id="eds6.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>The parents of an affected child are presumed to be heterozygous for a <i>PLOD1</i> pathogenic variant.</div></li><li class="half_rhythm"><div>If both <i>PLOD1</i> pathogenic variants have been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a <i>PLOD1</i> pathogenic variant and to allow reliable recurrence risk assessment.</div></li><li class="half_rhythm"><div>If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a <i>de novo</i> event in the proband or as a postzygotic <i>de novo</i> event in a mosaic parent [<a class="bibr" href="#eds6.REF.j_nsson.2017.519" rid="eds6.REF.j_nsson.2017.519">Jónsson et al 2017</a>]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:</div><ul><li class="half_rhythm"><div>A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;</div></li><li class="half_rhythm"><div>Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.</div></li></ul></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
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<b>Sibs of a proband</b>
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</p><ul><li class="half_rhythm"><div>If both parents are known to be heterozygous for a <i>PLOD1</i> pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p><b>Offspring of a proband.</b> The offspring of an individual with <i>PLOD1</i>-kEDS are obligate heterozygotes (carriers).</p><p><b>Other family members.</b> Each sib of the proband's parents is at a 50% risk of being a carrier of a <i>PLOD1</i> pathogenic variant.</p></div><div id="eds6.Carrier_Detection"><h3>Carrier Detection</h3><p><b>Molecular genetic testing.</b> Carrier testing for at-risk relatives requires prior identification of the <i>PLOD1</i> pathogenic variants in the family.</p><p><b>Biochemical testing.</b> Although carriers do tend to have a slightly elevated ratio of deoxypyridinoline (Dpyr) to pyridinoline (Pyr) cross-links in urine [<a class="bibr" href="#eds6.REF.kraenzlin.2008.1546" rid="eds6.REF.kraenzlin.2008.1546">Kraenzlin et al 2008</a>], carrier status cannot be reliably ascertained by biochemical testing or enzyme assay.</p></div><div id="eds6.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#eds6.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p>
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<b>Family planning</b>
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</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, are carriers, or are at risk of being carriers.</div></li><li class="half_rhythm"><div>Affected pregnant women may be at increased risk for miscarriage, premature rupture of membranes, and rupture of arteries (see <a href="#eds6.Pregnancy_Management">Pregnancy Management</a>).</div></li></ul></div><div id="eds6.Prenatal_Testing_and_Preimplantatio"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>PLOD1</i> pathogenic variants have been identified in an affected family member, molecular genetic 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="eds6.Resources"><h2 id="_eds6_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>Ehlers-Danlos Society - Europe</b>
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</div><div>United Kingdom</div><div><b>Phone:</b> +44 203 887 6132</div></li><li class="half_rhythm"><div>
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<b>Ehlers-Danlos Support UK</b>
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</div><div>United Kingdom</div><div><b>Phone:</b> 0800 907 8518</div><div>
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<a href="http://www.ehlers-danlos.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ehlers-danlos.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>The Ehlers-Danlos Society</b>
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</div><div><b>Phone:</b> 248-716-8336</div><div>
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<a href="https://www.ehlers-danlos.com/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ehlers-danlos.com</a>
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</div></li><li class="half_rhythm"><div>
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<b>MedlinePlus</b>
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</div><div>
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<a href="http://www.nlm.nih.gov/medlineplus/ehlersdanlossyndrome.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Ehlers-Danlos Syndrome</a>
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</div></li><li class="half_rhythm"><div>
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<b>DICE EDS and HSD Global Registry</b>
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</div><div>
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<a href="https://www.ehlers-danlos.com/eds-global-registry/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ehlers-danlos.com/eds-global-registry</a>
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</div></li></ul>
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</div><div id="eds6.Molecular_Genetics"><h2 id="_eds6_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figeds6molgenTA"><a href="/books/NBK1462/table/eds6.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobeds6molgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="eds6.molgen.TA"><a href="/books/NBK1462/table/eds6.molgen.TA/?report=objectonly" target="object" rid-ob="figobeds6molgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figeds6molgenTB"><a href="/books/NBK1462/table/eds6.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobeds6molgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="eds6.molgen.TB"><a href="/books/NBK1462/table/eds6.molgen.TB/?report=objectonly" target="object" rid-ob="figobeds6molgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome (View All in OMIM) </p></div></div><div id="eds6.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>PLOD1</i> encodes procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1; also called lysyl hydroxylase, or LH1). This enzyme hydroxylates lysyl residues in -Xaa-Lys-Gly- collagen sequences, which serve as sites of attachment for carbohydrate units and play an essential role in the formation of intra- and intermolecular collagen cross-links. Lack of PLOD1 leads to decreased hydroxylation and glycosylation of lysine-amino residues in collagen, resulting in compromised formation of collagen cross-links and subsequent mechanical instability in the tissues affected.</p><p><b>Mechanism of disease causation.</b> Loss of function. Western blot analysis using polyclonal antibody to recombinant PLOD1 showed decreased levels of PLOD1 in two individuals with <i>PLOD1</i>-related kyphoscoliotic Ehlers-Danlos syndrome [<a class="bibr" href="#eds6.REF.walker.2004.155" rid="eds6.REF.walker.2004.155">Walker et al 2004</a>].</p><p><b><i>PLOD1</i>-specific laboratory technical considerations.</b> A common pathogenic variant, a duplication of exons 10-16, is caused by a homologous recombination event between identical 44-bp Alu sequences in introns 9 and 16 [<a class="bibr" href="#eds6.REF.pousi.1994.899" rid="eds6.REF.pousi.1994.899">Pousi et al 1994</a>]. <i>PLOD1</i> testing should include analysis for this duplication.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figeds6Tplod1pathogenicvariantsreferen"><a href="/books/NBK1462/table/eds6.T.plod1_pathogenic_variants_referen/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobeds6Tplod1pathogenicvariantsreferen"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="eds6.T.plod1_pathogenic_variants_referen"><a href="/books/NBK1462/table/eds6.T.plod1_pathogenic_variants_referen/?report=objectonly" target="object" rid-ob="figobeds6Tplod1pathogenicvariantsreferen">Table 7. </a></h4><p class="float-caption no_bottom_margin"><i>PLOD1</i> Pathogenic Variants Referenced in This <i>GeneReview</i> </p></div></div></div></div><div id="eds6.Chapter_Notes"><h2 id="_eds6_Chapter_Notes_">Chapter Notes</h2><div id="eds6.Author_Notes"><h3>Author Notes</h3><p>
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<a href="https://www.uzh.ch/en/explore/hospitals/kispi.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">University Children's Hospital Zurich</a>
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</p></div><div id="eds6.Author_History"><h3>Author History</h3><p>Cecilia Giunta, PhD (2024-present)<br />Marianne Rohrbach, MD, PhD (2024-present)<br />Beat Steinmann, MD; University Children's Hospital Zurich (2008-2024)<br />Richard Wenstrup, MD; Cincinnati Children's Hospital Medical Center (1999-2008)<br />Heather N Yeowell, PhD; Duke University Medical Center (2005-2024)</p></div><div id="eds6.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>13 June 2024 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>12 April 2018 (ha) Comprehensive update posted live</div></li><li class="half_rhythm"><div>24 January 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>19 February 2008 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>12 July 2005 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>12 March 2003 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>2 February 2000 (me) Review posted live</div></li><li class="half_rhythm"><div>7 April 1999 (rw) Original submission</div></li></ul></div></div><div id="eds6.References"><h2 id="_eds6_References_">References</h2><div id="eds6.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="eds6.REF.abdalla.2015.105">Abdalla
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LC, Overstreet
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LC, Overstreet
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MA, Willing
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MC, Marini
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JC, Cabral
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HN. Heterogeneous basis of the type VIB form of Ehlers-Danlos syndrome (EDS VIB) that is unrelated to decreased collagen lysyl hydroxylation.
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[<a href="/pmc/articles/PMC8891444/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8891444</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35252061" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35252061</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="eds6.REF.yeowell.2000.90">Yeowell
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HN, Walker
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R. Mutational analysis of the lysyl hydroxylase 1 gene in six unrelated patients affected by Ehlers-Danlos syndrome type VI; prenatal exclusion of this disorder in one family.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/10874315" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10874315</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="eds6.REF.yeowell.2005.353">Yeowell
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HN, Walker
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LM. An Ehlers-Danlos syndrome type VIA patient with cystic malformations of the meninges.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/16172044" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16172044</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="eds6.REF.yi_.2008.210">Yiş
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U, Dirik
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C. Differential diagnosis of muscular hypotonia in infants: the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VI).
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Neuromuscul Disord.
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2008;18:210-4.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/18155911" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18155911</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="eds6.REF.zhao.2021.104269">Zhao
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Y, Sun
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J, Chen
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Y, Hu
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L. Two novel variants in PLOD1 causing hydrocephalus in female newborn with kyphoscoliotic Ehlers-Danlos syndrome.
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Eur J Med Genet.
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2021;64:104269.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/34161861" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34161861</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1462_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Marianne Rohrbach</span>, MD, PhD<div class="affiliation small">Division of Metabolism<br />University Children's Hospital Zurich<br />University of Zurich<br />Zurich, Switzerland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="hc.hzu.ipsik@hcabrhor.ennairam" class="oemail">hc.hzu.ipsik@hcabrhor.ennairam</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Cecilia Giunta</span>, PhD<div class="affiliation small">Division of Metabolism<br />University Children's Hospital Zurich<br />University of Zurich<br />Zurich, Switzerland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="hc.hzu.ipsik@atnuig.ailicec" class="oemail">hc.hzu.ipsik@atnuig.ailicec</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">February 2, 2000</span>; Last Update: <span itemprop="dateModified">June 13, 2024</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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a registered trademark of the University of Washington, Seattle. All rights
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reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
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Washington) are included with each copy; (ii) a link to the original material is provided
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whenever the material is published elsewhere on the Web; and (iii) reproducers,
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distributors, and/or translators comply with the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Rohrbach M, Giunta C. PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome. 2000 Feb 2 [Updated 2024 Jun 13]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/inad/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/pmd/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobeds6Tmoleculargenetictestingusedin"><div id="eds6.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>PLOD1</i>-Related Kyphoscoliotic Ehlers-Danlos Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1462/table/eds6.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds6.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds6.T.molecular_genetic_testing_used_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_eds6.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_eds6.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_eds6.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>PLOD1</i>
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</td><td headers="hd_h_eds6.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_eds6.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">67% <sup>4, 5</sup></td></tr><tr><td headers="hd_h_eds6.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>6</sup></td><td headers="hd_h_eds6.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">33% <sup>5</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="eds6.TF.1.1"><p class="no_margin">See <a href="/books/NBK1462/?report=reader#eds6.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="eds6.TF.1.2"><p class="no_margin">See <a href="#eds6.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="eds6.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 missense, nonsense, and splice site variants and small intragenic deletions/insertions; 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/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="eds6.TF.1.4"><p class="no_margin">
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<a class="bibr" href="#eds6.REF.brady.2017.70" rid="eds6.REF.brady.2017.70">Brady et al [2017]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="eds6.TF.1.5"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bibr" href="#eds6.REF.stenson.2020.1197" rid="eds6.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="eds6.TF.1.6"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobeds6Tplod1relatedkyphoscolioticehler"><div id="eds6.T.plod1related_kyphoscoliotic_ehler" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p><i>PLOD1</i>-Related Kyphoscoliotic Ehlers-Danlos Syndrome: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds6.T.plod1related_kyphoscoliotic_ehler_lrgtbl__"><table><thead><tr><th id="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons w/Feature</th><th id="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_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_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hypotonia</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Gross motor delay</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~60%</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Scoliosis/kyphoscoliosis</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">95%</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Recurrent dislocations</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~30%</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Clubfoot</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~20%</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Osteopenia/osteoporosis</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~20%</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Skin manifestations</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">97%</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hyperelastic & easily stretched skin</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cardiovascular manifestations</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~30%</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Vascular rupture</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Ocular manifestations</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">45%</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bluish sclerae, refractive errors, scleral & ocular fragility/rupture, microcornea</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hernias</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~15%</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Umbilical or inguinal</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobeds6Tselectedgenesofinterestinthe"><div id="eds6.T.selected_genes_of_interest_in_the" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Selected Genes of Interest in the Differential Diagnosis of <i>PLOD1</i>-Related Kyphoscoliotic Ehlers-Danlos Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1462/table/eds6.T.selected_genes_of_interest_in_the/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds6.T.selected_genes_of_interest_in_the_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_2" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Clinical Features of Disorder</th></tr><tr><th headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4" id="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/<i>PLOD1</i>-kEDS</th><th headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4" id="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from <i>PLOD1</i>-kEDS</th></tr></thead><tbody><tr><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_1 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_2 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_3 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_1 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_2" colspan="5" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">
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<b>Other forms of Ehlers-Danlos syndrome (EDS)</b>
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</td></tr><tr><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>AEBP1</i>
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</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Classical-like EDS type 2 (OMIM <a href="https://omim.org/entry/618000" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">618000</a>)</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Atrophic scarring, easy bruising</div></li><li class="half_rhythm"><div>Joint hypermobility</div></li><li class="half_rhythm"><div>Skin hyperextensibility</div></li></ul>
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</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Prematurely aged appearance</div></li><li class="half_rhythm"><div>Thinning of hair or (partial) alopecia</div></li></ul>
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</td></tr><tr><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>B3GALT6</i>
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<br />
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<i>B4GALT7</i>
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<br />
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<i>SLC39A13</i>
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</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Spondylodysplastic EDS (spEDS) (OMIM <a href="https://omim.org/entry/130070" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">130070</a>, <a href="https://omim.org/entry/612350" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">612350</a>, <a href="https://omim.org/entry/615349" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615349</a>)</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Joint hypermobility</div></li><li class="half_rhythm"><div>Poor wound healing</div></li><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>Skin hyperextensibility</div></li></ul>
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</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variable by related gene:
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<ul><li class="half_rhythm"><div>Progeroid characteristics</div></li><li class="half_rhythm"><div>Vertebral dysplasia w/moderate short stature & characteristic features of the hands (thenar atrophy, short metacarpals & phalanges, inability to adduct thumbs)</div></li></ul>
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</td></tr><tr><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CHST14</i>
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<br />
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<i>DSE</i>
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</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Musculocontractural EDS<br />(OMIM <a href="https://omim.org/entry/601776" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">601776</a>, <a href="https://omim.org/entry/615539" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615539</a>)</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Blue sclerae</div></li><li class="half_rhythm"><div>Marfanoid habitus</div></li><li class="half_rhythm"><div>Generalized joint hypermobility</div></li><li class="half_rhythm"><div>Scoliosis</div></li><li class="half_rhythm"><div>Skin hyperextensibility</div></li><li class="half_rhythm"><div>Easy bruising; atrophic scarring</div></li><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>Refractive errors</div></li></ul>
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</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Characteristic facies</div></li><li class="half_rhythm"><div>Adducted thumbs & feet <sup>1</sup></div></li><li class="half_rhythm"><div>Gastrointestinal & genitourinary manifestations</div></li></ul>
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</td></tr><tr><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>COL3A1</i><br />(<i>COL1A1</i>) <sup>2</sup></td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/eds4/?report=reader">Vascular EDS</a> (vEDS)</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD <sup>3</sup></td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Vascular rupture (may be a feature of <i>PLOD1</i>-kEDS)</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Intestinal rupture</div></li><li class="half_rhythm"><div>Uterine rupture during pregnancy</div></li></ul>
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</td></tr><tr><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>COL5A1</i><br /><i>COL5A2</i><br />(<i>COL1A1</i>) <sup>4</sup></td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/eds/?report=reader">Classic EDS</a> (cEDS)</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Atrophic scarring, easy bruising</div></li><li class="half_rhythm"><div>Joint hypermobility</div></li><li class="half_rhythm"><div>Skin hyperextensibility</div></li></ul>
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</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Absence of congenital muscular hypotonia</div></li><li class="half_rhythm"><div>Scoliosis rather than kyphoscoliosis</div></li></ul>
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</td></tr><tr><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FKBP14</i>
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</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/fkbp14-keds/?report=reader"><i>FKBP14</i>-kEDS</a>
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</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Congenital muscular hypotonia</div></li><li class="half_rhythm"><div>Congenital/early-onset kyphoscoliosis</div></li><li class="half_rhythm"><div>Generalized joint hypermobility</div></li></ul>
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</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Myopathy</div></li><li class="half_rhythm"><div>Hearing loss</div></li></ul>
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</td></tr><tr><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>TNXB</i>
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</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/tnxb-eds/?report=reader"><i>TNXB-</i>related classical-like EDS</a> (clEDS)</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Easy bruising</div></li><li class="half_rhythm"><div>Joint hypermobility</div></li><li class="half_rhythm"><div>Skin hyperextensibility, velvety skin</div></li></ul>
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</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absence of atrophic scarring & kyphoscoliosis</td></tr><tr><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_1 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_2 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_3 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_1 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_2" colspan="5" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">
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<b>Other disorders</b>
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</td></tr><tr><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>PRDM5</i>
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<br />
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<i>ZNF469</i>
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</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Brittle cornea syndrome (OMIM <a href="https://omim.org/phenotypicSeries/PS229200" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS229200</a>)</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Corneal disorder</div></li><li class="half_rhythm"><div>Skin hyperelasticity</div></li><li class="half_rhythm"><div>Joint hypermobility</div></li></ul>
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</td><td headers="hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_1_4 hd_h_eds6.T.selected_genes_of_interest_in_the_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Thinning of cornea w/risk of rupture</div></li><li class="half_rhythm"><div>Deafness (mixed conductive & sensorineural)</div></li></ul>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AR = autosomal recessive; EDS = Ehlers-Danlos syndrome; MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="eds6.TF.3.1"><p class="no_margin"><a class="bibr" href="#eds6.REF.malfait.2010.1233" rid="eds6.REF.malfait.2010.1233">Malfait et al [2010]</a>, <a class="bibr" href="#eds6.REF.janecke.2016.103" rid="eds6.REF.janecke.2016.103">Janecke et al [2016]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="eds6.TF.3.2"><p class="no_margin">Pathogenic variants in <i>COL1A1</i> are listed as a rare cause of vEDS in the 2017 International Classification of the Ehlers-Danlos Syndromes [<a class="bibr" href="#eds6.REF.malfait.2017.8" rid="eds6.REF.malfait.2017.8">Malfait et al 2017</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="eds6.TF.3.3"><p class="no_margin">Vascular EDS is almost always inherited in an autosomal dominant manner, but rare examples of biallelic inheritance have been reported.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="eds6.TF.3.4"><p class="no_margin">The proportion of cEDS attributed to pathogenic variants in <i>COL5A1</i> is 75%-78%; in <i>COL5A2</i>, 14%; and in <i>COL1A1</i>, <1%. The associated gene is unknown in ≤10% of individuals with cEDS.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobeds6Tplod1relatedkyphoscolioticehler1"><div id="eds6.T.plod1related_kyphoscoliotic_ehler_1" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p><i>PLOD1</i>-Related Kyphoscoliotic Ehlers-Danlos Syndrome: Recommended Evaluations Following Initial Diagnosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds6.T.plod1related_kyphoscoliotic_ehler_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neuromuscular</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PT eval to develop plan for ongoing therapy to strengthen large muscle groups & prevent recurrent shoulder dislocation</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Musculoskeletal</b>
|
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval for kyphoscoliosis incl photographs & radiographs</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Documentation is recommended in view of progressive kyphoscoliosis.</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Referral to orthopedics for those w/clubfoot</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Skin</b>
|
|
</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/dermatologist to review skin findings & discuss treatment of abnormal wound healing</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cardiovascular</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of aortic root size & assessment of heart valves by echocardiogram</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At diagnosis or by age 5 yrs</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Visualization of entire aorta w/CT or MRA</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By young adulthood, or earlier if aortic or arterial dilatation is identified on echocardiogram</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Eyes</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Formal ophthalmologic eval for myopia, astigmatism, & retinal detachment</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hernia</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to surgery for those needing hernia repair</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Genetic counseling</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of <i>PLOD1</i>-kEDS to facilitate medical & personal decision making</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">MOI = mode of inheritance; MRA = magnetic resonance angiogram; <i>PLOD1</i>-kEDS = <i>PLOD1</i>-related kyphoscoliotic Ehlers-Danlos syndrome; PT = physical therapy</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="eds6.TF.4.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobeds6Tplod1relatedkyphoscolioticehler2"><div id="eds6.T.plod1related_kyphoscoliotic_ehler_2" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p><i>PLOD1</i>-Related Kyphoscoliotic Ehlers-Danlos Syndrome: Treatment of Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler_2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds6.T.plod1related_kyphoscoliotic_ehler_2_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neuromuscular</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>PT for older children, adolescents, & adults to strengthen large muscle groups, particularly at the shoulder girdle, & to prevent recurrent shoulder dislocation</div></li><li class="half_rhythm"><div>Swimming is recommended.</div></li></ul>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Musculoskeletal</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Referral to orthopedic surgeon for mgmt of kyphoscoliosis</div></li><li class="half_rhythm"><div>Bracing may be required to support unstable joints.</div></li></ul>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedic surgery is not contraindicated in persons w/<i>PLOD1</i>-kEDS & can be performed as necessary.</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Skin</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Due to skin fragility, protective pads over knees, shins, & elbows may prevent lacerations, particularly in children.</div></li><li class="half_rhythm"><div>Use of helmets for active sports</div></li><li class="half_rhythm"><div>Close dermal wounds w/o tension, preferably in 2 layers.</div></li><li class="half_rhythm"><div>Apply deep stitches generously.</div></li><li class="half_rhythm"><div>Leave cutaneous stitches in place twice as long as usual, & additional fixation of adjacent skin w/adhesive tape can help prevent stretching of the scar.</div></li></ul>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cardiovascular</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Treatment per cardiologist</div></li><li class="half_rhythm"><div>Vigilant observation & control of blood pressure can ↓ risk of arterial rupture.</div></li><li class="half_rhythm"><div>Those w/aortic dilatation may require treatment w/beta-blockers to prevent further expansion.</div></li><li class="half_rhythm"><div>Those w/mitral valve prolapse should follow standard AHA guidelines for antimicrobial prophylaxis.</div></li></ul>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Vascular surgery is fraught w/danger. While virtually no surgical literature exists on <i>PLOD1</i>-kEDS, see <a class="bibr" href="#eds6.REF.freeman.1996.869" rid="eds6.REF.freeman.1996.869">Freeman et al [1996]</a> for review of similar surgical complications reported in vascular EDS.</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Ophthalmologic</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Corrective lenses for myopia &/or astigmatism</div></li><li class="half_rhythm"><div>Laser treatment of retina in those w/imminent detachment</div></li></ul>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hernia</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Careful stitching is required for hernia repair.</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AHA = American Heart Association; EDS = Ehlers-Danlos syndrome; <i>PLOD1</i>-kEDS = <i>PLOD1</i>-related kyphoscoliotic Ehlers-Danlos syndrome; PT = physical therapy</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobeds6Tplod1relatedkyphoscolioticehler3"><div id="eds6.T.plod1related_kyphoscoliotic_ehler_3" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p><i>PLOD1</i>-Related Kyphoscoliotic Ehlers-Danlos Syndrome: Recommended Surveillance</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1462/table/eds6.T.plod1related_kyphoscoliotic_ehler_3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds6.T.plod1related_kyphoscoliotic_ehler_3_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neuromuscular</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PT assessment for weakness & motor issues</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Annually or more frequently as needed</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Musculoskeletal</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics assessment for kyphoscoliosis & recurrent dislocations</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Assessment for osteopenia per orthopedist</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As needed beginning at age 10-12 yrs</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Respiratory</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment for respiratory complications due to severe kyphoscoliosis per pulmonologist</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As needed in those w/severe kyphoscoliosis</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cardiovascular</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assessment w/cardiologist</div></li><li class="half_rhythm"><div>Echocardiogram</div></li></ul>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 5 yrs beginning at age 5 yrs, or as recommended by cardiologist</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">CT or MRA for medium-sized arteries & entire aorta</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider intermittently beginning in young adults & at least annually in those w/aortic or arterial dilatation</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Monitor blood pressure.</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per cardiologist</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Ophthalmologic</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic exam for mgmt of myopia & early detection of glaucoma or retinal detachment</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hernia</b>
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</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Exam for inguinal hernia</td><td headers="hd_h_eds6.T.plod1related_kyphoscoliotic_ehler_3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually or as needed</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">MRA = magnetic resonance angiogram; PT = physical therapy</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobeds6molgenTA"><div id="eds6.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1462/table/eds6.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds6.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_eds6.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_eds6.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_eds6.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_eds6.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_eds6.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_eds6.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_eds6.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/5351" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>PLOD1</i>
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</a>
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</td><td headers="hd_b_eds6.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=5351" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">1p36<wbr style="display:inline-block"></wbr>​.22</a>
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</td><td headers="hd_b_eds6.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/Q02809" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1</a>
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</td><td headers="hd_b_eds6.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://databases.lovd.nl/shared/genes/PLOD1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PLOD1 @ LOVD</a>
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</td><td headers="hd_b_eds6.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PLOD1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PLOD1</a>
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</td><td headers="hd_b_eds6.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=PLOD1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PLOD1</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="eds6.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
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chromosome locus from
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
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<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobeds6molgenTB"><div id="eds6.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome (<a href="/omim/153454,225400" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1462/table/eds6.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds6.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/153454" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">153454</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PROCOLLAGEN-LYSINE, 2-OXOGLUTARATE 5-DIOXYGENASE; PLOD1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/225400" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">225400</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EHLERS-DANLOS SYNDROME, KYPHOSCOLIOTIC TYPE, 1; EDSKSCL1</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobeds6Tplod1pathogenicvariantsreferen"><div id="eds6.T.plod1_pathogenic_variants_referen" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p><i>PLOD1</i> Pathogenic Variants Referenced in This <i>GeneReview</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1462/table/eds6.T.plod1_pathogenic_variants_referen/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__eds6.T.plod1_pathogenic_variants_referen_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000302.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000302<wbr style="display:inline-block"></wbr>​.3</a>
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</td><td headers="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">8.9-kb duplication of exons 10-16 <sup>1</sup></td><td headers="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Most common pathogenic variant; allele frequency was 30% in probands from 73 families [<a class="bibr" href="#eds6.REF.yeowell.2005.353" rid="eds6.REF.yeowell.2005.353">Yeowell et al 2005</a>, <a class="bibr" href="#eds6.REF.brady.2017.70" rid="eds6.REF.brady.2017.70">Brady et al 2017</a>].</td></tr><tr><td headers="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000302.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000302<wbr style="display:inline-block"></wbr>​.3</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000293.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000293<wbr style="display:inline-block"></wbr>​.2</a>
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</td><td headers="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.955C>T</td><td headers="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg319Ter</td><td headers="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Common variant in Arab population [<a class="bibr" href="#eds6.REF.brady.2017.70" rid="eds6.REF.brady.2017.70">Brady et al 2017</a>]</td></tr><tr><td headers="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1533C>G</td><td headers="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Tyr511Ter</td><td headers="hd_h_eds6.T.plod1_pathogenic_variants_referen_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Third most common pathogenic variant [<a class="bibr" href="#eds6.REF.brady.2017.70" rid="eds6.REF.brady.2017.70">Brady et al 2017</a>]</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>). See <a href="/books/n/gene/app3/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.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></div></div>
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