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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Thanatophoric Dysplasia - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_title" content="Thanatophoric Dysplasia">
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<meta name="citation_date" content="2023/05/18">
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<meta name="citation_author" content="Tegan French">
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<meta name="citation_author" content="Ravi Savarirayan">
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id="jr-pm-right" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Next Page</text></svg></nav><nav id="jr-fip" class="hidden"><nav id="jr-fip-term-p"><input type="search" placeholder="search this page" id="jr-fip-term" autocorrect="off" autocomplete="off" /><a id="jr-fip-mg" class="wsprkl btn" title="Find"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 550 600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-fip-done" class="wsprkl btn" title="Dismiss find">✘</a></nav><nav id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches 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="_NBK1366_"><span class="title" itemprop="name">Thanatophoric Dysplasia</span></h1><p class="contribs">French T, Savarirayan R.</p><p class="fm-aai"><a href="#_NBK1366_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 29 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="td.Summary" itemprop="description"><h2 id="_td_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Thanatophoric dysplasia (TD) is a short-limb skeletal dysplasia that is usually lethal in the perinatal period. TD is divided into subtypes:</p><ul><li class="half_rhythm"><div>TD type 1 is characterized by micromelia with bowed femurs and, uncommonly, the presence of craniosynostosis of varying severity.</div></li><li class="half_rhythm"><div>TD type 2 is characterized by micromelia with straight femurs and uniform presence of moderate-to-severe craniosynostosis with cloverleaf skull deformity.</div></li></ul><p>Other features common to type 1 and type 2 include: short ribs, narrow thorax, relative macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. Most affected infants die of respiratory insufficiency shortly after birth. Rare long-term survivors have been reported.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of TD is established in a proband with characteristic clinical and/or radiologic features and/or a heterozygous pathogenic variant in <i>FGFR3</i> identified on molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Most individuals with TD die in the perinatal period because of the multisystem complications of the disorder. Management goals should be established with the family and may focus on provision of comfort care. Newborns require long-term respiratory support (typically with tracheostomy and ventilation) to survive. Anesthetic management guidelines for skeletal dysplasias are applicable to individuals with TD. Other treatment measures may include shunt placement for hydrocephalus, suboccipital decompression for relief of craniocervical junction constriction, anti-seizure medication to control seizures, and hearing aids.</p><p><i>Surveillance</i>: Long-term survivors need neuroimaging to monitor for craniocervical constriction, assessment of neurologic status, and EEG to monitor for seizure activity, as well as developmental, orthopedic, and audiology evaluations.</p><p><i>Pregnancy management:</i> When TD is diagnosed prenatally, treatment goals are to avoid potential pregnancy complications including prematurity, polyhydramnios, malpresentation, and delivery complications from macrocephaly and/or a flexed and rigid neck; cephalocentesis and cesarean section may be considered to avoid maternal complications.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>TD is inherited in an autosomal dominant manner; the majority of probands have a <i>de novo</i>
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<i>FGFR3</i> pathogenic variant. Risk of sib recurrence for parents who have had one affected child is not significantly increased over that of the general population. Germline mosaicism in healthy parents, although not reported to date, remains a theoretic possibility. Prenatal diagnosis is possible by ultrasound examination and molecular genetic testing.</p></div></div><div id="td.GeneReview_Scope"><h2 id="_td_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figtdTc"><a href="/books/NBK1366/table/td.Tc/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobtdTc"><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="td.Tc"><a href="/books/NBK1366/table/td.Tc/?report=objectonly" target="object" rid-ob="figobtdTc">Table</a></h4><p class="float-caption no_bottom_margin">Thanatophoric dysplasia type 1 (<i>FGFR3</i>-related thanatophoric dysplasia type 1) Thanatophoric dysplasia type 2 (<i>FGFR3</i>-related thanatophoric dysplasia type 2)</p></div></div></div><div id="td.Diagnosis"><h2 id="_td_Diagnosis_">Diagnosis</h2><p>Formal diagnostic criteria for thanatophoric dysplasia (TD) have not been established.</p><div id="td.Suggestive_Findings"><h3>Suggestive Findings</h3><p>TD <b>should be suspected</b> in a fetus with the following prenatal imaging findings, or a neonate with the following clinical and radiographic features.</p><p><b>Prenatal ultrasound examination</b> [<a class="bibr" href="#td.REF.tonni.2010.314" rid="td.REF.tonni.2010.314">Tonni et al 2010</a>, <a class="bibr" href="#td.REF.khalil.2011.115" rid="td.REF.khalil.2011.115">Khalil et al 2011</a>, <a class="bibr" href="#td.REF.mart_nezfr_as.2011.197" rid="td.REF.mart_nezfr_as.2011.197">Martínez-Frías et al 2011</a>, <a class="bibr" href="#td.REF.bondioni.2017.880" rid="td.REF.bondioni.2017.880">Bondioni et al 2017</a>] findings by trimester:</p><ul><li class="half_rhythm"><div>First trimester</div><ul><li class="half_rhythm"><div>Shortening of the long bones, possibly visible as early as 12 to 14 weeks' gestation</div></li><li class="half_rhythm"><div>Increased nuchal translucency</div></li></ul></li><li class="half_rhythm"><div>Second/third trimester</div><ul><li class="half_rhythm"><div>Growth deficiency with limb length below fifth centile recognizable by 20 weeks' gestation</div></li><li class="half_rhythm"><div>Well-ossified spine and skull</div></li><li class="half_rhythm"><div>Platyspondyly</div></li><li class="half_rhythm"><div>Ventriculomegaly</div></li><li class="half_rhythm"><div>Narrow chest cavity with short ribs</div></li><li class="half_rhythm"><div>Polyhydramnios</div></li><li class="half_rhythm"><div>Bowed femurs (TD type 1)</div></li><li class="half_rhythm"><div>Brain anomalies</div></li><li class="half_rhythm"><div>Cloverleaf skull. Craniosynostosis involving coronal, lambdoid, and sagittal sutures, resulting in a trilobed skull shape (previously referred to as <i>Kleeblattschädel</i> (often in TD type 2; occasionally in TD type 1)</div></li><li class="half_rhythm"><div>Relative macrocephaly</div></li></ul></li></ul><p>
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<b>Postnatal physical examination</b>
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</p><ul><li class="half_rhythm"><div>Relative macrocephaly</div></li><li class="half_rhythm"><div>Cloverleaf skull (always in TD type 2; sometimes in TD type 1)</div></li><li class="half_rhythm"><div>Large anterior fontanelle</div></li><li class="half_rhythm"><div>Frontal bossing, flat facies with a depressed nasal bridge, ocular proptosis</div></li><li class="half_rhythm"><div>Marked shortening of the limbs (micromelia)</div></li><li class="half_rhythm"><div>Redundant skin folds</div></li><li class="half_rhythm"><div>Narrow bell-shaped thorax with short ribs and protuberant abdomen</div></li><li class="half_rhythm"><div>Relatively normal trunk length</div></li><li class="half_rhythm"><div>Brachydactyly with trident hand</div></li><li class="half_rhythm"><div>Bowed femurs (TD type 1)</div></li><li class="half_rhythm"><div>Generalized hypotonia</div></li></ul><p><b>Radiographs / other imaging studies</b> [<a class="bibr" href="#td.REF.wilcox.1998.274" rid="td.REF.wilcox.1998.274">Wilcox et al 1998</a>, <a class="bibr" href="#td.REF.lemyre.1999.185" rid="td.REF.lemyre.1999.185">Lemyre et al 1999</a>, <a class="bibr" href="#td.REF.bondioni.2017.880" rid="td.REF.bondioni.2017.880">Bondioni et al 2017</a>]</p><ul><li class="half_rhythm"><div>Rhizomelic shortening of the long bones</div></li><li class="half_rhythm"><div>Irregular metaphyses of the long bones</div></li><li class="half_rhythm"><div>Platyspondyly</div></li><li class="half_rhythm"><div>Small foramen magnum with brain stem compression</div></li><li class="half_rhythm"><div>Bowed femurs (TD type 1)</div></li><li class="half_rhythm"><div>Cloverleaf skull (always in TD type 2; sometimes in TD type 1)</div></li><li class="half_rhythm"><div>CNS abnormalities including temporal lobe malformations, hydrocephalus, brain stem hypoplasia, neuronal migration abnormalities [<a class="bibr" href="#td.REF.wang.2014.588" rid="td.REF.wang.2014.588">Wang et al 2014</a>]</div></li></ul><p><b>Other rarely reported findings that are not part of the core phenotype</b> include cardiac defects, renal abnormalities, and abnormalities of lymphatic development (see <a href="#td.Clinical_Characteristics">Clinical Characteristics</a>).</p></div><div id="td.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of thanatophoric dysplasia <b>is established</b> in a proband with the above clinical and radiographic features and/or a heterozygous pathogenic (or likely pathogenic) variant in <i>FGFR3</i> identified by molecular genetic testing (see <a href="/books/NBK1366/table/td.T.molecular_genetic_testing_used_in_t/?report=objectonly" target="object" rid-ob="figobtdTmoleculargenetictestingusedint">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [<a class="bibr" href="#td.REF.richards.2015.405" rid="td.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous <i>FGFR3</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> (targeted analysis, single-gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, genome sequencing) depending on the phenotype.</p><p>Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of thanatophoric dysplasia is broad, individuals with the distinctive findings described in <a href="#td.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#td.Option_1">Option 1</a>), whereas those with a phenotype indistinguishable from many other lethal skeletal dysplasias are more likely to be diagnosed using genomic testing (see <a href="#td.Option_2">Option 2</a>).</p><div id="td.Option_1"><h4>Option 1</h4><p>When the phenotypic findings suggest the diagnosis of thanatophoric dysplasia, molecular genetic testing approaches can include <b>targeted analysis</b>, <b>single-gene testing</b>, or use of a <b>multigene panel</b>.</p><p>
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<b>Targeted analysis</b>
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</p><ul><li class="half_rhythm"><div>If TD type 2 is suspected on the basis of straight femurs and cloverleaf skull, targeted testing for the <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Lys650Glu</a> pathogenic variant identified in >99% of individuals with TD type 2 may be an appropriate first step. Sequence analysis of <i>FGFR3</i> exon 15 can be considered next if no pathogenic variant is identified.</div></li><li class="half_rhythm"><div>If TD type 1 is suspected, sequence analysis of <i>FGFR3</i> can be considered.</div></li></ul><p><b>Single-gene testing.</b> Sequence analysis of <i>FGFR3</i> detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: (1) Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. (2) Since TD occurs through a gain-of-function mechanism and large intragenic <i>FGFR</i> deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.</p><p><b>A skeletal dysplasia</b>
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<b>multigene panel</b> that includes <i>FGFR3</i> and other genes of interest (see <a href="#td.Differential_Diagnosis">Differential Diagnosis</a>) can 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.</p><p>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>.</p></div><div id="td.Option_2"><h4>Option 2</h4><p>When the phenotype is indistinguishable from many other lethal skeletal dysplasias, <b>comprehensive</b>
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<b>genomic testing</b> (which does not require the clinician to determine which gene[s] are likely involved) is the best option. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</p><p>If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – <b>exome array</b> (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date such variants have not been identified as a cause of TD.</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="figtdTmoleculargenetictestingusedint"><a href="/books/NBK1366/table/td.T.molecular_genetic_testing_used_in_t/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobtdTmoleculargenetictestingusedint"><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="td.T.molecular_genetic_testing_used_in_t"><a href="/books/NBK1366/table/td.T.molecular_genetic_testing_used_in_t/?report=objectonly" target="object" rid-ob="figobtdTmoleculargenetictestingusedint">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Thanatophoric Dysplasia </p></div></div></div></div></div><div id="td.Clinical_Characteristics"><h2 id="_td_Clinical_Characteristics_">Clinical Characteristics</h2><div id="td.Clinical_Description"><h3>Clinical Description</h3><p>The clinical and radiographic features of thanatophoric dysplasia (TD) types 1 and 2 are evident prenatally or in the immediate newborn period. Respiratory insufficiency typically results in early neonatal death, and is due to a small chest cavity and/or foramen magnum narrowing with brain stem compression. However, long-term survivors have been reported, including rare reports of survival to adulthood with aggressive ventilatory support and surgical management of neurologic complications.</p><p>To date, more than 200 individuals with TD have been identified with a pathogenic variant in <i>FGFR3</i> [<a class="bibr" href="#td.REF.xue.2014.497" rid="td.REF.xue.2014.497">Xue et al 2014</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="figtdTselectfeaturesofthanatophoricdy"><a href="/books/NBK1366/table/td.T.select_features_of_thanatophoric_dy/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobtdTselectfeaturesofthanatophoricdy"><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="td.T.select_features_of_thanatophoric_dy"><a href="/books/NBK1366/table/td.T.select_features_of_thanatophoric_dy/?report=objectonly" target="object" rid-ob="figobtdTselectfeaturesofthanatophoricdy">Table 2. </a></h4><p class="float-caption no_bottom_margin">Select Features of Thanatophoric Dysplasia </p></div></div><p><b>Respiratory insufficiency.</b> Most affected infants die of respiratory insufficiency in the first hours or days of life. Respiratory insufficiency may be secondary to a small chest with lung hypoplasia and/or compression of the brain stem due to a small foramen magnum. Some affected children have survived into childhood, universally requiring tracheostomy and aggressive ventilatory support. <a class="bibr" href="#td.REF.nikkel.2013.75" rid="td.REF.nikkel.2013.75">Nikkel et al [2013]</a> described a long-term survivor with TD at age 28 years. Her course was exceptional, as she did not require invasive ventilatory support until age four months and required full-time ventilatory support from age 15 years.</p><p><b>Neurologic complications</b> include small foramen magnum with brain stem compression, brain malformations (predominantly involving the temporal lobe), hydrocephalus, seizures, and profound developmental impairment in rare long-term survivors.</p><p>One infant reported at age 11 months required suboccipital decompression due to clonus and decreased limb movements secondary to a narrow foramen magnum [<a class="bibr" href="#td.REF.thompson.2011.92" rid="td.REF.thompson.2011.92">Thompson et al 2011</a>]. One individual reported at age 28 years underwent surgical decompression of a small foramen magnum and insertion of a ventriculoperitoneal shunt [<a class="bibr" href="#td.REF.nikkel.2013.75" rid="td.REF.nikkel.2013.75">Nikkel et al 2013</a>]. Despite this intervention, the individual developed cervical spinal cord compression and quadriplegia.</p><p>Temporal lobe malformations and megalencephaly are likely universal [<a class="bibr" href="#td.REF.hevner.2005.208" rid="td.REF.hevner.2005.208">Hevner 2005</a>, <a class="bibr" href="#td.REF.itoh.2013.663" rid="td.REF.itoh.2013.663">Itoh et al 2013</a>]. Temporal lobe abnormalities include enlargement, abnormal gyration and sulcation, polymicrogyria, and hippocampal abnormalities. Hydrocephalus is also common [<a class="bibr" href="#td.REF.hevner.2005.208" rid="td.REF.hevner.2005.208">Hevner 2005</a>].</p><p>Brain malformations are the most likely etiology of seizures in individuals with TD; however, additional complications such as hypoxia related to respiratory insufficiency may also play a role.</p><p>Severe developmental delay is reported, with a stall in developmental progress at a developmental age of 12-20 months (see <a href="/books/NBK1366/table/td.T.thanatophoric_dysplasia_clinical_fe/?report=objectonly" target="object" rid-ob="figobtdTthanatophoricdysplasiaclinicalfe">Table 3</a>). Motor skills may be more significantly impaired due to the skeletal features and micromelia. Later deterioration in abilities following complications such as cord compression is described [<a class="bibr" href="#td.REF.nikkel.2013.75" rid="td.REF.nikkel.2013.75">Nikkel et al 2013</a>].</p><p>Less common neurologic findings include hypoplasia or agenesis of the corpus callosum. Encephalocele has been reported, likely as a secondary consequence of raised intracranial pressure and abnormal skull formation [<a class="bibr" href="#td.REF.mart_nezfr_as.2011.197" rid="td.REF.mart_nezfr_as.2011.197">Martínez-Frías et al 2011</a>].</p><p><b>Craniofacial.</b> Relative macrocephaly is present at birth. Craniosynostosis with cloverleaf skull in individuals with TD type 2 contributes to hydrocephalus and neurologic complications. Dysmorphic facial features including frontal bossing, flat facies, depressed nasal bridge, and ocular proptosis are present.</p><p><b>Musculoskeletal complications</b> in long-term survivors include kyphosis, osteopenia, and both joint hypermobility and joint contractures.</p><p><b>Growth deficiency.</b> Prenatal short-limb short stature is present in all individuals. Growth deficiency persists with micromelia and redundant skin folds. Global growth deficiency is present in long-term survivors (see <a href="/books/NBK1366/table/td.T.thanatophoric_dysplasia_clinical_fe/?report=objectonly" target="object" rid-ob="figobtdTthanatophoricdysplasiaclinicalfe">Table 3</a>).</p><p><b>Integument.</b> Extensive acanthosis nigricans has been reported with development of seborrheic keratoses in adult survivors [<a class="bibr" href="#td.REF.nakai.2010.656" rid="td.REF.nakai.2010.656">Nakai et al 2010</a>, <a class="bibr" href="#td.REF.nikkel.2013.75" rid="td.REF.nikkel.2013.75">Nikkel et al 2013</a>].</p><p><b>Hearing impairment</b> is reported in several long-term survivors (see <a href="/books/NBK1366/table/td.T.thanatophoric_dysplasia_clinical_fe/?report=objectonly" target="object" rid-ob="figobtdTthanatophoricdysplasiaclinicalfe">Table 3</a>), but the etiology is not clear. The presence of midface hypoplasia in individuals with TD type 1, and recognition that <i>FGFR3</i> may be implicated in inner ear development [<a class="bibr" href="#td.REF.colvin.1996.390" rid="td.REF.colvin.1996.390">Colvin et al 1996</a>], suggest that hearing loss in individuals with TD type 1 may be multifactorial.</p><p><b>Vision.</b> Intermittent exotropia has been reported in a long-term survivor [<a class="bibr" href="#td.REF.nikkel.2013.75" rid="td.REF.nikkel.2013.75">Nikkel et al 2013</a>].</p><p><b>Other rarely</b>
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<b>reported findings</b> that do not have a proven association with TD include:</p><ul><li class="half_rhythm"><div>Cardiac defects. Truncus arteriosus, ventricular septal defect, and patent foramen ovale have been reported [<a class="bibr" href="#td.REF.mcbrien.2008.259" rid="td.REF.mcbrien.2008.259">McBrien et al 2008</a>]. Bradycardia has been reported in two individuals [<a class="bibr" href="#td.REF.baker.1997.427" rid="td.REF.baker.1997.427">Baker et al 1997</a>, <a class="bibr" href="#td.REF.nikkel.2013.75" rid="td.REF.nikkel.2013.75">Nikkel et al 2013</a>].</div></li><li class="half_rhythm"><div>Renal abnormalities [<a class="bibr" href="#td.REF.prontera.2006.407" rid="td.REF.prontera.2006.407">Prontera et al 2006</a>]. In two long-term survivors, renal calculi were reported [<a class="bibr" href="#td.REF.baker.1997.427" rid="td.REF.baker.1997.427">Baker et al 1997</a>, <a class="bibr" href="#td.REF.kuno.2000.s141" rid="td.REF.kuno.2000.s141">Kuno et al 2000</a>].</div></li><li class="half_rhythm"><div>Protein losing enteropathy with intestinal lymphangestasia, reported in one individual [<a class="bibr" href="#td.REF.yang.2016.2993" rid="td.REF.yang.2016.2993">Yang & Dehner 2016</a>]. An infant with TD was reported to have chylous ascites [<a class="bibr" href="#td.REF.sookyeong.2018.363" rid="td.REF.sookyeong.2018.363">Soo-Kyeong et al 2018</a>].</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figtdTthanatophoricdysplasiaclinicalfe"><a href="/books/NBK1366/table/td.T.thanatophoric_dysplasia_clinical_fe/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobtdTthanatophoricdysplasiaclinicalfe"><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="td.T.thanatophoric_dysplasia_clinical_fe"><a href="/books/NBK1366/table/td.T.thanatophoric_dysplasia_clinical_fe/?report=objectonly" target="object" rid-ob="figobtdTthanatophoricdysplasiaclinicalfe">Table 3. </a></h4><p class="float-caption no_bottom_margin">Thanatophoric Dysplasia: Clinical Features of Long-Term Survivors </p></div></div><p><b>Mosaicism.</b> A female age 47 years who was mosaic for the common TD type 1-causing pathogenic variant <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Arg248Cys</a> had asymmetric limb length, bilateral congenital hip dislocation, focal areas of bone bowing, an S-shaped humerus, extensive acanthosis nigricans, redundant skin folds along the length of the limbs, and flexion deformities of the knees and elbows [<a class="bibr" href="#td.REF.hyland.2003.157" rid="td.REF.hyland.2003.157">Hyland et al 2003</a>]. She had delayed developmental milestones as a child. Academic achievements were below those of healthy sibs, but she is able to read and write and is employed as a factory worker. Her only pregnancy ended with the stillbirth at 30 weeks' gestation of a male with a short-limb skeletal dysplasia and pulmonary hypoplasia.</p><p><a class="bibr" href="#td.REF.takagi.2012.247" rid="td.REF.takagi.2012.247">Takagi et al [2012]</a> described an individual with somatic mosaicism for the <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Arg248Cys</a> substitution in <i>FGFR3</i> (a pathogenic variant which typically results in TD type 1) who presented with features labeled as atypical achondroplasia.</p></div><div id="td.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p><b>TD type 1.</b>
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<i>FGFR3</i> pathogenic variants reported as causing the TD type 1 phenotype can be divided into three categories:</p><ul><li class="half_rhythm"><div><b>Missense variants</b> [<a class="bibr" href="#td.REF.passosbueno.1999.115" rid="td.REF.passosbueno.1999.115">Passos-Bueno et al 1999</a>]. The two common variants <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Arg248Cys</a> and <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Tyr373Cys</a> probably account for 90% of TD type 1 [<a class="bibr" href="#td.REF.xue.2014.497" rid="td.REF.xue.2014.497">Xue et al 2014</a>].</div></li><li class="half_rhythm"><div><b>No-stop codon variants</b> represent fewer than 10% of TD type 1-causing variants (see <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">Table 9</a>).</div></li><li class="half_rhythm"><div>An <b>insertion variant</b> has been reported in one individual [<a class="bibr" href="#td.REF.lindy.2016.1573" rid="td.REF.lindy.2016.1573">Lindy et al 2016</a>] (see <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">Table 9</a>).</div></li></ul><p><b>TD type 2.</b> A single <i>FGFR3</i> pathogenic variant (<a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Lys650Glu</a>) has been identified in all individuals with TD type 2 [<a class="bibr" href="#td.REF.bellus.2000.1411" rid="td.REF.bellus.2000.1411">Bellus et al 2000</a>]. Other pathogenic variants at this position give rise to different phenotypes: <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Lys650Met</a> has been identified in TD type 1, and p.Lys650Gln is seen in SADDAN (see <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">Table 9</a>).</p></div><div id="td.Penetrance"><h3>Penetrance</h3><p>The penetrance is 100%.</p></div><div id="td.Nomenclature"><h3>Nomenclature</h3><p>Thanatophoric dysplasia was originally described as thanatophoric dwarfism, a term no longer in use. The descriptor "thanatophoric" is derived from the Greek for "death bearing," and refers to the very high incidence of perinatal death due to the multisystem complications of this condition. However, aggressive management has resulted in rare reports of long-term survivors, contradicting this initial description.</p><p>The lethal platyspondylic dysplasia (San Diego type) was previously considered a separate clinical entity, but is now recognized as the same condition as TD [<a class="bibr" href="#td.REF.brodie.1999.476" rid="td.REF.brodie.1999.476">Brodie et al 1999</a>, <a class="bibr" href="#td.REF.hall.2002.65" rid="td.REF.hall.2002.65">Hall 2002</a>].</p><p>In the 2023 revision of the Nosology of Genetic Skeletal Disorders [<a class="bibr" href="#td.REF.unger.2023.1164" rid="td.REF.unger.2023.1164">Unger et al 2023</a>], TD type 1 is referred to as <i>FGFR3-</i>related thanatophoric dysplasia (type 1), and TD type 2 is referred to as <i>FGFR3-</i>related thanatophoric dysplasia (type 2); both are included in the <i>FGFR3</i> chondrodysplasias group.</p></div><div id="td.Prevalence"><h3>Prevalence</h3><p>The incidence of TD is reported to be 1:20,000 [<a class="bibr" href="#td.REF.barbosabuck.2012.1038" rid="td.REF.barbosabuck.2012.1038">Barbosa-Buck et al 2012</a>] or higher (1:12,000 in Northern Ireland) in a population with optimized ascertainment [<a class="bibr" href="#td.REF.donnelly.2010.114" rid="td.REF.donnelly.2010.114">Donnelly et al 2010</a>].</p></div></div><div id="td.Genetically_Related_Allelic_Disorders"><h2 id="_td_Genetically_Related_Allelic_Disorders_">Genetically Related (Allelic) Disorders</h2><p><i>FGFR3</i> pathogenic variants have been identified in several disorders with highly variable phenotypes (see <a href="/books/NBK1366/table/td.T.fgfr3_allelic_disorders_to_consider/?report=objectonly" target="object" rid-ob="figobtdTfgfr3allelicdisorderstoconsider">Table 4a</a> and <a href="/books/NBK1366/table/td.T.fgfr3_allelic_disorders_not_in_the/?report=objectonly" target="object" rid-ob="figobtdTfgfr3allelicdisordersnotinthe">Table 4b</a>). Disorders included in <a href="/books/NBK1366/table/td.T.fgfr3_allelic_disorders_to_consider/?report=objectonly" target="object" rid-ob="figobtdTfgfr3allelicdisorderstoconsider">Table 4a</a> may have phenotypic features that overlap with thanatophoric dysplasia (TD) and should be considered in the differential diagnosis.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figtdTfgfr3allelicdisorderstoconsider"><a href="/books/NBK1366/table/td.T.fgfr3_allelic_disorders_to_consider/?report=objectonly" target="object" title="Table 4a. " class="img_link icnblk_img" rid-ob="figobtdTfgfr3allelicdisorderstoconsider"><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="td.T.fgfr3_allelic_disorders_to_consider"><a href="/books/NBK1366/table/td.T.fgfr3_allelic_disorders_to_consider/?report=objectonly" target="object" rid-ob="figobtdTfgfr3allelicdisorderstoconsider">Table 4a. </a></h4><p class="float-caption no_bottom_margin"><i>FGFR3</i> Allelic Disorders to Consider in the Differential Diagnosis of Thanatophoric Dysplasia </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figtdTfgfr3allelicdisordersnotinthe"><a href="/books/NBK1366/table/td.T.fgfr3_allelic_disorders_not_in_the/?report=objectonly" target="object" title="Table 4b. " class="img_link icnblk_img" rid-ob="figobtdTfgfr3allelicdisordersnotinthe"><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="td.T.fgfr3_allelic_disorders_not_in_the"><a href="/books/NBK1366/table/td.T.fgfr3_allelic_disorders_not_in_the/?report=objectonly" target="object" rid-ob="figobtdTfgfr3allelicdisordersnotinthe">Table 4b. </a></h4><p class="float-caption no_bottom_margin"><i>FGFR3</i> Allelic Disorders Not in the Differential Diagnosis of Thanatophoric Dysplasia </p></div></div></div><div id="td.Differential_Diagnosis"><h2 id="_td_Differential_Diagnosis_">Differential Diagnosis</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figtdTothergenesofinterestinthediff"><a href="/books/NBK1366/table/td.T.other_genes_of_interest_in_the_diff/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobtdTothergenesofinterestinthediff"><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="td.T.other_genes_of_interest_in_the_diff"><a href="/books/NBK1366/table/td.T.other_genes_of_interest_in_the_diff/?report=objectonly" target="object" rid-ob="figobtdTothergenesofinterestinthediff">Table 5. </a></h4><p class="float-caption no_bottom_margin">Other Genes of Interest in the Differential Diagnosis of Thanatophoric Dysplasia </p></div></div></div><div id="td.Management"><h2 id="_td_Management_">Management</h2><div id="td.Evaluations_Following_Initial_Diagnos"><h3>Evaluations Following Initial Diagnosis</h3><p>Diagnosis of thanatophoric dysplasia (TD) most often occurs prenatally. When TD has been diagnosed prenatally, referral should be made to a maternal-fetal medicine specialist for assessment and management advice (see <a href="#td.Pregnancy_Management">Pregnancy Management</a>).</p><p>Long-term survivors are rare and require aggressive intervention for complications of the condition. The family should be informed of prognosis on the basis of the reports of complications in long-term survivors.</p><p><a href="/books/NBK1366/table/td.T.recommended_evaluations_following_i/?report=objectonly" target="object" rid-ob="figobtdTrecommendedevaluationsfollowingi">Table 6</a>, <a href="/books/NBK1366/table/td.T.treatment_of_manifestations_in_indi/?report=objectonly" target="object" rid-ob="figobtdTtreatmentofmanifestationsinindi">Table 7</a>, and <a href="/books/NBK1366/table/td.T.recommended_surveillance_for_indivi/?report=objectonly" target="object" rid-ob="figobtdTrecommendedsurveillanceforindivi">Table 8</a> are only relevant to the small number of long-term survivors. To establish the extent of disease and needs in a newborn diagnosed with thanatophoric dysplasia (TD), the evaluations summarized in <a href="/books/NBK1366/table/td.T.recommended_evaluations_following_i/?report=objectonly" target="object" rid-ob="figobtdTrecommendedevaluationsfollowingi">Table 6</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="figtdTrecommendedevaluationsfollowingi"><a href="/books/NBK1366/table/td.T.recommended_evaluations_following_i/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobtdTrecommendedevaluationsfollowingi"><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="td.T.recommended_evaluations_following_i"><a href="/books/NBK1366/table/td.T.recommended_evaluations_following_i/?report=objectonly" target="object" rid-ob="figobtdTrecommendedevaluationsfollowingi">Table 6. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with Thanatophoric Dysplasia </p></div></div></div><div id="td.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Decisions about management should be made following consultation with parents and a discussion of the complications, clinical course, and prognosis of the condition. Considerations may include the parents' desire for extreme life-support measures or provision of comfort care for the newborn.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figtdTtreatmentofmanifestationsinindi"><a href="/books/NBK1366/table/td.T.treatment_of_manifestations_in_indi/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobtdTtreatmentofmanifestationsinindi"><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="td.T.treatment_of_manifestations_in_indi"><a href="/books/NBK1366/table/td.T.treatment_of_manifestations_in_indi/?report=objectonly" target="object" rid-ob="figobtdTtreatmentofmanifestationsinindi">Table 7. </a></h4><p class="float-caption no_bottom_margin">Treatment of Manifestations in Individuals with Thanatophoric Dysplasia </p></div></div></div><div id="td.Surveillance"><h3>Surveillance</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figtdTrecommendedsurveillanceforindivi"><a href="/books/NBK1366/table/td.T.recommended_surveillance_for_indivi/?report=objectonly" target="object" title="Table 8. " class="img_link icnblk_img" rid-ob="figobtdTrecommendedsurveillanceforindivi"><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="td.T.recommended_surveillance_for_indivi"><a href="/books/NBK1366/table/td.T.recommended_surveillance_for_indivi/?report=objectonly" target="object" rid-ob="figobtdTrecommendedsurveillanceforindivi">Table 8. </a></h4><p class="float-caption no_bottom_margin">Recommended Surveillance for Individuals with Thanatophoric Dysplasia </p></div></div></div><div id="td.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#td.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="td.Pregnancy_Management"><h3>Pregnancy Management</h3><p>When TD has been diagnosed prenatally, referral should be made to a maternal-fetal medicine specialist for assessment and management advice. Potential pregnancy complications include prematurity, polyhydramnios, malpresentation, and cephalopelvic disproportion caused by macrocephaly from hydrocephalus or a flexed and rigid neck. Cephalocentesis and cesarean section may be considered to avoid maternal complications.</p><p>Management of an affected pregnancy is determined following discussion between the medical team and family regarding prognosis and the need for aggressive life-saving measures in survivors. This is often center-specific. Indicators of lethality on ultrasound can provide additional information.</p><p>Consensus guidelines on perinatal management of skeletal dysplasias have been published [<a class="bibr" href="#td.REF.savarirayan.2018.545" rid="td.REF.savarirayan.2018.545">Savarirayan et al 2018</a>]. Management considerations can be addressed on three levels:</p><ul><li class="half_rhythm"><div><b>Maternal.</b> Surveillance for cephalopelvic disproportion, polyhydramnios, and/or preterm labor; avoidance of emergency C-section for fetal distress</div></li><li class="half_rhythm"><div><b>Fetal.</b> Surveillance for malpresentation, periodic prenatal ultrasound monitoring of head circumference, MRI for fetal lung volume, and/or fetal stress testing</div></li><li class="half_rhythm"><div><b>Perinatal.</b> Establishment of a plan for assessment, care, and/or withdrawal of care after delivery. Postnatal clinical and radiographic assessment should occur. In terminated pregnancies, postmortem evaluation including radiography and storage of DNA in case of diagnostic uncertainty should be discussed.</div></li></ul></div><div id="td.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Over the past five years several new precision therapies have begun to emerge for achondroplasia (an allelic <i>FGFR3</i> skeletal dysplasia) that are now in Phase II and Phase III human clinical trials. These new therapeutic approaches include: use of C-type natriuretic peptides (CNP) to modulate downstream <i>FGFR3</i> signaling [<a class="bibr" href="#td.REF.savarirayan.2019a.25" rid="td.REF.savarirayan.2019a.25">Savarirayan et al 2019a</a>, <a class="bibr" href="#td.REF.breinholt.2019.459" rid="td.REF.breinholt.2019.459">Breinholt et al 2019</a>], blocking of <i>FGFR3</i> using selective tyrosine kinase inhibitors [<a class="bibr" href="#td.REF.komlaebri.2016.1871" rid="td.REF.komlaebri.2016.1871">Komla-Ebri et al 2016</a>], and ligand traps to decrease the quantity of growth factors able to bind to mutated FGFR3 receptors [<a class="bibr" href="#td.REF.garcia.2013.203ra124" rid="td.REF.garcia.2013.203ra124">Garcia et al 2013</a>]. These treatments could also be effective for TD, given a similar underlying molecular mechanism [<a class="bibr" href="#td.REF.savarirayan.2019b.1291" rid="td.REF.savarirayan.2019b.1291">Savarirayan et al 2019b</a>], but how this very severe phenotype would be modified is currently unknown.</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="td.Genetic_Counseling"><h2 id="_td_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="td.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Thanatophoric dysplasia (TD) is an autosomal dominant disorder typically caused by a <i>de novo</i> pathogenic variant.</p></div><div id="td.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>Almost all probands reported to date with TD represent simplex cases (i.e., the only affected family member) and have the disorder as a result of a <i>de novo FGFR3</i> pathogenic variant. The parents of a proband with a <i>de novo FGFR3</i> pathogenic variant are not affected.</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a proband with an apparent <i>de novo</i> pathogenic variant to confirm the genetic status of the parents and to facilitate reliable recurrence risk assessment.</div></li><li class="half_rhythm"><div>If the <i>FGFR3</i> pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred <i>de novo</i> in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with somatic and/or germline mosaicism. (Note: Parental somatic mosaicism is difficult to detect in leukocyte DNA using standard molecular genetic techniques.)</div><ul><li class="half_rhythm"><div>Somatic and germline mosaicism for the <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Arg248Cys</a>
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<i>FGFR3</i> pathogenic variant was reported in a parent with a skeletal dysplasia; this individual's only offspring had a lethal skeletal dysplasia with findings consistent with TD [<a class="bibr" href="#td.REF.hyland.2003.157" rid="td.REF.hyland.2003.157">Hyland et al 2003</a>].</div></li><li class="half_rhythm"><div>Although no instances of mosaicism in an individual without signs of a skeletal dysplasia have been reported in the literature, it remains a theoretic possibility.</div></li></ul></li><li class="half_rhythm"><div>An advanced paternal age effect has been reported [<a class="bibr" href="#td.REF.donnelly.2010.114" rid="td.REF.donnelly.2010.114">Donnelly et al 2010</a>].</div></li></ul><p><b>Sibs of a proband.</b> The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the <i>FGFR3</i> pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent and neither parent has signs of a skeletal dysplasia, the recurrence risk to sibs is presumed to be low but slightly greater than that of the general population because of the possibility of parental mosaicism [<a class="bibr" href="#td.REF.hyland.2003.157" rid="td.REF.hyland.2003.157">Hyland et al 2003</a>].</p><p><b>Offspring of a proband.</b> Individuals with TD do not reproduce.</p><p><b>Other family members.</b> Extended family members of the proband are not at increased risk.</p></div><div id="td.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p><b>Family planning.</b> The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</p><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bibr" href="#td.REF.huang.2022.389" rid="td.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="td.Prenatal_Testing_and_Preimplantation"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p><b>High-risk pregnancies.</b> Once the <i>FGFR3</i> pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for TD are possible.</p><p><b>Low-risk pregnancies.</b> Routine prenatal ultrasound examination may identify skeletal findings (e.g., cloverleaf skull, very short extremities, small thorax) that raise the possible diagnosis of TD in a fetus not known to be at risk. Once a lethal skeletal dysplasia is identified prenatally, it is often difficult to pinpoint a specific diagnosis. Consideration of molecular genetic testing for <i>FGFR3</i> pathogenic variants in these situations is appropriate.</p><p>Cell-free DNA testing techniques have been reported for noninvasive prenatal diagnosis of TD [<a class="bibr" href="#td.REF.chitty.2015.656" rid="td.REF.chitty.2015.656">Chitty et al 2015</a>, <a class="bibr" href="#td.REF.zhang.2019.439" rid="td.REF.zhang.2019.439">Zhang et al 2019</a>].</p><p>Note: When TD has been diagnosed prenatally, referral should be made to a maternal-fetal medicine specialist for assessment and management advice (see <a href="#td.Pregnancy_Management">Pregnancy Management</a>).</p></div></div><div id="td.Resources"><h2 id="_td_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>Born a Hero</b>
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</div><div>
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<a href="https://www.bornahero.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.bornahero.org</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="https://medlineplus.gov/genetics/condition/thanatophoric-dysplasia/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Thanatophoric dysplasia</a>
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</div></li><li class="half_rhythm"><div>
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<b>Compassionate Friends</b>
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</div><div>
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<i>Supporting Family After a Child Dies</i>
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</div><div><b>Phone:</b> 877-969-0010</div><div>
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<a href="http://www.compassionatefriends.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">compassionatefriends.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Helping After Neonatal Death (HAND)</b>
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</div><div>PO Box 341</div><div>Los Gatos CA 95031</div><div><b>Phone:</b> 888-908-HAND (4263)</div><div>
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<a href="http://handonline.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.handonline.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Medline Plus</b>
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</div><div>
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<a href="http://www.nlm.nih.gov/medlineplus/dwarfism.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Dwarfism</a>
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</div></li><li class="half_rhythm"><div>
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<b>UCLA International Skeletal Dysplasia Registry (ISDR)</b>
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</div><div><b>Phone:</b> 310-825-8998</div><div>
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<a href="https://www.uclahealth.org/ortho/isdr" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">International Skeletal Dysplasia Registry</a>
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</div></li></ul>
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</div><div id="td.Molecular_Genetics"><h2 id="_td_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="figtdmolgenTA"><a href="/books/NBK1366/table/td.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobtdmolgenTA"><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="td.molgen.TA"><a href="/books/NBK1366/table/td.molgen.TA/?report=objectonly" target="object" rid-ob="figobtdmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Thanatophoric Dysplasia: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figtdmolgenTB"><a href="/books/NBK1366/table/td.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobtdmolgenTB"><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="td.molgen.TB"><a href="/books/NBK1366/table/td.molgen.TB/?report=objectonly" target="object" rid-ob="figobtdmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Thanatophoric Dysplasia (View All in OMIM) </p></div></div><div id="td.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>FGFR3</i> encodes fibroblast growth factor receptor 3 (FGFR3), a negative regulator of bone growth during ossification [<a class="bibr" href="#td.REF.cohen.2002.304" rid="td.REF.cohen.2002.304">Cohen 2002</a>]. Mice with knockout variants of <i>Fgfr3</i> have expanded growth plates and are overgrown, with elongated vertebrae, femurs, and tails.</p><p>Pathogenic variants in <i>FGFR3</i> are gain-of-function variants that facilitate dimerization and activation of FGFR3 in the absence of ligand binding [<a class="bibr" href="#td.REF.baitner.2000.594" rid="td.REF.baitner.2000.594">Baitner et al 2000</a>, <a class="bibr" href="#td.REF.cohen.2002.304" rid="td.REF.cohen.2002.304">Cohen 2002</a>]. This constitutional activation leads to premature differentiation of proliferative chondrocytes into prehypertrophic chondrocytes, and ultimately to premature maturation of the bone [<a class="bibr" href="#td.REF.cohen.2002.304" rid="td.REF.cohen.2002.304">Cohen 2002</a>, <a class="bibr" href="#td.REF.legeaimallet.2004.26" rid="td.REF.legeaimallet.2004.26">Legeai-Mallet et al 2004</a>].</p><p><i>FGFR3</i>-related skeletal dysplasias display a spectrum of phenotypic severity. The level of increased tyrosine kinase activity conferred by different <i>FGFR3</i> pathogenic variants correlates with the severity of disorganization of endochondral ossification and, therefore, with the skeletal phenotype [<a class="bibr" href="#td.REF.bellus.1999.53" rid="td.REF.bellus.1999.53">Bellus et al 1999</a>, <a class="bibr" href="#td.REF.bellus.2000.1411" rid="td.REF.bellus.2000.1411">Bellus et al 2000</a>, <a class="bibr" href="#td.REF.foldynovatrantirkova.2012.29" rid="td.REF.foldynovatrantirkova.2012.29">Foldynova-Trantirkova et al 2012</a>].</p><p><b>Mechanism of disease causation.</b> Gain of function.</p><ul><li class="half_rhythm"><div>Of note, no-stop variants resulting in protein extension are associated with thanatophoric dysplasia (TD).</div></li><li class="half_rhythm"><div>Missense variants causing TD type 1 introduce a cysteine (Tyr373Cys, Arg428Cys) resulting in dimerization by covalent bonding (see <a href="#td.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>).</div></li><li class="half_rhythm"><div>Missense variants involving residue 650 (e.g., Lys650Met [TD type 1] or Lys650Glu [TD type 2]) mimic conformational changes in the tyrosine kinase domain, which mimic the conformational changes that occur with ligand binding.</div></li><li class="half_rhythm"><div>The <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Lys650Glu</a> pathogenic variant causing TD type 2 has been shown to cause accumulation of intermediate, activated forms of FGFR3 in the endoplasmic reticulum [<a class="bibr" href="#td.REF.lievens.2003.17344" rid="td.REF.lievens.2003.17344">Lievens & Liboi 2003</a>]. It is unclear how this may contribute to the more severe phenotype in TD type 2.</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figtdTnotablefgfr3pathogenicvariants"><a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" title="Table 9. " class="img_link icnblk_img" rid-ob="figobtdTnotablefgfr3pathogenicvariants"><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="td.T.notable_fgfr3_pathogenic_variants"><a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">Table 9. </a></h4><p class="float-caption no_bottom_margin">Notable <i>FGFR3</i> Pathogenic Variants </p></div></div></div></div><div id="td.Chapter_Notes"><h2 id="_td_Chapter_Notes_">Chapter Notes</h2><div id="td.Author_History"><h3>Author History</h3><p>Garry R Cutting, MD; Johns Hopkins University (2004–2020)<br />Tegan French, BMBS (2020–present)<br />Barbara Karczeski, MS, MA; Johns Hopkins University (2004–2020)<br />Ravi Savarirayan, MBBS, MD, FRACP, ARCPA (Hon) (2020–present)</p></div><div id="td.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>18 May 2023 (sw) Revision: <a href="#td.GeneReview_Scope"><i>GeneReview</i> Scope</a> table included; Nosology of Genetic Skeletal Disorders: 2023 Revision [<a class="bibr" href="#td.REF.unger.2023.1164" rid="td.REF.unger.2023.1164">Unger et al 2023</a>] added to <a href="#td.Nomenclature">Nomenclature</a></div></li><li class="half_rhythm"><div>18 June 2020 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>12 September 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>30 September 2008 (cg) Comprehensive update posted live</div></li><li class="half_rhythm"><div>7 July 2006 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>21 May 2004 (me) Review posted live</div></li><li class="half_rhythm"><div>27 February 2004 (bk, gc) Original submission</div></li></ul></div></div><div id="td.References"><h2 id="_td_References_">References</h2><div id="td.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="td.REF.baitner.2000.594">Baitner AC, Maurer SG, Gruen MB, Di Cesare PE. The genetic basis of the osteochondrodysplasias. <span><span class="ref-journal">J Pediatr Orthop. </span>2000;<span class="ref-vol">20</span>:594–605.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11008738" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11008738</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="td.REF.baker.1997.427">Baker KM, Olson DS, Harding CO, Pauli RM. Long-term survival in typical thanatophoric dysplasia type 1. <span><span class="ref-journal">Am J Med Genet. </span>1997;<span class="ref-vol">70</span>:427–36.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9182787" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9182787</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="td.REF.barbosabuck.2012.1038">Barbosa-Buck CO, Orioli IM, Dutra MG, Lopez-Camelo J, Castilla EE, Cavalcanti DP. Clinical epidemiology of skeletal dysplasias in South America. <span><span class="ref-journal">Am J Med Genet Part A. </span>2012;<span class="ref-vol">158A</span>:1038–45.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22407836" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22407836</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="td.REF.bellus.1999.53">Bellus GA, Bamshad MJ, Przylepa KA, Dorst J, Lee RR, Hurko O, Jabs EW, Curry CJ, Wilcox WR, Lachman RS, Rimoin DL, Francomano CA. Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3. <span><span class="ref-journal">Am J Med Genet. </span>1999;<span class="ref-vol">85</span>:53–65.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10377013" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10377013</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="td.REF.bellus.2000.1411">Bellus GA, Spector EB, Speiser PW, Weaver CA, Garber AT, Bryke CR, Israel J, Rosengren SS, Webster MK, Donoghue DJ, Francomano CA. 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Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. <span><span class="ref-journal">Nat Genet. </span>1996;<span class="ref-vol">12</span>:390–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8630492" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8630492</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="td.REF.donnelly.2010.114">Donnelly DE, McConnell V, Paterson A, Morrison PJ. The prevalence of thanatophoric dysplasia and lethal osteogenesis imperfecta type II in Northern Ireland - a complete population study. <span><span class="ref-journal">Ulster Med J. </span>2010;<span class="ref-vol">79</span>:114–8.</span> [<a href="/pmc/articles/PMC3284715/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3284715</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22375084" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22375084</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="td.REF.foldynovatrantirkova.2012.29">Foldynova-Trantirkova S, Wilcox WR, Krejci P. Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. <span><span class="ref-journal">Hum Mutat. </span>2012;<span class="ref-vol">33</span>:29–41.</span> [<a href="/pmc/articles/PMC3240715/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3240715</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22045636" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22045636</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="td.REF.garcia.2013.203ra124">Garcia S, Dirat B, Tognacci T, Rochet N, Mouska X, Bonnafous S, Patouraux S, Tran A, Gual P, Le Marchand-Brustel Y, Gennero I, Gouze E. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. <span><span class="ref-journal">Sci Transl Med. </span>2013;<span class="ref-vol">5</span>:203ra124. </span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24048522" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24048522</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="td.REF.hall.2002.65">Hall CM. International Nosology and Classification of Constitutional Disorders of Bone (2001). <span><span class="ref-journal">Am J Med Genet. </span>2002;<span class="ref-vol">113</span>:65–77.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12400068" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12400068</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="td.REF.hevner.2005.208">Hevner RF. 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use.</p><p class="small">For more information, see 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>French T, Savarirayan R. Thanatophoric Dysplasia. 2004 May 21 [Updated 2023 May 18]. 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/tetra-amelia/?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/trma/?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="figobtdTc"><div id="td.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1366/table/td.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__td.Tc_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_td.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Thanatophoric Dysplasia: Included Phenotypes</th></tr></thead><tbody><tr><td headers="hd_h_td.Tc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Thanatophoric dysplasia type 1 (<i>FGFR3</i>-related thanatophoric dysplasia type 1)</div></li><li class="half_rhythm"><div>Thanatophoric dysplasia type 2 (<i>FGFR3</i>-related thanatophoric dysplasia type 2)</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">For synonyms and outdated names, see <a href="#td.Nomenclature">Nomenclature</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobtdTmoleculargenetictestingusedint"><div id="td.T.molecular_genetic_testing_used_in_t" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Thanatophoric Dysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1366/table/td.T.molecular_genetic_testing_used_in_t/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__td.T.molecular_genetic_testing_used_in_t_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_td.T.molecular_genetic_testing_used_in_t_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_td.T.molecular_genetic_testing_used_in_t_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_td.T.molecular_genetic_testing_used_in_t_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_td.T.molecular_genetic_testing_used_in_t_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FGFR3</i>
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</td><td headers="hd_h_td.T.molecular_genetic_testing_used_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Targeted analysis for <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Lys650Glu</a></td><td headers="hd_h_td.T.molecular_genetic_testing_used_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>99% of probands w/TD type 2 <sup>3, 4</sup></td></tr><tr><td headers="hd_h_td.T.molecular_genetic_testing_used_in_t_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Targeted analysis for <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Arg248Cys</a> & <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Tyr373Cys</a></td><td headers="hd_h_td.T.molecular_genetic_testing_used_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~90% of probands w/TD type 1 <sup>4</sup></td></tr><tr><td headers="hd_h_td.T.molecular_genetic_testing_used_in_t_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>5</sup></td><td headers="hd_h_td.T.molecular_genetic_testing_used_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>99% <sup>4, 6</sup></td></tr><tr><td headers="hd_h_td.T.molecular_genetic_testing_used_in_t_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>7</sup></td><td headers="hd_h_td.T.molecular_genetic_testing_used_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported <sup>4</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="td.TF.1.1"><p class="no_margin">See <a href="/books/NBK1366/?report=reader#td.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="td.TF.1.2"><p class="no_margin">See <a href="#td.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="td.TF.1.3"><p class="no_margin">
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<a class="bibr" href="#td.REF.xue.2014.497" rid="td.REF.xue.2014.497">Xue et al [2014]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="td.TF.1.4"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bibr" href="#td.REF.stenson.2020.1197" rid="td.REF.stenson.2020.1197">Stenson et al 2020</a>] and <a class="bibr" href="#td.REF.xue.2014.497" rid="td.REF.xue.2014.497">Xue et al [2014]</a> (See <a href="#td.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>.)</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="td.TF.1.5"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="td.TF.1.6"><p class="no_margin">TD due to two <i>FGFR3</i> pathogenic variants <i>in</i>
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<i>cis</i> has been reported [<a class="bibr" href="#td.REF.pannier.2009.1296" rid="td.REF.pannier.2009.1296">Pannier et al 2009</a>, <a class="bibr" href="#td.REF.marquisnicholson.2013.80" rid="td.REF.marquisnicholson.2013.80">Marquis-Nicholson et al 2013</a>]. In both instances one pathogenic variant was previously reported to be associated with hypochondroplasia and one was a novel pathogenic missense variant.</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="td.TF.1.7"><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="figobtdTselectfeaturesofthanatophoricdy"><div id="td.T.select_features_of_thanatophoric_dy" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Select Features of Thanatophoric Dysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1366/table/td.T.select_features_of_thanatophoric_dy/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__td.T.select_features_of_thanatophoric_dy_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Feature</th><th id="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">% of Persons w/Feature</th><th id="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Respiratory insufficiency</b>
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</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Long-term survivors have all required mechanical ventilation.</td></tr><tr><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Foramen magnum narrowing</b>
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</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~100% <sup>1</sup></td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Temporal lobe dysplasia</b>
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</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~100% <sup>1, 2</sup></td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hydrocephalus</b>
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</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">56% <sup>2</sup></td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cloverleaf skull (multiple craniosynostosis)</b>
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</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% in persons w/TD type 2; rarely in persons w/TD type 1</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Dysmorphic facial features</b>
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</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frontal bossing, flat facies, depressed nasal bridge, ocular proptosis</td></tr><tr><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Relative macrocephaly</b>
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</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Growth deficiency</b>
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</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Birth length well < 3rd centile</div></li><li class="half_rhythm"><div>Birth weight & head circumference may be normal, but growth restriction of these parameters occurs in infancy & childhood.</div></li></ul>
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</td></tr><tr><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Bowed femurs</b>
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</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% in persons w/TD type 1; absent in persons w/TD type 2</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Survival past age 1 yr</b>
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</td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5 persons <sup>3</sup></td><td headers="hd_h_td.T.select_features_of_thanatophoric_dy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reports exist of long-term survivors into adulthood, all of whom have required long-term mechanical ventilation.</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="td.TF.2.1"><p class="no_margin">
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<a class="bibr" href="#td.REF.hevner.2005.208" rid="td.REF.hevner.2005.208">Hevner [2005]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="td.TF.2.2"><p class="no_margin">
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<a class="bibr" href="#td.REF.wang.2014.588" rid="td.REF.wang.2014.588">Wang et al [2014]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="td.TF.2.3"><p class="no_margin">Five long-term survivors reported [<a class="bibr" href="#td.REF.macdonald.1989.508" rid="td.REF.macdonald.1989.508">MacDonald et al 1989</a>, <a class="bibr" href="#td.REF.baker.1997.427" rid="td.REF.baker.1997.427">Baker et al 1997</a>, <a class="bibr" href="#td.REF.katsumata.1998.s171" rid="td.REF.katsumata.1998.s171">Katsumata et al 1998</a>, <a class="bibr" href="#td.REF.kuno.2000.s141" rid="td.REF.kuno.2000.s141">Kuno et al 2000</a>, <a class="bibr" href="#td.REF.nikkel.2013.75" rid="td.REF.nikkel.2013.75">Nikkel et al 2013</a>]</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobtdTthanatophoricdysplasiaclinicalfe"><div id="td.T.thanatophoric_dysplasia_clinical_fe" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Thanatophoric Dysplasia: Clinical Features of Long-Term Survivors</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1366/table/td.T.thanatophoric_dysplasia_clinical_fe/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__td.T.thanatophoric_dysplasia_clinical_fe_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_1" style="text-align:left;vertical-align:middle;"></th><th id="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2" colspan="5" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Long-Term Survivor: Sex, Age at Report</th></tr><tr><th headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2" id="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Male, age 4.75 yrs <sup>1</sup></th><th headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2" id="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Female, age 28 yrs <sup>2</sup></th><th headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2" id="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Male, age 9 yrs <sup>3</sup></th><th headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2" id="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Female, age 23 yrs <sup>4</sup></th><th headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2" id="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Male, age 8 yrs <sup>5</sup></th></tr></thead><tbody><tr><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Method of diagnosis</b>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical / radiographic</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Molecular (<a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Arg248Cys</a>)</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Molecular (<a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Arg248Cys</a>)</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Molecular (<a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Arg248Cys</a>)</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Molecular (<a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Gly370Cys</a>)</td></tr><tr><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Ventilated from age</b>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neonate</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2 mos</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">9 yrs</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ND</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2 days</td></tr><tr><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Estimated developmental age</b>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2 mos</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">8-18 mos as a teenager <sup>6</sup></td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">18 mos</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ND</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-12 mos</td></tr><tr><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Hydrocephalus requiring shunt</div></li><li class="half_rhythm"><div>Suboccipital decompression</div></li><li class="half_rhythm"><div>Seizures</div></li></ul>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Hydrocephalus requiring shunt</div></li><li class="half_rhythm"><div>Suboccipital decompression</div></li><li class="half_rhythm"><div>Seizures</div></li></ul>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Mild ventriculomegaly</div></li><li class="half_rhythm"><div>Marked stenosis of skull base & upper cervical spine</div></li><li class="half_rhythm"><div>Clinically suspected high cervical myelopathy but no surgery</div></li><li class="half_rhythm"><div>Seizures</div></li></ul>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ND</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_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_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ND</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Acanthosis nigricans & seborrheic keratoses</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Acanthosis nigricans</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Acanthosis nigricans & seborrheic keratoses</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Acanthosis nigricans</td></tr><tr><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hearing</b>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing impairment</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Significant hearing impairment</div></li><li class="half_rhythm"><div>Cholesteatoma</div></li></ul>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Mixed hearing impairment</div></li><li class="half_rhythm"><div>Bilateral hearing aids</div></li></ul>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ND</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Growth parameters at birth</b>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ND</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Weight: 2.1 kg</div></li><li class="half_rhythm"><div>Length: 37 cm</div></li><li class="half_rhythm"><div>OFC: 35 cm</div></li></ul>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Weight: 3.26 kg</div></li><li class="half_rhythm"><div>Length: 41 cm</div></li><li class="half_rhythm"><div>OFC: 39.5 cm</div></li></ul>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ND</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Weight: 2.6 kg</div></li><li class="half_rhythm"><div>Length: 37 cm</div></li><li class="half_rhythm"><div>OFC: 37 cm</div></li></ul>
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</td></tr><tr><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Growth parameters at specified age</b>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At age 4.75 yrs:
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<ul><li class="half_rhythm"><div>Weight: 8.82 kg</div></li><li class="half_rhythm"><div>Length: 65 cm</div></li><li class="half_rhythm"><div>OFC: 47.5 cm</div></li></ul></td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At age 3.75 yrs: <sup>7</sup>
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<ul><li class="half_rhythm"><div>Weight: 6.5 kg</div></li><li class="half_rhythm"><div>Length: 55 cm</div></li><li class="half_rhythm"><div>OFC: 49 cm</div></li></ul></td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 8.</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ND</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At age 9 yrs:
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<ul><li class="half_rhythm"><div>Weight: 4.7 kg</div></li><li class="half_rhythm"><div>Length: 49 cm</div></li><li class="half_rhythm"><div>OFC: 46.1 cm</div></li></ul></td></tr><tr><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Other</b>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intermittent exotropia</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Craniosynostosis</div></li><li class="half_rhythm"><div>Renal calculi</div></li><li class="half_rhythm"><div>Generalized joint hypermobility</div></li><li class="half_rhythm"><div>Hip & knee flexion contractures</div></li></ul>
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</td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_1_2 hd_h_td.T.thanatophoric_dysplasia_clinical_fe_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Renal calculi</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">ND = not documented; OFC = occipitofrontal head circumference</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="td.TF.3.1"><p class="no_margin">
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<a class="bibr" href="#td.REF.macdonald.1989.508" rid="td.REF.macdonald.1989.508">MacDonald et al [1989]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="td.TF.3.2"><p class="no_margin"><a class="bibr" href="#td.REF.macdonald.1989.508" rid="td.REF.macdonald.1989.508">MacDonald et al [1989]</a> (patient 2), <a class="bibr" href="#td.REF.nikkel.2013.75" rid="td.REF.nikkel.2013.75">Nikkel et al [2013]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="td.TF.3.3"><p class="no_margin">Unpublished data are referenced describing a boy age 9 years with TD [<a class="bibr" href="#td.REF.baker.1997.427" rid="td.REF.baker.1997.427">Baker et al 1997</a>]. No information regarding diagnostic features is reported, but the individual is reported to have been ventilated from birth, with severe developmental delay, hydrocephalus, hearing impairment, and acanthosis nigricans.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="td.TF.3.4"><p class="no_margin">
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<a class="bibr" href="#td.REF.nakai.2010.656" rid="td.REF.nakai.2010.656">Nakai et al [2010]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="td.TF.3.5"><p class="no_margin"><a class="bibr" href="#td.REF.katsumata.1998.s171" rid="td.REF.katsumata.1998.s171">Katsumata et al [1998]</a>, <a class="bibr" href="#td.REF.kuno.2000.s141" rid="td.REF.kuno.2000.s141">Kuno et al [2000]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="td.TF.3.6"><p class="no_margin">Further deterioration by third decade of life and no longer able to use limbs or lift head</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="td.TF.3.7"><p class="no_margin">Growth parameter estimates based on growth charts</p></div></dd></dl><dl class="bkr_refwrap"><dt>8. </dt><dd><div id="td.TF.3.8"><p class="no_margin">Slow linear growth, -6 to -6.5 SD below the mean on the achondroplasia growth charts; OFC at +1 SD in infancy and at -1.7 SD at age 8.7 years</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobtdTfgfr3allelicdisorderstoconsider"><div id="td.T.fgfr3_allelic_disorders_to_consider" class="table"><h3><span class="label">Table 4a. </span></h3><div class="caption"><p><i>FGFR3</i> Allelic Disorders to Consider in the Differential Diagnosis of Thanatophoric Dysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1366/table/td.T.fgfr3_allelic_disorders_to_consider/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__td.T.fgfr3_allelic_disorders_to_consider_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_td.T.fgfr3_allelic_disorders_to_consider_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_td.T.fgfr3_allelic_disorders_to_consider_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th><th id="hd_h_td.T.fgfr3_allelic_disorders_to_consider_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing Clinical Features</th></tr></thead><tbody><tr><td headers="hd_h_td.T.fgfr3_allelic_disorders_to_consider_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Homozygous <a href="/books/n/gene/achondroplasia/?report=reader">achondroplasia</a></td><td headers="hd_h_td.T.fgfr3_allelic_disorders_to_consider_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Typically lethal in perinatal period</div></li><li class="half_rhythm"><div>Clinical presentation similar to TD, w/short limbs & foramen magnum stenosis</div></li></ul>
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</td><td headers="hd_h_td.T.fgfr3_allelic_disorders_to_consider_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Family history of achondroplasia in both parents</div></li><li class="half_rhythm"><div>These conditions can be impossible to distinguish on clinical & radiographic grounds.</div></li></ul>
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</td></tr><tr><td headers="hd_h_td.T.fgfr3_allelic_disorders_to_consider_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">SADDAN (<i>s</i>evere <i>a</i>chondroplasia w/<i>d</i>evelopmental <i>d</i>elay & <i>a</i>canthosis <i>n</i>igricans) (OMIM <a href="https://omim.org/entry/616482" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">616482</a>)</td><td headers="hd_h_td.T.fgfr3_allelic_disorders_to_consider_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Rare disorder characterized by extremely short stature, severe tibial bowing, seizures, foramen magnum stenosis, hydrocephalus, structural brain malformations, developmental delay, & acanthosis nigricans</div></li><li class="half_rhythm"><div>Caused by <i>FGFR3</i> pathogenic variant <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Lys650Met</a> <sup>1</sup></div></li></ul>
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</td><td headers="hd_h_td.T.fgfr3_allelic_disorders_to_consider_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Tibial bowing</div></li><li class="half_rhythm"><div>Clavicular bowing</div></li><li class="half_rhythm"><div>Unlike TD, persons w/SADDAN dysplasia often survive beyond infancy w/o ventilatory support. However, respiratory support or ventilation may be required in neonatal period & neonatal death is reported.</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>1. </dt><dd><div id="td.TF.4a.1"><p class="no_margin"><a class="bibr" href="#td.REF.bellus.1999.53" rid="td.REF.bellus.1999.53">Bellus et al [1999]</a>, <a class="bibr" href="#td.REF.tavormina.1999.722" rid="td.REF.tavormina.1999.722">Tavormina et al [1999]</a></p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobtdTfgfr3allelicdisordersnotinthe"><div id="td.T.fgfr3_allelic_disorders_not_in_the" class="table"><h3><span class="label">Table 4b. </span></h3><div class="caption"><p><i>FGFR3</i> Allelic Disorders Not in the Differential Diagnosis of Thanatophoric Dysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1366/table/td.T.fgfr3_allelic_disorders_not_in_the/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__td.T.fgfr3_allelic_disorders_not_in_the_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Associated <i>FGFR3</i> Pathogenic Variant(s)</th></tr></thead><tbody><tr><td headers="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/achondroplasia/?report=reader">Achondroplasia</a>
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</td><td headers="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly380Arg & p.Gly375Cys (identified in nearly 100% of persons w/achondroplasia) <sup>1</sup></td></tr><tr><td headers="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/hypochondroplasia/?report=reader">Hypochondroplasia</a>
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</td><td headers="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~80% of persons w/hypochondroplasia have an identified <i>FGFR3</i> pathogenic variant.</td></tr><tr><td headers="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Crouzon syndrome w/acanthosis nigricans <sup>2</sup></td><td headers="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ala391Glu</td></tr><tr><td headers="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Familial acanthosis nigricans</td><td headers="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Lys650Thr was identified in several affected family members w/AD acanthosis nigricans & short stature.</td></tr><tr><td headers="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/muenke/?report=reader">Muenke syndrome</a> <sup>2</sup></td><td headers="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Pro250Arg <sup>3</sup></td></tr><tr><td headers="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lacrimoauriculodentodigital (LADD) syndrome (OMIM <a href="https://omim.org/entry/149730" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">149730</a>) (aka Levy Hollister syndrome)</td><td headers="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asp513Asn reported in 1 family <sup>4</sup></td></tr><tr><td headers="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Camptodactyly, tall stature, & hearing loss syndrome (OMIM <a href="https://www.omim.org/entry/610474" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">610474</a>)</td><td headers="hd_h_td.T.fgfr3_allelic_disorders_not_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg621His <sup>5</sup></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</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="td.TF.4b.1"><p class="no_margin"><a class="bibr" href="#td.REF.camera.2001.277" rid="td.REF.camera.2001.277">Camera et al [2001]</a> reported an individual with the common TD type 1-causing variant <a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobtdTnotablefgfr3pathogenicvariants">p.Arg248Cys</a> and a clinical phenotype of achondroplasia. Although mosaicism remains a possible explanation for the mild phenotype, no mosaicism was identified in either buccal mucosal cells or blood.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="td.TF.4b.2"><p class="no_margin">See <a href="/books/n/gene/craniosynostosis/?report=reader"><i>FGFR</i> Craniosynostosis Syndromes Overview</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="td.TF.4b.3"><p class="no_margin"><a class="bibr" href="#td.REF.passosbueno.1999.115" rid="td.REF.passosbueno.1999.115">Passos-Bueno et al [1999]</a>, <a class="bibr" href="#td.REF.mcintosh.2000.85" rid="td.REF.mcintosh.2000.85">McIntosh et al [2000]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="td.TF.4b.4"><p class="no_margin">
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<a class="bibr" href="#td.REF.rohmann.2006.414" rid="td.REF.rohmann.2006.414">Rohmann et al [2006]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="td.TF.4b.5"><p class="no_margin">A dominant-negative mechanism is suspected to cause decreased <i>FGFR3</i> function in this condition [<a class="bibr" href="#td.REF.toydemir.2006.935" rid="td.REF.toydemir.2006.935">Toydemir et al 2006</a>].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobtdTothergenesofinterestinthediff"><div id="td.T.other_genes_of_interest_in_the_diff" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Other Genes of Interest in the Differential Diagnosis of Thanatophoric Dysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1366/table/td.T.other_genes_of_interest_in_the_diff/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__td.T.other_genes_of_interest_in_the_diff_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Features of Differential Diagnosis Disorder</th></tr><tr><th headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4" id="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/TD</th><th headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4" id="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from TD</th></tr></thead><tbody><tr><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CFAP410</i>
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<br />
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<i>CEP120</i>
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<br />
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<i>DYNC2H1</i>
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<br />
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<i>DYNC2I1</i>
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<br />
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<i>DYNC2I2</i>
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<br />
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<i>DYNC2LI1</i>
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<br />
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<i>IFT52</i>
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<br />
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<i>IFT80</i>
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<br />
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<i>IFT81</i>
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<br />
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<i>IFT122</i>
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<br />
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<i>IFT140</i>
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<br />
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<i>IFT172</i>
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<br />
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<i>KIAA0586</i>
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<br />
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<i>KIAA0753</i>
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<br />
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<i>NEK1</i>
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<br />
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<i>TRAF3IP1</i>
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<br />
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<i>TCTEX1D2</i>
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<br />
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<i>TTC21B</i>
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<br />
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<i>WDR19</i>
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<br />
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<i>WDR35</i>
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</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Skeletal ciliopathies: incl perinatal lethal short-rib polydactyly syndromes & Jeune asphyxiating thoracic dystrophy (See OMIM <a href="https://omim.org/phenotypicSeries/PS208500" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS208500</a>.)</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />Digenic <sup>1</sup></td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>May be lethal in perinatal period or infancy</div></li><li class="half_rhythm"><div>Narrow thorax & short ribs; short stature & short limbs noted in infancy (But survivors may manifest only mild-to-moderate short stature.)</div></li></ul>
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</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Polydactyly & wide variety of multisystem features common; may involve cardiac, renal, liver, pancreatic, intestinal, genital, retinal, & ectodermal tissues <sup>2</sup></div></li><li class="half_rhythm"><div>Improvement in respiratory status occurs in some survivors w/skeletal ciliopathies, & persons may manifest only mild-to-moderate short stature.</div></li></ul>
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</td></tr><tr><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL1A1</i>
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<br />
|
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<i>COL1A2</i>
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</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Perinatally lethal osteogenesis imperfecta <sup>3</sup> (previously OI type II) (See <a href="/books/n/gene/oi/?report=reader"><i>COL1A1/2</i>-OI</a>.)</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Typically lethal in perinatal period</div></li><li class="half_rhythm"><div>Markedly shortened & bowed long bones; severe short stature</div></li></ul>
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</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Absence of severe micromelia; craniosynostosis; small iliac bones, narrow sacroiliac notch, & platyspondyly; bowing more significant than in TD</div></li><li class="half_rhythm"><div>Note: TD is not assoc w/undermineralization, fractures, wormian bones, dentinogenesis imperfecta, or dark blue sclera.</div></li></ul>
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</td></tr><tr><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL2A1</i>
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<br />
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<i>SLC26A2</i>
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<br />
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<i>TRIP11</i>
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</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Achondrogenesis (ACG) type IA, <a href="/books/n/gene/achon1b/?report=reader">type IB</a>, & type II (OMIM <a href="https://www.omim.org/phenotypicSeries/PS200600" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS200600</a>)</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />AD</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Typically lethal in perinatal period</div></li><li class="half_rhythm"><div>Short stature w/micromelia, relative macrocephaly, short ribs, & brachydactyly</div></li></ul>
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</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Minimal or absent ossification of vertebral bodies, iliac, & ischial bones in ACG</div></li><li class="half_rhythm"><div>Rib fractures in type II ACG</div></li><li class="half_rhythm"><div>Distinctive facial features, short neck w/excess soft tissue</div></li></ul>
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</td></tr><tr><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL2A1</i>
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</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Platyspondylic lethal skeletal dysplasia, Torrance type (PLSD-T) <sup>4</sup> (OMIM <a href="https://omim.org/entry/151210" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">151210</a>)</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>Typically lethal in perinatal period</div></li><li class="half_rhythm"><div>Short long bones w/ragged metaphyses, platyspondyly, & short ribs</div></li></ul>
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</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Bowed radius/tibia may be present.</div></li><li class="half_rhythm"><div>PLSD-T can be differentiated histologically by presence of dilated loops of endoplasmic reticulum in chondrocytes.</div></li></ul>
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</td></tr><tr><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FGFR3</i>
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</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Homozygous <a href="/books/n/gene/achondroplasia/?report=reader">achondroplasia</a></td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Codominant</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_1" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#td.Genetically_Related_Allelic_Disorders">Allelic Disorders</a>.</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#td.Genetically_Related_Allelic_Disorders">Allelic Disorders</a>.</td></tr><tr><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">SADDAN</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td></tr><tr><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>GPX4</i>
|
|
</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Spondylometaphyseal dysplasia, Sedaghatian type (OMIM <a href="https://omim.org/entry/250220" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">250220</a>)</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>Typically lethal in perinatal period</div></li><li class="half_rhythm"><div>Short long bones, metaphyseal abnormalities, cupped ribs, platyspondyly, brachydactyly</div></li><li class="half_rhythm"><div>Cerebral ventriculomegaly, other CNS abnormalities</div></li></ul>
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</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>Irregular ("lacy") ossifications in iliac wings & calcaneus</div></li><li class="half_rhythm"><div>Disproportionately long fibulae</div></li><li class="half_rhythm"><div>Cardiac anomalies incl structural congenital heart disease</div></li></ul>
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|
</td></tr><tr><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>HSPG2</i>
|
|
</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dyssegmental dysplasia, Silverman-Handmaker type (OMIM <a href="https://omim.org/entry/224410" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">224410</a>)</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>Typically lethal in perinatal period</div></li><li class="half_rhythm"><div>Narrow thorax, short stature, bowed limbs</div></li></ul>
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|
</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<ul><li class="half_rhythm"><div>Spine anisospondyly is present.</div></li><li class="half_rhythm"><div>Cleft palate & encephalocele may be present.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>INPPL1</i>
|
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</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Opsismodysplasia (OMIM <a href="https://omim.org/entry/258480" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">258480</a>)</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>May be lethal in perinatal period</div></li><li class="half_rhythm"><div>Short long bones, platyspondyly, relative macrocephaly, small chest</div></li></ul>
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</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Delayed bone maturation & poor bone quality</td></tr><tr><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>PAM16</i>
|
|
</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type (OMIM <a href="https://omim.org/entry/613320" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613320</a>)</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>May be lethal in perinatal period</div></li><li class="half_rhythm"><div>Short limbed short stature, narrow chest w/short ribs, narrowed cervical canal, platyspondyly</div></li><li class="half_rhythm"><div>Frontal bossing, depressed nasal bridge</div></li><li class="half_rhythm"><div>Developmental delay</div></li><li class="half_rhythm"><div>Hearing impairment</div></li></ul>
|
|
</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>Absence of epiphyseal ossification of the knees</div></li><li class="half_rhythm"><div>Square iliac bones</div></li><li class="half_rhythm"><div>Horizontal acetabulae w/medial & lateral spurs</div></li><li class="half_rhythm"><div>Hypoplastic ischia</div></li></ul>
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|
</td></tr><tr><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>PEX7</i>
|
|
</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Classic <a href="/books/n/gene/rcdp/?report=reader">rhizomelic chondrodysplasia punctata type 1</a> (RCDP1)</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>Most affected children do not survive 1st decade of life; a proportion die in the neonatal period.</div></li><li class="half_rhythm"><div>Rhizomelia, punctate calcifications in cartilage w/epiphyseal & metaphyseal abnormalities, coronal cleft or notch of vertebral bodies</div></li><li class="half_rhythm"><div>Brain malformations</div></li></ul>
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|
</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>Punctate epiphyseal dysplasia evident as stippled epiphyses on radiography; coronal vertebral clefts may be present.</div></li><li class="half_rhythm"><div>Rhizomelia prominent (compared to micromelia in TD)</div></li><li class="half_rhythm"><div>Birth weight, length, & head circumference often at lower range of normal</div></li><li class="half_rhythm"><div>Cataracts usually present at birth or in 1st few mos of life</div></li></ul>
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|
</td></tr><tr><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SLC35D1</i>
|
|
</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Schneckenbecken dysplasia (OMIM <a href="https://omim.org/entry/269250" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">269250</a>)</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>Typically lethal in perinatal period</div></li><li class="half_rhythm"><div>Short-limbed short stature</div></li><li class="half_rhythm"><div>Platyspondyly</div></li></ul>
|
|
</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>Hypoplastic iliac bones w/characteristic appearance resembling a snail</div></li><li class="half_rhythm"><div>Broad long bones</div></li><li class="half_rhythm"><div>Precocious ossification of the tarsus</div></li><li class="half_rhythm"><div>Hydrops</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>SOX9</i>
|
|
</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/campo-dysp/?report=reader">Campomelic dysplasia</a> (CD)</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>Typically lethal in perinatal period</div></li><li class="half_rhythm"><div>Variable stature (short to normal), w/short limbs & narrow thorax</div></li></ul>
|
|
</td><td headers="hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_1_4 hd_h_td.T.other_genes_of_interest_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Profound hypoplasia of the body of the scapulae (compared to globally small scapulae in TD)</div></li><li class="half_rhythm"><div>Tibial & femoral bowing (w/longer femurs compared to TD)</div></li><li class="half_rhythm"><div>Tubular bones are poorly developed & show immature ossification, w/nonossification of thoracic pedicles.</div></li><li class="half_rhythm"><div>Many have 11 pairs of ribs.</div></li><li class="half_rhythm"><div>Skin dimples are often present.</div></li><li class="half_rhythm"><div>≤75% of persons w/CD w/a 46,XY karyotype have either female external genitalia or ambiguous genitalia.</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; CNS = central nervous system; MOI = mode of inheritance; TD = thanatophoric dysplasia</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="td.TF.5.1"><p class="no_margin">Biallelic inheritance of pathogenic variants in <i>DYNC2H1</i> and <i>NEK1</i> has been reported (see OMIM <a href="https://omim.org/entry/613091" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613091</a>).</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="td.TF.5.2"><p class="no_margin">
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<a class="bibr" href="#td.REF.huber.2012.165" rid="td.REF.huber.2012.165">Huber & Cormier-Daire [2012]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="td.TF.5.3"><p class="no_margin">Clinically, osteogenesis imperfecta (OI) was classified into four types; the type most reminiscent of TD is OI type II (perinatally lethal OI).</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="td.TF.5.4"><p class="no_margin">The Luton type is considered to be a mild form of the Torrance type [<a class="bibr" href="#td.REF.nishimura.2004.75" rid="td.REF.nishimura.2004.75">Nishimura et al 2004</a>].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobtdTrecommendedevaluationsfollowingi"><div id="td.T.recommended_evaluations_following_i" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Thanatophoric Dysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1366/table/td.T.recommended_evaluations_following_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__td.T.recommended_evaluations_following_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_td.T.recommended_evaluations_following_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_td.T.recommended_evaluations_following_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_td.T.recommended_evaluations_following_i_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_td.T.recommended_evaluations_following_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Respiratory</b>
|
|
</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Assessment of respiratory rate, skin color, & oxygen saturations</div></li><li class="half_rhythm"><div>Arterial blood gases may be helpful in infants who survive immediate postnatal period.</div></li><li class="half_rhythm"><div>Polysomnography</div></li><li class="half_rhythm"><div>Assessment for foramen magnum stenosis</div></li></ul>
|
|
</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If tracheostomy & long-term ventilatory support is considered, consult w/respiratory physician & multidisciplinary team w/expertise in tracheostomy care.</td></tr><tr><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Foramen magnum</b>
|
|
<br />
|
|
<b>narrowing,</b>
|
|
<br />
|
|
<b>hydrocephalus,</b>
|
|
<br />
|
|
<b>&/or other CNS</b>
|
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<br />
|
|
<b>abnormalities</b>
|
|
</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Head & spine CT or MRI</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>Brain stem compression may contribute to respiratory insufficiency.</div></li><li class="half_rhythm"><div>Cervical myelopathy may → quadriplegia.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Craniosynostosis</b>
|
|
</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Head CT in persons w/clinical evidence of craniosynostosis</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Seizures</b>
|
|
</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider assessment w/neurologist &/or EEG if episodes suspicious for seizures.</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Audiology</b>
|
|
</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologic assessment</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Ophthalmology</b>
|
|
</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmology eval for exotropia</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Developmental delay</b>
|
|
</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.recommended_evaluations_following_i_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>
|
|
</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professional <sup>1</sup></td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & families re nature, MOI, & implications of TD to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Family support</b>
|
|
<br />
|
|
<b>& resources</b>
|
|
</td><td headers="hd_h_td.T.recommended_evaluations_following_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for:
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<ul><li class="half_rhythm"><div>Community or <a href="#td.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Social work involvement for parental support;</div></li><li class="half_rhythm"><div>Home nursing referral.</div></li></ul></td><td headers="hd_h_td.T.recommended_evaluations_following_i_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">CNS = central nervous system; MOI = mode of inheritance; TD = thanatophoric dysplasia</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="td.TF.6.1"><p class="no_margin">Medical geneticist, certified genetic counselor, or certified advanced genetic nurse.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobtdTtreatmentofmanifestationsinindi"><div id="td.T.treatment_of_manifestations_in_indi" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Thanatophoric Dysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1366/table/td.T.treatment_of_manifestations_in_indi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__td.T.treatment_of_manifestations_in_indi_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_td.T.treatment_of_manifestations_in_indi_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_td.T.treatment_of_manifestations_in_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Respiratory insufficiency</b>
|
|
</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neonates typically require aggressive respiratory support (e.g., ventilation, tracheostomy) to survive.</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1 long-term survivor required supplemental oxygen in neonatal period & ventilatory support from age 2 mos. <sup>1</sup></td></tr><tr><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Perioperative management <sup>2</sup></b>
|
|
</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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|
<ul><li class="half_rhythm"><div>Assessment of pulmonary function</div></li><li class="half_rhythm"><div>Assessment of previous spine imaging for "spine at risk" findings</div></li><li class="half_rhythm"><div>Availability of ICU care</div></li><li class="half_rhythm"><div>Availability of anesthesia staff w/experience in mgmt of skeletal dysplasias</div></li><li class="half_rhythm"><div>Maintenance of cervical spine in a neutral position (may require intubation using specialized intubation equipment)</div></li><li class="half_rhythm"><div>Consideration of spinal monitoring during the procedure to evaluate safety during intraoperative manipulations</div></li></ul>
|
|
</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Use of evoked potential monitoring requires avoidance of volatile anesthetic agents & muscle relaxants, which could affect evoked potential recordings.</td></tr><tr><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hydrocephalus</b>
|
|
</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval by neurosurgeon for shunt placement</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Craniocervical junction constriction</b>
|
|
</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>Eval by neurosurgeon for suboccipital decompression</div></li><li class="half_rhythm"><div>Standard mgmt of complications of spinal cord compression such as spasticity</div></li></ul>
|
|
</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Surgical decompression may only provide temporary benefit, w/return of respiratory insufficiency & neurologic compromise. <sup>1, 3</sup></td></tr><tr><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Seizures</b>
|
|
</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard anti-seizure treatment</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Hearing impairment</b>
|
|
</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing aids per audiologist &/or otolaryngologist</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Vision</b>
|
|
</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mgmt of exotropia by ophthalmologist</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Development</b>
|
|
</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Individualized developmental support by allied health clinicians</td><td headers="hd_h_td.T.treatment_of_manifestations_in_indi_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>1. </dt><dd><div id="td.TF.7.1"><p class="no_margin">
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<a class="bibr" href="#td.REF.nikkel.2013.75" rid="td.REF.nikkel.2013.75">Nikkel et al [2013]</a>
|
|
</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="td.TF.7.2"><p class="no_margin">Consensus perioperative management guidelines for individuals with skeletal dysplasia have been published [<a class="bibr" href="#td.REF.white.2017.2584" rid="td.REF.white.2017.2584">White et al 2017</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="td.TF.7.3"><p class="no_margin">
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<a class="bibr" href="#td.REF.macdonald.1989.508" rid="td.REF.macdonald.1989.508">MacDonald et al [1989]</a>
|
|
</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobtdTrecommendedsurveillanceforindivi"><div id="td.T.recommended_surveillance_for_indivi" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Thanatophoric Dysplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1366/table/td.T.recommended_surveillance_for_indivi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__td.T.recommended_surveillance_for_indivi_lrgtbl__"><table><thead><tr><th id="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_td.T.recommended_surveillance_for_indivi_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_td.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Respiratory</b>
|
|
<br />
|
|
<b>insufficiency</b>
|
|
</td><td headers="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>Assessment of respiratory status</div></li><li class="half_rhythm"><div>Neuroimaging in event of respiratory deterioration to evaluate for compression of brain stem at craniocervical junction</div></li></ul>
|
|
</td><td headers="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annual clinical eval in long-term survivors</td></tr><tr><td headers="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Neurologic</b>
|
|
<br />
|
|
<b>complications</b>
|
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</td><td headers="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<ul><li class="half_rhythm"><div>Assessment of neurologic status</div></li><li class="half_rhythm"><div>EEG in event of seizure activity</div></li><li class="half_rhythm"><div>Neuroimaging if signs/symptoms of spinal cord compression</div></li></ul>
|
|
</td><td headers="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annual clinical eval for signs & symptoms in long-term survivors</td></tr><tr><td headers="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Joint contracture</b>
|
|
<br />
|
|
<b>or joint hypermobility</b>
|
|
</td><td headers="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics eval</td><td headers="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_3" rowspan="4" colspan="1" style="text-align:left;vertical-align:middle;">Annual clinical eval in long-term survivors</td></tr><tr><td headers="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hearing impairment</b>
|
|
</td><td headers="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiology assessment</td></tr><tr><td headers="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Vision</b>
|
|
</td><td headers="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmology eval</td></tr><tr><td headers="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Development</b>
|
|
</td><td headers="hd_h_td.T.recommended_surveillance_for_indivi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobtdmolgenTA"><div id="td.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Thanatophoric Dysplasia: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1366/table/td.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__td.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_td.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_td.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_td.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_td.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_td.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_td.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_td.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="/gene/2261" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
|
<i>FGFR3</i>
|
|
</a>
|
|
</td><td headers="hd_b_td.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=2261" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">4p16<wbr style="display:inline-block"></wbr>​.3</a>
|
|
</td><td headers="hd_b_td.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/P22607" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Fibroblast growth factor receptor 3</a>
|
|
</td><td headers="hd_b_td.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.lovd.nl/FGFR3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FGFR3 @ LOVD</a>
|
|
</td><td headers="hd_b_td.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=FGFR3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FGFR3</a>
|
|
</td><td headers="hd_b_td.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=FGFR3[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FGFR3</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 id="td.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
|
|
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
|
chromosome locus from
|
|
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
|
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
|
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
|
<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobtdmolgenTB"><div id="td.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Thanatophoric Dysplasia (<a href="/omim/134934,187600,187601" 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/NBK1366/table/td.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__td.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/134934" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">134934</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">FIBROBLAST GROWTH FACTOR RECEPTOR 3; FGFR3</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/187600" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">187600</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THANATOPHORIC DYSPLASIA, TYPE I; TD1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/187601" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">187601</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THANATOPHORIC DYSPLASIA, TYPE II; TD2</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobtdTnotablefgfr3pathogenicvariants"><div id="td.T.notable_fgfr3_pathogenic_variants" class="table"><h3><span class="label">Table 9. </span></h3><div class="caption"><p>Notable <i>FGFR3</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1366/table/td.T.notable_fgfr3_pathogenic_variants/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__td.T.notable_fgfr3_pathogenic_variants_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Phenotype</th><th id="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide<br />Change</th><th id="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted<br />Protein Change</th><th id="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_1" rowspan="13" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000142.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000142<wbr style="display:inline-block"></wbr>​.3</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000133.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000133<wbr style="display:inline-block"></wbr>​.1</a>
|
|
</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_2" rowspan="12" colspan="1" style="text-align:left;vertical-align:middle;">TD type 1</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.742C>T</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg248Cys</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">One of the most common pathogenic variants [<a class="bibr" href="#td.REF.xue.2014.497" rid="td.REF.xue.2014.497">Xue et al 2014</a>] <sup>1</sup></td></tr><tr><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.742_743insTGT</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg248delinsLeuCys</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Insertion variant [<a class="bibr" href="#td.REF.lindy.2016.1573" rid="td.REF.lindy.2016.1573">Lindy et al 2016</a>] <sup>1</sup></td></tr><tr><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1108G>T</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly370Cys</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="/books/NBK1366/table/td.T.thanatophoric_dysplasia_clinical_fe/?report=objectonly" target="object" rid-ob="figobtdTthanatophoricdysplasiaclinicalfe">Table 3</a>.</td></tr><tr><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1118A>G</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Tyr373Cys</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">One of the most common pathogenic variants [<a class="bibr" href="#td.REF.xue.2014.497" rid="td.REF.xue.2014.497">Xue et al 2014</a>] <sup>1</sup></td></tr><tr><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1949A>T</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Lys650Met</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2420G>T</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ter807LeuextTer101</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_5" rowspan="7" colspan="1" style="text-align:left;vertical-align:middle;">No-stop variants → protein extension <sup>1, 2</sup></td></tr><tr><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2419T>G</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ter807GlyextTer101</td></tr><tr><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2419T>C</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ter807ArgextTer101</td></tr><tr><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2419T>A</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ter807ArgextTer101</td></tr><tr><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2421A>T</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ter807CysextTer101</td></tr><tr><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2421A>C</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ter807CysextTer101</td></tr><tr><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2421A>G</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ter807TrpextTer101</td></tr><tr><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">TD type 2</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1948A>G</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Lys650Glu</td><td headers="hd_h_td.T.notable_fgfr3_pathogenic_variants_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In all persons w/TD type 2</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 class="bkr_refwrap"><dt>1. </dt><dd><div id="td.TF.9.1"><p class="no_margin">See <a href="#td.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="td.TF.9.2"><p class="no_margin">Also known as non-stop variants.</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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