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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Muenke Syndrome - GeneReviews® - NCBI Bookshelf</title>
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<meta name="jr-prev-unit" content="/books/n/gene/mps7/?report=reader">
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<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
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<meta name="citation_title" content="Muenke Syndrome">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2023/03/30">
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<meta name="citation_author" content="Paul Kruszka">
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<meta name="citation_author" content="Myron Rolle">
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<meta name="citation_author" content="Kristopher T Kahle">
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<meta name="citation_author" content="Maximilian Muenke">
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<meta name="citation_pmid" content="20301588">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1415/">
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<meta name="citation_keywords" content="Fibroblast growth factor receptor 3">
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<meta name="citation_keywords" content="FGFR3">
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<meta name="citation_keywords" content="Muenke Syndrome">
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<meta name="DC.Title" content="Muenke Syndrome">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Paul Kruszka">
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<meta name="DC.Contributor" content="Myron Rolle">
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<meta name="DC.Contributor" content="Kristopher T Kahle">
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<meta name="DC.Contributor" content="Maximilian Muenke">
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<meta name="DC.Date" content="2023/03/30">
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<meta name="description" content='Muenke syndrome is characterized by considerable phenotypic variability; features may include coronal synostosis (more often bilateral than unilateral); synostosis of other sutures, all sutures (pan synostosis), or no sutures; or macrocephaly. Bilateral coronal synostosis typically results in brachycephaly, although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Unilateral coronal synostosis results in anterior plagiocephaly. Other craniofacial findings typically include temporal bossing, widely spaced eyes, ptosis or mild proptosis, mild midface retrusion, and highly arched palate or cleft lip and palate. Strabismus is common. Other findings can include hearing loss, developmental delay, intellectual disability, behavioral issues, intracranial anomalies, epilepsy, ocular anomalies, brachydactyly, carpal and/or tarsal bone fusions, broad thumbs and great toes, clinodactyly, and radiographic findings of short and broad middle phalanges and/or cone-shaped epiphyses. Of note, some individuals who have the p.Pro250Arg pathogenic variant may have no signs of Muenke syndrome on physical or radiographic examination.'>
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<meta name="og:title" content="Muenke Syndrome">
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<meta name="og:description" content='Muenke syndrome is characterized by considerable phenotypic variability; features may include coronal synostosis (more often bilateral than unilateral); synostosis of other sutures, all sutures (pan synostosis), or no sutures; or macrocephaly. Bilateral coronal synostosis typically results in brachycephaly, although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Unilateral coronal synostosis results in anterior plagiocephaly. Other craniofacial findings typically include temporal bossing, widely spaced eyes, ptosis or mild proptosis, mild midface retrusion, and highly arched palate or cleft lip and palate. Strabismus is common. Other findings can include hearing loss, developmental delay, intellectual disability, behavioral issues, intracranial anomalies, epilepsy, ocular anomalies, brachydactyly, carpal and/or tarsal bone fusions, broad thumbs and great toes, clinodactyly, and radiographic findings of short and broad middle phalanges and/or cone-shaped epiphyses. Of note, some individuals who have the p.Pro250Arg pathogenic variant may have no signs of Muenke syndrome on physical or radiographic examination.'>
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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="_NBK1415_"><span class="title" itemprop="name">Muenke Syndrome</span></h1><p class="contribs">Kruszka P, Rolle M, Kahle KT, et al.</p><p class="fm-aai"><a href="#_NBK1415_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 26 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="muenke.Summary" itemprop="description"><h2 id="_muenke_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Muenke syndrome is characterized by considerable phenotypic variability; features may include coronal synostosis (more often bilateral than unilateral); synostosis of other sutures, all sutures (pan synostosis), or no sutures; or macrocephaly. Bilateral coronal synostosis typically results in brachycephaly, although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Unilateral coronal synostosis results in anterior plagiocephaly. Other craniofacial findings typically include temporal bossing, widely spaced eyes, ptosis or mild proptosis, mild midface retrusion, and highly arched palate or cleft lip and palate. Strabismus is common. Other findings can include hearing loss, developmental delay, intellectual disability, behavioral issues, intracranial anomalies, epilepsy, ocular anomalies, brachydactyly, carpal and/or tarsal bone fusions, broad thumbs and great toes, clinodactyly, and radiographic findings of short and broad middle phalanges and/or cone-shaped epiphyses. Of note, some individuals who have the p.Pro250Arg pathogenic variant may have no signs of Muenke syndrome on physical or radiographic examination.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of Muenke syndrome is established by the identification of the <i>FGFR3</i> pathogenic variant c.749C>G (p.Pro250Arg) by molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Children with Muenke syndrome and craniosynostosis are best managed by a pediatric craniofacial clinic, which typically includes a craniofacial surgeon and neurosurgeon, clinical geneticist, ophthalmologist, otolaryngologist, pediatrician, radiologist, psychologist, dentist, audiologist, speech therapist, and social worker. Depending on severity, the first craniosynostosis repair (fronto-orbital advancement and cranial vault remodeling) is typically performed between ages three and six months. An alternative approach is endoscopic strip craniectomy, which is a less invasive procedure and is typically performed prior to age three months. Postoperative increased intracranial pressure and/or the need for secondary or tertiary extracranial contouring may occur. Standard treatments for hearing loss; early speech therapy and intervention programs for those with developmental delay, intellectual impairment, behavioral issues, and/or hearing loss; surgical correction for strabismus; lubrication for exposure keratopathy.</p><p><i>Surveillance</i>: Affected individuals benefit from integrated multidisciplinary care and protocol-driven management from birth to maturity that includes audiograms to screen for acquired or progressive hearing loss; developmental and behavioral assessments; neurologic assessment for seizures; ophthalmology assessment for strabismus; and social work assessment.</p><p><i>Evaluation of relatives at risk:</i> It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from institution of treatment and preventive measures.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Muenke syndrome is inherited in an autosomal dominant manner. Each child of an individual with Muenke syndrome has a 50% chance of inheriting the pathogenic variant. Because penetrance is reduced and the phenotype is variable within families, the manifestations in a child who inherits the pathogenic variant cannot be predicted based on the phenotypes of other heterozygous family members. Once the <i>FGFR3</i> p.Pro250Arg pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Muenke syndrome are possible.</p></div></div><div id="muenke.Diagnosis"><h2 id="_muenke_Diagnosis_">Diagnosis</h2><div id="muenke.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Muenke syndrome <b>should be suspected</b> in individuals with the following clinical, radiographic, and family history findings. The phenotype is variable and ranges from no detectable clinical manifestations to the presence of craniosynostosis along with other classic features.</p><p>
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<b>Clinical features</b>
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</p><ul><li class="half_rhythm"><div>Facial asymmetry</div></li><li class="half_rhythm"><div>Brachycephaly, turribrachycephaly (a "tower-shaped" skull), or cloverleaf skull</div></li><li class="half_rhythm"><div>Sutural ridging over both (or less commonly one) of the coronal sutures accompanied by:</div><ul><li class="half_rhythm"><div>Ipsilaterally: flattening of the forehead, elevation of the superior orbital rim, elevation of the eyebrow, anterior placement of the ear, deviation of the nasal root</div></li><li class="half_rhythm"><div>Contralaterally: frontal bossing of the forehead, depression of the eyebrow</div></li></ul></li><li class="half_rhythm"><div>Temporal bossing</div></li><li class="half_rhythm"><div>Macrocephaly without craniosynostosis</div></li><li class="half_rhythm"><div>Craniosynostosis with sensorineural hearing loss</div></li></ul><p>
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<b>Radiographic findings</b>
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</p><ul><li class="half_rhythm"><div>Head CT with three-dimensional reconstruction demonstrating:</div><ul><li class="half_rhythm"><div>Unilateral coronal craniosynostosis</div></li><li class="half_rhythm"><div>Bilateral coronal craniosynostosis</div></li><li class="half_rhythm"><div>Synostosis of other sutures (lambdoid, metopic, sagittal, squamosal)</div></li></ul></li><li class="half_rhythm"><div>Extracranial radiographic features can include:</div><ul><li class="half_rhythm"><div>Fusion of the carpal bones (commonly the capitate and hamate or trapezoid and trapezium bones) [<a class="bibr" href="#muenke.REF.muenke.1997.555" rid="muenke.REF.muenke.1997.555">Muenke et al 1997</a>, <a class="bibr" href="#muenke.REF.trusen.2003.168" rid="muenke.REF.trusen.2003.168">Trusen et al 2003</a>, <a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>]</div></li><li class="half_rhythm"><div>Fusion of the tarsal bones (commonly the calcaneus and cuboid bones) [<a class="bibr" href="#muenke.REF.muenke.1997.555" rid="muenke.REF.muenke.1997.555">Muenke et al 1997</a>, <a class="bibr" href="#muenke.REF.trusen.2003.168" rid="muenke.REF.trusen.2003.168">Trusen et al 2003</a>, <a class="bibr" href="#muenke.REF.agochukwu.2013.453" rid="muenke.REF.agochukwu.2013.453">Agochukwu et al 2013</a>, <a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>]</div></li><li class="half_rhythm"><div>Thimble-like (short and broad) middle phalanges of the hands and feet [<a class="bibr" href="#muenke.REF.muenke.1997.555" rid="muenke.REF.muenke.1997.555">Muenke et al 1997</a>, <a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>]</div></li><li class="half_rhythm"><div>Epiphyseal coning [<a class="bibr" href="#muenke.REF.muenke.1997.555" rid="muenke.REF.muenke.1997.555">Muenke et al 1997</a>, <a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>]</div></li></ul></li></ul><p><b>Family history</b> is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.</p></div><div id="muenke.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of Muenke syndrome <b>is established</b> in a proband by the identification of a heterozygous <a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">c.749C>G (p.Pro250Arg)</a> pathogenic variant in <i>FGFR3</i> by molecular genetic testing (see <a href="/books/NBK1415/table/muenke.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobmuenkeTmoleculargenetictestingused">Table 1</a>).</p><p>Molecular genetic testing approaches can include <b>single-gene testing</b> or use of a <b>multigene panel</b>.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-gene testing.</b> Sequence analysis of <i>FGFR3</i> can be performed first. Note: Targeted analysis for the <a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant in <i>FGFR3</i> is rarely performed because the clinical features of Muenke syndrome overlap with those of other craniosynostosis syndromes caused by different heterozygous pathogenic variants in <i>FGFR3</i> and other craniosynostosis-related genes (see <a href="#muenke.Differential_Diagnosis">Differential Diagnosis</a>).</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A multigene panel</b> that includes <i>FGFR3</i> and other genes of interest (see <a href="#muenke.Differential_Diagnosis">Differential Diagnosis</a>) may also be considered. 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>; thus, clinicians need to determine which multigene panel is most likely 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. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmuenkeTmoleculargenetictestingused"><a href="/books/NBK1415/table/muenke.T.molecular_genetic_testing_used/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobmuenkeTmoleculargenetictestingused"><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="muenke.T.molecular_genetic_testing_used"><a href="/books/NBK1415/table/muenke.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobmuenkeTmoleculargenetictestingused">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Muenke Syndrome </p></div></div></div></div><div id="muenke.Clinical_Characteristics"><h2 id="_muenke_Clinical_Characteristics_">Clinical Characteristics</h2><div id="muenke.Clinical_Description"><h3>Clinical Description</h3><p>Muenke syndrome is characterized by coronal synostosis, and occasionally synostosis of other sutures, abnormal skull shape in those with synostosis, characteristic facies, hearing loss, and strabismus. Additional features can include developmental delay, intellectual disability, epilepsy, intracranial anomalies, brachydactyly, broad thumbs and great toes, and/or clinodactyly. Penetrance is incomplete, and phenotypic variability is considerable even within the same family. Some individuals have minor clinical signs such as macrocephaly and subtle facial findings without craniosynostosis; some have only radiographic features [<a class="bibr" href="#muenke.REF.muenke.1997.555" rid="muenke.REF.muenke.1997.555">Muenke et al 1997</a>]. To date, more than 100 individuals have been identified with a <a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant in <i>FGFR3</i> [<a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</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="figmuenkeTmuenkesyndromefrequencyofse"><a href="/books/NBK1415/table/muenke.T.muenke_syndrome_frequency_of_se/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobmuenkeTmuenkesyndromefrequencyofse"><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="muenke.T.muenke_syndrome_frequency_of_se"><a href="/books/NBK1415/table/muenke.T.muenke_syndrome_frequency_of_se/?report=objectonly" target="object" rid-ob="figobmuenkeTmuenkesyndromefrequencyofse">Table 2. </a></h4><p class="float-caption no_bottom_margin">Muenke Syndrome: Frequency of Select Features </p></div></div><p><b>Craniosynostosis and craniofacial features.</b> Coronal synostosis may be bilateral (~2/3 of affected individuals) or unilateral (~1/3 of affected individuals) [<a class="bibr" href="#muenke.REF.keller.2007.374" rid="muenke.REF.keller.2007.374">Keller et al 2007</a>, <a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>]. Occasionally, other sutures may be involved, including the metopic suture (leading to trigonocephaly), the sagittal suture, the squamosal suture, or – rarely – all sutures (pan synostosis) [<a class="bibr" href="#muenke.REF.van_der_meulen.2006.2493" rid="muenke.REF.van_der_meulen.2006.2493">van der Meulen et al 2006</a>, <a class="bibr" href="#muenke.REF.doumit.2014.429" rid="muenke.REF.doumit.2014.429">Doumit et al 2014</a>, <a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>]. Craniosynostosis is not always present; approximately 12%-15% of individuals heterozygous for the <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant had no evidence of craniosynostosis [<a class="bibr" href="#muenke.REF.renier.2000.631" rid="muenke.REF.renier.2000.631">Renier et al 2000</a>, <a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>].</p><p>Bilateral coronal synostosis typically results in brachycephaly, although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Unilateral coronal synostosis results in anterior plagiocephaly (asymmetry of the skull and face).</p><p>Other craniofacial findings typically include temporal bossing, widely spaced eyes, ptosis or proptosis (usually mild), and midface retrusion (usually mild). Rarer craniofacial features include malar flattening, a short nose with anteverted nares and a depressed nasal bridge, deviation of the nasal septum, an overhanging nasal tip, high-arched palate, cleft lip and/or palate, dental malocclusion, mild retrognathia, hypoplastic auricles, and low-set ears.</p><p><b>Hearing loss.</b> In a large international cohort, more than 70% of individuals with Muenke syndrome had hearing loss, with a majority of individuals with hearing loss having bilateral sensorineural hearing loss (70.8%) and the remainder having conductive (22%) and mixed forms of hearing loss (8.6%). There is evidence that sensorineural hearing loss (usually mild and mid-to-low frequency) is specific to Muenke syndrome compared to other <i>FGFR</i>-related craniosynostosis syndromes [<a class="bibr" href="#muenke.REF.agochukwu.2014a.135" rid="muenke.REF.agochukwu.2014a.135">Agochukwu et al 2014a</a>], sometimes occurring in individuals with Muenke syndrome who do not have craniosynostosis [<a class="bibr" href="#muenke.REF.hollway.1998.877" rid="muenke.REF.hollway.1998.877">Hollway et al 1998</a>].</p><p>Children with Muenke syndrome and craniosynostosis can develop hearing loss following a normal newborn hearing screen [E Doherty & M Muenke, personal observation]. Individuals may have recurrent episodes of otitis media treated with myringotomy tube placement [<a class="bibr" href="#muenke.REF.didolkar.2009.1011" rid="muenke.REF.didolkar.2009.1011">Didolkar et al 2009</a>, <a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>], which may explain the occurrence of conductive hearing loss in some individuals. Additionally, some individuals may have progressive hearing loss.</p><p><b>Developmental delay and behavioral issues.</b> In a large international study, 40.8% of individuals with Muenke syndrome were reported to have intellectual disability and 66.3% had developmental delay, with speech delay the most common type of developmental delay (61.1%) [<a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>]. Developmental delay and/or intellectual disability is usually mild. Individuals with Muenke syndrome were more likely to be intellectually impaired than individuals with Crouzon syndrome [<a class="bibr" href="#muenke.REF.flapper.2009.1252" rid="muenke.REF.flapper.2009.1252">Flapper et al 2009</a>] and had slightly lower IQ than other individuals with craniosynostosis without the <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant [<a class="bibr" href="#muenke.REF.arnaud.2002.6" rid="muenke.REF.arnaud.2002.6">Arnaud et al 2002</a>].</p><p>Compared to normative populations, individuals with Muenke syndrome have also been reported to be at increased risk for developing some behavioral and emotional issues [<a class="bibr" href="#muenke.REF.maliepaard.2014.e1608" rid="muenke.REF.maliepaard.2014.e1608">Maliepaard et al 2014</a>]. <a class="bibr" href="#muenke.REF.bannink.2011.233" rid="muenke.REF.bannink.2011.233">Bannink et al [2011]</a> found behavioral issues to be more common in boys with Muenke syndrome, with a prevalence of 50%. Approximately 24% of individuals with Muenke syndrome had a diagnosis of attention-deficit/hyperactivity disorder [<a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>].</p><p>Individuals with Muenke syndrome were at increased risk for developing adaptive and executive functioning issues [<a class="bibr" href="#muenke.REF.yarnell.2015.428" rid="muenke.REF.yarnell.2015.428">Yarnell et al 2015</a>]. Interestingly, the change in behavior in the affected cohort was not dependent on the presence or absence of craniosynostosis or hearing loss, raising the question of an intrinsic brain effect of the <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant that is distinct from the change in skull shape.</p><p><b>Neurologic abnormalities.</b> Differences in patterns of the expression, formation, and structure of the central nervous system may be partly responsible for the developmental delay and intellectual disability observed in Muenke syndrome.</p><ul><li class="half_rhythm"><div>The following intracranial anomalies have been reported:</div><ul><li class="half_rhythm"><div>Hippocampus and bilateral medial temporal dysgenesis in one person [<a class="bibr" href="#muenke.REF.grosso.2003.88" rid="muenke.REF.grosso.2003.88">Grosso et al 2003</a>], described as developmentally normal</div></li><li class="half_rhythm"><div>Bilateral lateral ventricular dilatation and a small cerebellum in one person [<a class="bibr" href="#muenke.REF.yu.2010.1086" rid="muenke.REF.yu.2010.1086">Yu et al 2010</a>]</div></li><li class="half_rhythm"><div>Porencephalic cyst of the occipital horn of left ventricle and absence of the corpus callosum in one person [<a class="bibr" href="#muenke.REF.escobar.2009.1273" rid="muenke.REF.escobar.2009.1273">Escobar et al 2009</a>]</div></li></ul></li><li class="half_rhythm"><div>Epilepsy was reported in 13 individuals with Muenke syndrome by <a class="bibr" href="#muenke.REF.agochukwu.2012.1447" rid="muenke.REF.agochukwu.2012.1447">Agochukwu et al [2012]</a>. More recently, 20 of 99 (20.2%) individuals with Muenke syndrome had a history of seizures [<a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>].</div></li><li class="half_rhythm"><div>One individual had a cranial nerve VI deficit leading to paralytic strabismus [<a class="bibr" href="#muenke.REF.lowry.2001.112" rid="muenke.REF.lowry.2001.112">Lowry et al 2001</a>].</div></li></ul><p>
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<b>Ocular anomalies</b>
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</p><ul><li class="half_rhythm"><div>Strabismus is the most common ocular finding in Muenke syndrome. Children with Muenke syndrome also have a higher incidence of anisometropia, downward lateral canthal dystopia, and amblyopia [<a class="bibr" href="#muenke.REF.jadico.2006.435" rid="muenke.REF.jadico.2006.435">Jadico et al 2006</a>].</div></li><li class="half_rhythm"><div>Ptosis of the upper eyelids has been described in 13 affected individuals [<a class="bibr" href="#muenke.REF.de_jong.2011.571" rid="muenke.REF.de_jong.2011.571">de Jong et al 2011</a>, <a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>].</div></li><li class="half_rhythm"><div>Nystagmus has been described in four affected individuals [<a class="bibr" href="#muenke.REF.jadico.2006.435" rid="muenke.REF.jadico.2006.435">Jadico et al 2006</a>, <a class="bibr" href="#muenke.REF.singh.2014.1230" rid="muenke.REF.singh.2014.1230">Singh et al 2014</a>, <a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>].</div></li></ul><p><b>Limb findings.</b> Most individuals with Muenke syndrome have normal-appearing hands and feet with normal range of motion of all joints; many of the limb findings in Muenke syndrome are identified on radiographs, including short, broad middle phalanges of the fingers, absent or hypoplastic middle phalanges of the toes, carpal and/or tarsal fusion, and cone-shaped epiphyses [<a class="bibr" href="#muenke.REF.hughes.2001.47" rid="muenke.REF.hughes.2001.47">Hughes et al 2001</a>, <a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>]. Broad thumbs and great toes have also been described in individuals with Muenke syndrome. Cutaneous syndactyly has been described in 13 affected individuals [<a class="bibr" href="#muenke.REF.golla.1997.683" rid="muenke.REF.golla.1997.683">Golla et al 1997</a>, <a class="bibr" href="#muenke.REF.passosbueno.1999.115" rid="muenke.REF.passosbueno.1999.115">Passos-Bueno et al 1999</a>, <a class="bibr" href="#muenke.REF.chun.2002.136" rid="muenke.REF.chun.2002.136">Chun et al 2002</a>, <a class="bibr" href="#muenke.REF.trusen.2003.168" rid="muenke.REF.trusen.2003.168">Trusen et al 2003</a>, <a class="bibr" href="#muenke.REF.shah.2006.2794" rid="muenke.REF.shah.2006.2794">Shah et al 2006</a>, <a class="bibr" href="#muenke.REF.baynam.2010.297" rid="muenke.REF.baynam.2010.297">Baynam & Goldblatt 2010</a>, <a class="bibr" href="#muenke.REF.de_jong.2011.571" rid="muenke.REF.de_jong.2011.571">de Jong et al 2011</a>].</p><p><b>Obstructive sleep apnea,</b> a common finding in craniosynostosis syndromes in general, is less prevalent in those with Muenke syndrome [<a class="bibr" href="#muenke.REF.bannink.2011.233" rid="muenke.REF.bannink.2011.233">Bannink et al 2011</a>, <a class="bibr" href="#muenke.REF.dentino.2015.s20" rid="muenke.REF.dentino.2015.s20">Dentino et al 2015</a>].</p></div><div id="muenke.Penetrance"><h3>Penetrance</h3><p>Penetrance is reduced. Some individuals heterozygous for the <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant have no clinical or radiographic features of Muenke syndrome [<a class="bibr" href="#muenke.REF.robin.1998.296" rid="muenke.REF.robin.1998.296">Robin et al 1998</a>, <a class="bibr" href="#muenke.REF.moko.2001.22" rid="muenke.REF.moko.2001.22">Moko & Blandin de Chalain 2001</a>, <a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>]. There was no sex-based difference in penetrance in a cohort of 106 individuals [<a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>].</p></div><div id="muenke.Nomenclature"><h3>Nomenclature</h3><p>The phrase "Muenke nonsyndromic coronal craniosynostosis" is occasionally used to mean Muenke syndrome. The authors discourage the use of this phrase because it inaccurately implies a "non-genetic" cause of Muenke syndrome.</p><p>The term "Adelaide-type craniosynostosis" is no longer used to describe Muenke syndrome.</p></div><div id="muenke.Prevalence"><h3>Prevalence</h3><p>The birth prevalence of Muenke syndrome is approximately one in 30,000.</p><p>In a prospective study of 214 individuals with craniosynostosis born between 1993 and 2005, <a class="bibr" href="#muenke.REF.morrisskay.2005.637" rid="muenke.REF.morrisskay.2005.637">Morriss-Kay & Wilkie [2005]</a> reported that of the 60 who had a specific molecular diagnosis, 28.5% had the <a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant; thus, 8% of the 214 individuals had Muenke syndrome.</p><p>Muenke syndrome is estimated to account for 25%-30% of all genetic causes of craniosynostosis [<a class="bibr" href="#muenke.REF.morrisskay.2005.637" rid="muenke.REF.morrisskay.2005.637">Morriss-Kay & Wilkie 2005</a>, <a class="bibr" href="#muenke.REF.wilkie.2010.e391" rid="muenke.REF.wilkie.2010.e391">Wilkie et al 2010</a>].</p><p><i>FGFR3</i> pathogenic variant <a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> is estimated to occur at a rate of 7.6-8 x 10<sup>-6</sup> per haploid genome, one of the highest known rates for a human transversion [<a class="bibr" href="#muenke.REF.moloney.1997.1059" rid="muenke.REF.moloney.1997.1059">Moloney et al 1997</a>, <a class="bibr" href="#muenke.REF.rannaneliya.2004.200" rid="muenke.REF.rannaneliya.2004.200">Rannan-Eliya et al 2004</a>].</p></div></div><div id="muenke.Genetically_Related_Allelic_Disor"><h2 id="_muenke_Genetically_Related_Allelic_Disor_">Genetically Related (Allelic) Disorders</h2><p>Other craniosynostosis phenotypes associated with germline pathogenic variants in <i>FGFR3</i> are summarized in <a href="/books/NBK1415/table/muenke.T.allelic_craniosynostosis_disord/?report=objectonly" target="object" rid-ob="figobmuenkeTalleliccraniosynostosisdisord">Table 3a</a>; allelic disorders not known to be associated with craniosynostosis are summarized in <a href="/books/NBK1415/table/muenke.T.other_clinically_distinct_allel/?report=objectonly" target="object" rid-ob="figobmuenkeTotherclinicallydistinctallel">Table 3b</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmuenkeTalleliccraniosynostosisdisord"><a href="/books/NBK1415/table/muenke.T.allelic_craniosynostosis_disord/?report=objectonly" target="object" title="Table 3a. " class="img_link icnblk_img" rid-ob="figobmuenkeTalleliccraniosynostosisdisord"><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="muenke.T.allelic_craniosynostosis_disord"><a href="/books/NBK1415/table/muenke.T.allelic_craniosynostosis_disord/?report=objectonly" target="object" rid-ob="figobmuenkeTalleliccraniosynostosisdisord">Table 3a. </a></h4><p class="float-caption no_bottom_margin">Allelic Craniosynostosis Disorders </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmuenkeTotherclinicallydistinctallel"><a href="/books/NBK1415/table/muenke.T.other_clinically_distinct_allel/?report=objectonly" target="object" title="Table 3b. " class="img_link icnblk_img" rid-ob="figobmuenkeTotherclinicallydistinctallel"><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="muenke.T.other_clinically_distinct_allel"><a href="/books/NBK1415/table/muenke.T.other_clinically_distinct_allel/?report=objectonly" target="object" rid-ob="figobmuenkeTotherclinicallydistinctallel">Table 3b. </a></h4><p class="float-caption no_bottom_margin">Other Clinically Distinct Allelic Disorders and Associated <i>FGFR3</i> Pathogenic Variants </p></div></div></div><div id="muenke.Differential_Diagnosis"><h2 id="_muenke_Differential_Diagnosis_">Differential Diagnosis</h2><p><b>Syndromic craniosynostosis.</b>
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<a href="/books/NBK1415/table/muenke.T.comparison_of_muenke_syndrome_w/?report=objectonly" target="object" rid-ob="figobmuenkeTcomparisonofmuenkesyndromew">Table 4</a> compares and contrasts Muenke syndrome with similar autosomal dominant craniosynostosis syndromes. Because of phenotypic overlap and/or mild phenotypes, clinical differentiation of these syndromes may be difficult.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmuenkeTcomparisonofmuenkesyndromew"><a href="/books/NBK1415/table/muenke.T.comparison_of_muenke_syndrome_w/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobmuenkeTcomparisonofmuenkesyndromew"><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="muenke.T.comparison_of_muenke_syndrome_w"><a href="/books/NBK1415/table/muenke.T.comparison_of_muenke_syndrome_w/?report=objectonly" target="object" rid-ob="figobmuenkeTcomparisonofmuenkesyndromew">Table 4. </a></h4><p class="float-caption no_bottom_margin">Comparison of Muenke Syndrome with Other <i>FGFR</i>-Related Craniosynostosis Syndromes and Saethre-Chotzen Syndrome </p></div></div><p>For an overview of other primary and secondary forms of craniosynostosis, see <a href="/books/n/gene/craniosynostosis/?report=reader"><i>FGFR</i> Craniosynostosis Syndromes Overview</a>.</p></div><div id="muenke.Management"><h2 id="_muenke_Management_">Management</h2><div id="muenke.Evaluations_Following_Initial_Dia"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with Muenke syndrome, the evaluations summarized in <a href="/books/NBK1415/table/muenke.T.recommended_evaluations_followi/?report=objectonly" target="object" rid-ob="figobmuenkeTrecommendedevaluationsfollowi">Table 5</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="figmuenkeTrecommendedevaluationsfollowi"><a href="/books/NBK1415/table/muenke.T.recommended_evaluations_followi/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobmuenkeTrecommendedevaluationsfollowi"><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="muenke.T.recommended_evaluations_followi"><a href="/books/NBK1415/table/muenke.T.recommended_evaluations_followi/?report=objectonly" target="object" rid-ob="figobmuenkeTrecommendedevaluationsfollowi">Table 5. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with Muenke Syndrome </p></div></div></div><div id="muenke.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Children with Muenke syndrome and craniosynostosis should be referred to a craniofacial clinic with pediatric experience. These individuals benefit most from a multidisciplinary approach to care. A craniofacial clinic associated with a major pediatric medical center usually includes a surgical team (craniofacial surgeon and neurosurgeon), clinical geneticist, ophthalmologist, otolaryngologist, pediatrician, radiologist, psychologist, dentist, audiologist, speech therapist, and social worker. Other disciplines are involved as needed.</p><p><b>Craniosynostosis.</b> Depending on the severity, the first craniosynostosis repair is typically performed between ages three and six months. This procedure is usually transcranial (i.e., the skull is opened down to the dura so that the bones can be physically repositioned during a procedure such as a midface advancement). Early surgical reconstruction for craniosynostosis may reduce the risk for complications including cosmetic defects and sequelae related to increased intracranial pressure (e.g., behavioral changes, hydrocephalus due to venous outflow obstruction).</p><p>Newer approaches being performed include endoscopic strip craniectomy and posterior distraction.</p><ul><li class="half_rhythm"><div>Endoscopic strip craniectomy is typically performed before the affected child reaches age three months. This minimally invasive surgery limits blood loss and has an overall long-term improved symmetry compared to traditional cranial vault remodeling and fronto-orbital advancement.</div></li><li class="half_rhythm"><div>Posterior distraction (PD) is used to manage individuals with severe brachycephaly or turribrachycephaly. It is a well-planned surgery using distractor devices. PD requires nuanced technical skill and the commitment of both the surgeon and the family several weeks postoperatively. PD has associated risks, yet severe complications are rare [<a class="bibr" href="#muenke.REF.wiberg.2012.799" rid="muenke.REF.wiberg.2012.799">Wiberg et al 2012</a>, <a class="bibr" href="#muenke.REF.thomas.2014.1721" rid="muenke.REF.thomas.2014.1721">Thomas et al 2014</a>, <a class="bibr" href="#muenke.REF.salokorpi.2021.3127" rid="muenke.REF.salokorpi.2021.3127">Salokorpi et al 2021</a>].</div></li></ul><p>Following craniosynostosis repair, the need for a second procedure is increased in those with Muenke syndrome compared to those with craniosynostosis without the defining pathogenic variant. The reasons for a second procedure vary by individual and can include the following:</p><ul><li class="half_rhythm"><div>Severe initial clinical presentation requiring a staged repair</div></li><li class="half_rhythm"><div>Cranial vault abnormalities including temporal bulging and recurrent supraorbital retrusion requiring extracranial contouring (i.e., use of a cement such as calcium phosphate to contour the surface of the skull)</div></li><li class="half_rhythm"><div>Postoperative increased intracranial pressure (ICP)</div></li><li class="half_rhythm"><div>Recurrent deformity requiring a second transcranial repair:</div><ul><li class="half_rhythm"><div>The need for a surgical revision for aesthetic reasons (typically temporal bulging) has been reported in multiple series [<a class="bibr" href="#muenke.REF.renier.2000.631" rid="muenke.REF.renier.2000.631">Renier et al 2000</a>, <a class="bibr" href="#muenke.REF.cassileth.2001.1849" rid="muenke.REF.cassileth.2001.1849">Cassileth et al 2001</a>, <a class="bibr" href="#muenke.REF.arnaud.2002.6" rid="muenke.REF.arnaud.2002.6">Arnaud et al 2002</a>, <a class="bibr" href="#muenke.REF.thomas.2005.347" rid="muenke.REF.thomas.2005.347">Thomas et al 2005</a>, <a class="bibr" href="#muenke.REF.honnebier.2008.919" rid="muenke.REF.honnebier.2008.919">Honnebier et al 2008</a>].</div></li><li class="half_rhythm"><div>According to <a class="bibr" href="#muenke.REF.thomas.2005.347" rid="muenke.REF.thomas.2005.347">Thomas et al [2005]</a>, individuals with craniosynostosis and Muenke syndrome were more likely to require early intervention with a posterior release operation (at approximately age six months) to prevent excess frontal bulging than were those with other causes of craniosynostosis.</div></li><li class="half_rhythm"><div>Seven of 29 individuals (24.1%) with the <a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant underwent a second surgery (6/7 had increased ICP) as compared to two (4.3%) of 47 without the pathogenic variant. This difference in reoperation rate was statistically significant (p=0.048) [<a class="bibr" href="#muenke.REF.thomas.2005.347" rid="muenke.REF.thomas.2005.347">Thomas et al 2005</a>].</div></li><li class="half_rhythm"><div>In the report of <a class="bibr" href="#muenke.REF.honnebier.2008.919" rid="muenke.REF.honnebier.2008.919">Honnebier et al [2008]</a>, 16 individuals with Muenke syndrome required a second procedure: seven required a second transcranial procedure, and 15 were expected to undergo extracranial contouring. Note that none had increased ICP.</div></li><li class="half_rhythm"><div>However, a study by <a class="bibr" href="#muenke.REF.ridgway.2011.455" rid="muenke.REF.ridgway.2011.455">Ridgway et al [2011]</a> challenges the above findings, reporting a frequency of frontal revision in individuals with Muenke syndrome who had fronto-orbital advancements that was lower than previously reported. This study found that the need for secondary revision procedures was inversely related to the age of the affected individual at the time of the initial repair. The location of the fused/synostotic suture, type of fixation, and the use of bone grafting did not have a significant effect on the need for revision.</div></li></ul></li></ul><p>In Muenke syndrome a discrepancy between severity of the craniofacial findings (e.g., severe midface retrusion, widely spaced eyes) and neurologic findings (e.g., increased ICP, hydrocephalus, structural brain anomalies, severe developmental delay, or severe intellectual disability) has been noted [<a class="bibr" href="#muenke.REF.lajeunie.1999.9" rid="muenke.REF.lajeunie.1999.9">Lajeunie et al 1999</a>, <a class="bibr" href="#muenke.REF.arnaud.2002.6" rid="muenke.REF.arnaud.2002.6">Arnaud et al 2002</a>, <a class="bibr" href="#muenke.REF.honnebier.2008.919" rid="muenke.REF.honnebier.2008.919">Honnebier et al 2008</a>]: severe early clinical findings such as recurrent deformity and the need for a second major procedure did not correlate with postoperative risk for increased ICP.</p><p><b>Hearing loss.</b> Hearing loss is often sensorineural. Standard treatments for hearing loss apply, including special accommodations for school-aged children, hearing aids, and (potentially) cochlear implants (see <a href="/books/n/gene/deafness-overview/?report=reader">Hereditary Hearing Loss and Deafness Overview</a>) [<a class="bibr" href="#muenke.REF.agochukwu.2014b.2037" rid="muenke.REF.agochukwu.2014b.2037">Agochukwu et al 2014b</a>].</p><p><b>Developmental and neurobehavioral issues.</b> Individuals with Muenke syndrome are at increased risk for developmental delay, intellectual disability, and behavioral issues [<a class="bibr" href="#muenke.REF.maliepaard.2014.e1608" rid="muenke.REF.maliepaard.2014.e1608">Maliepaard et al 2014</a>, <a class="bibr" href="#muenke.REF.yarnell.2015.428" rid="muenke.REF.yarnell.2015.428">Yarnell et al 2015</a>]; thus, referral for speech therapy and early intervention is indicated. Referral to a developmental and/or behavioral specialist for assessment and treatment is recommended.</p><p>
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<b>Ocular abnormalities</b>
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</p><ul><li class="half_rhythm"><div>Strabismus surgery/correction is indicated to prevent amblyopia.</div></li><li class="half_rhythm"><div>Because surgical correction of craniosynostosis is a priority, delay in strabismus surgery in the first two years of life is common; however, earlier correction of strabismus should be considered to achieve binocularity.</div></li><li class="half_rhythm"><div>In those with proptosis, lubrication for exposure keratopathy is indicated.</div></li></ul></div><div id="muenke.Surveillance"><h3>Surveillance</h3><p>Protocol-driven approaches to surveillance currently in use include those of <a class="bibr" href="#muenke.REF.flapper.2009.1252" rid="muenke.REF.flapper.2009.1252">Flapper et al [2009]</a> and <a class="bibr" href="#muenke.REF.de_jong.2010.1635" rid="muenke.REF.de_jong.2010.1635">de Jong et al [2010]</a>. This ideally involves multidisciplinary care by specialists in relevant fields (see <a href="/books/NBK1415/table/muenke.T.recommended_surveillance_for_in/?report=objectonly" target="object" rid-ob="figobmuenkeTrecommendedsurveillanceforin">Table 6</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmuenkeTrecommendedsurveillanceforin"><a href="/books/NBK1415/table/muenke.T.recommended_surveillance_for_in/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobmuenkeTrecommendedsurveillanceforin"><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="muenke.T.recommended_surveillance_for_in"><a href="/books/NBK1415/table/muenke.T.recommended_surveillance_for_in/?report=objectonly" target="object" rid-ob="figobmuenkeTrecommendedsurveillanceforin">Table 6. </a></h4><p class="float-caption no_bottom_margin">Recommended Surveillance for Individuals with Muenke Syndrome </p></div></div></div><div id="muenke.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from institution of treatment and preventive measures (particularly in individuals affected with craniosynostosis, hearing loss, developmental delay, and/or cognitive disability). Evaluation includes targeted molecular genetic testing for the <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">c.749C>G (p.Pro250Arg)</a> pathogenic variant.</p><p>See <a href="#muenke.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="muenke.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p><a class="bibr" href="#muenke.REF.mansour.2009.43" rid="muenke.REF.mansour.2009.43">Mansour et al [2009]</a> determined that in the mouse model of Muenke syndrome all mice had low-frequency sensorineural hearing loss. The characteristic sensorineural hearing loss is probably due to abnormal development of the auditory sensory epithelium of the inner ear, including excess pillar cells, too few Deiters cells, and extra outer hair cells in the organ of Corti. A further study revealed that the rescue of cochlear function and hearing loss phenotype of these mice is possible with a reduction in FGF-10, which normally activates FGFR-2b or FGFR-1b [<a class="bibr" href="#muenke.REF.mansour.2013.2320" rid="muenke.REF.mansour.2013.2320">Mansour et al 2013</a>]. Aberrant signaling through the FGF signaling pathway that includes <i>FGFR3</i> may be the cause of the abnormal development of auditory sensory cells in Muenke syndrome [<a class="bibr" href="#muenke.REF.agochukwu.2014a.135" rid="muenke.REF.agochukwu.2014a.135">Agochukwu et al 2014a</a>].</p><p>Animal models indicate that <i>FGFR3</i> is expressed at its highest levels in the developing central nervous system.</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="muenke.Genetic_Counseling"><h2 id="_muenke_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="muenke.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Muenke syndrome is inherited in an autosomal dominant manner.</p></div><div id="muenke.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 class="half_rhythm">More than half of individuals diagnosed with Muenke syndrome inherited the <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant from a parent [<a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>].</div></li><li class="half_rhythm"><div class="half_rhythm">A proband with Muenke syndrome may have the disorder as the result of a <i>de novo</i> pathogenic variant. <i>De novo</i> pathogenic variants causing Muenke syndrome appear to be exclusively of paternal origin [<a class="bibr" href="#muenke.REF.rannaneliya.2004.200" rid="muenke.REF.rannaneliya.2004.200">Rannan-Eliya et al 2004</a>] and to be associated with advanced paternal age [<a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>].</div></li><li class="half_rhythm"><div class="half_rhythm">If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband include:</div><ul><li class="half_rhythm"><div>Physical examination and radiographs of the skull, hands, and feet;</div></li><li class="half_rhythm"><div>Molecular genetic testing for the <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.</div></li></ul><div class="half_rhythm">Evaluation of the parents may determine that one is heterozygous for the <a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant but has a mild phenotype.</div></li><li class="half_rhythm"><div class="half_rhythm">If the <a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The proband has a <i>de novo</i> pathogenic variant.</div></li><li class="half_rhythm"><div>The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.</div></li></ul></li><li class="half_rhythm"><div class="half_rhythm">The family history of some individuals diagnosed with Muenke syndrome may appear to be negative because of subtle or absent clinical findings in a heterozygous parent or failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the <a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant.</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:</p><ul><li class="half_rhythm"><div>If a parent of the proband is affected and/or is known to have the defining <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because penetrance is reduced and the phenotype is variable within families, the manifestations in a sib who inherits the pathogenic variant cannot be predicted based on the phenotypes of other heterozygous family members (see <a href="#muenke.Penetrance">Penetrance</a>). Sibs who inherit the <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant may be more or less severely affected than their parent(s). Uni- and bilateral coronal synostosis as well as absence of synostosis may be seen in individuals in the same family.</div></li><li class="half_rhythm"><div>If the <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [<a class="bibr" href="#muenke.REF.rahbari.2016.126" rid="muenke.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>If the parents have not been tested for the <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> but are clinically unaffected, sibs are still presumed to be at increased risk for Muenke syndrome because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.</div></li></ul><p><b>Offspring of a proband.</b> Each child of an individual with Muenke syndrome has a 50% chance of inheriting the pathogenic variant.</p><p><b>Other family members.</b> The risk to other family members depends on the genetic status of the proband's parents: if a parent has the <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant, the parent's family members are at risk.</p></div><div id="muenke.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>Consideration of molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Management, <a href="#muenke.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a>). Prior to testing sibs, parents, and extended family members, discussion should be held with a genetic counselor regarding the risks, benefits, and limitations of testing.</p><p>Generally, in individuals of school age and older who have no developmental issues, developmental delay, hearing loss, craniosynostosis, or other features of Muenke syndrome, the likelihood of Muenke syndrome is quite low, though the <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant has been identified in seemingly unaffected individuals [<a class="bibr" href="#muenke.REF.kruszka.2016.918" rid="muenke.REF.kruszka.2016.918">Kruszka et al 2016</a>]. Children who inherit the <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant may be more or less severely affected than their parent(s). Uni- and bilateral coronal synostosis as well as absence of synostosis may be seen in individuals in the same family.</p><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.</div></li></ul></div><div id="muenke.Prenatal_Testing_and_Preimplantat"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p><b>Molecular genetic testing.</b> Once the <i>FGFR3</i>
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<a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Muenke syndrome are possible.</p><p><b>Ultrasound examination.</b> Craniosynostosis should be suspected when the cephalic index, cranial shape, or fetal face shape is abnormal [<a class="bibr" href="#muenke.REF.tonni.2011.909" rid="muenke.REF.tonni.2011.909">Tonni et al 2011</a>]. Although difficult, prenatal diagnosis may be possible by ultrasound examination of the calvarial sutures. When present, additional craniofacial features of Muenke syndrome (i.e., midface hypoplasia, ocular hypertelorism) may also be apparent [<a class="bibr" href="#muenke.REF.shaw.2011.770" rid="muenke.REF.shaw.2011.770">Shaw et al 2011</a>].</p><p>In a family known to have the pathogenic variant, if craniosynostosis or other craniofacial features (i.e., midface hypoplasia, ocular hypertelorism) are seen on prenatal ultrasound examination, the index of suspicion for Muenke syndrome should be high.</p><p>On prenatal ultrasound examination of twins with Muenke syndrome, <a class="bibr" href="#muenke.REF.escobar.2009.1273" rid="muenke.REF.escobar.2009.1273">Escobar et al [2009]</a> found normal anatomy in one twin and congenital anomalies in the other twin; the diagnosis of Muenke syndrome was molecularly confirmed after birth in both twins.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="muenke.Resources"><h2 id="_muenke_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/muenke-syndrome/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Muenke syndrome</a>
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</div></li><li class="half_rhythm"><div>
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<b>Children's Craniofacial Association</b>
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</div><div><b>Phone:</b> 800-535-3643</div><div><b>Email:</b> contactCCA@ccakids.com</div><div>
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<a href="https://ccakids.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ccakids.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Face Equality International</b>
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</div><div>United Kingdom</div><div>
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<a href="https://faceequalityinternational.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">faceequalityinternational.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>National Institute of Neurological Disorders and Stroke (NINDS)</b>
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</div><div><b>Phone:</b> 800-352-9424</div><div>
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<a href="https://www.ninds.nih.gov/Disorders/All-Disorders/Craniosynostosis-Information-Page" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Craniosynostosis</a>
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</div></li></ul>
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</div><div id="muenke.Molecular_Genetics"><h2 id="_muenke_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="figmuenkemolgenTA"><a href="/books/NBK1415/table/muenke.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobmuenkemolgenTA"><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="muenke.molgen.TA"><a href="/books/NBK1415/table/muenke.molgen.TA/?report=objectonly" target="object" rid-ob="figobmuenkemolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Muenke Syndrome: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmuenkemolgenTB"><a href="/books/NBK1415/table/muenke.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobmuenkemolgenTB"><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="muenke.molgen.TB"><a href="/books/NBK1415/table/muenke.molgen.TB/?report=objectonly" target="object" rid-ob="figobmuenkemolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Muenke Syndrome (View All in OMIM) </p></div></div><div id="muenke.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>The fibroblast growth factor receptor (FGFR) family is a group of receptor tyrosine kinases. FGFRs 1-4 have an extracellular ligand-binding domain containing three immunoglobulin-like loops, a single-pass transmembrane domain, and a split intracellular kinase domain. FGFRs bind fibroblast growth factors (FGFs) and dimerize to affect downstream intracellular signaling [<a class="bibr" href="#muenke.REF.green.1996.639" rid="muenke.REF.green.1996.639">Green et al 1996</a>]. FGFR3 negatively regulates chondrocyte differentiation and proliferation in developing endochondral bone (appendicular skeleton) [<a class="bibr" href="#muenke.REF.ornitz.2002.1446" rid="muenke.REF.ornitz.2002.1446">Ornitz & Marie 2002</a>].</p><p>The genetics of intramembranous bone (skull vault) formation are complex, and the role of FGFR3 is not yet well understood. FGFR3 is detected in coronal suture osteogenic fronts but at lower levels than FGFR1 and FGFR2 [<a class="bibr" href="#muenke.REF.iseki.1999.5611" rid="muenke.REF.iseki.1999.5611">Iseki et al 1999</a>]. FGFR3 is mainly expressed in mature chondrocytes of the cartilage growth plate [<a class="bibr" href="#muenke.REF.cunningham.2007.67" rid="muenke.REF.cunningham.2007.67">Cunningham et al 2007</a>]. FGFR3 mRNA is found in its highest amounts in the developing central nervous system [<a class="bibr" href="#muenke.REF.robin.1999.1060" rid="muenke.REF.robin.1999.1060">Robin 1999</a>]. It is also present in the skeletal precursors for all bones during the period of endochondral ossification and resting cartilage [<a class="bibr" href="#muenke.REF.robin.1999.1060" rid="muenke.REF.robin.1999.1060">Robin 1999</a>].</p><p>The <a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">p.Pro250Arg</a> pathogenic variant results in enhanced FGF binding [<a class="bibr" href="#muenke.REF.ibrahimi.2004.69" rid="muenke.REF.ibrahimi.2004.69">Ibrahimi et al 2004</a>]. This pathogenic variant is located in the linker region between the second and third immunoglobulin-like domains (see <a class="figpopup" href="/books/NBK1415/figure/muenke.F1/?report=objectonly" target="object" rid-figpopup="figmuenkeF1" rid-ob="figobmuenkeF1">Figure 1</a>) [<a class="bibr" href="#muenke.REF.park.1995.321" rid="muenke.REF.park.1995.321">Park et al 1995</a>, <a class="bibr" href="#muenke.REF.wilkie.1995.165" rid="muenke.REF.wilkie.1995.165">Wilkie et al 1995</a>]. Kinetic ligand binding studies and x-ray crystallography of linker region pathogenic variants demonstrate that the pathogenic variant results in increased ligand affinity (FGF9) and altered specificity [<a class="bibr" href="#muenke.REF.cunningham.2007.67" rid="muenke.REF.cunningham.2007.67">Cunningham et al 2007</a>]. Overactivation of FGFR3 appears to lead to craniosynostosis because bone differentiation is accelerated [<a class="bibr" href="#muenke.REF.funato.2001.7416" rid="muenke.REF.funato.2001.7416">Funato et al 2001</a>].</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figmuenkeF1" co-legend-rid="figlgndmuenkeF1"><a href="/books/NBK1415/figure/muenke.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figmuenkeF1" rid-ob="figobmuenkeF1"><img class="small-thumb" src="/books/NBK1415/bin/muenke-Image001.gif" src-large="/books/NBK1415/bin/muenke-Image001.jpg" alt="Figure 1. " /></a><div class="icnblk_cntnt" id="figlgndmuenkeF1"><h4 id="muenke.F1"><a href="/books/NBK1415/figure/muenke.F1/?report=objectonly" target="object" rid-ob="figobmuenkeF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">Schema of the FGFR3 protein The loops represent the three immunoglobulin domains (left to right: IgI, IgII, IgIII). The p.Pro250Arg protein change (indicated with a black dot) is in the linker region between the second and third immunoglobulin domains. <a href="/books/NBK1415/figure/muenke.F1/?report=objectonly" target="object" rid-ob="figobmuenkeF1">(more...)</a></p></div></div><p><b>Mechanism of disease causation.</b> Gain of function</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figmuenkeTnotablefgfr3pathogenicvarian"><a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian"><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="muenke.T.notable_fgfr3_pathogenic_varian"><a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">Table 7. </a></h4><p class="float-caption no_bottom_margin">Notable <i>FGFR3</i> Pathogenic Variants </p></div></div></div></div><div id="muenke.Chapter_Notes"><h2 id="_muenke_Chapter_Notes_">Chapter Notes</h2><div id="muenke.Acknowledgments"><h3>Acknowledgments</h3><p>The authors are indebted to the affected individuals they work with and their families. This work was supported by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health.</p></div><div id="muenke.Author_History"><h3>Author History</h3><p>Yonit A Addissie, BA; National Human Genome Research Institute (2016-2023)<br />Nneamaka B Agochukwu, MD; National Human Genome Research Institute (2006-2023)<br />Emily S Doherty, MD, FAAP, FACMG; Carilion Clinic (2006-2023)<br />Kristopher T Kahle, MD, PhD (2023-present)<br />Paul Kruszka, MD, MPH (2016-present)<br />Maximilian Muenke, MD, FACMG (2006-present)<br />Myron Rolle, MD (2023-present)</p></div><div id="muenke.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>30 March 2023 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>10 November 2016 (ma) Comprehensive update posted live</div></li><li class="half_rhythm"><div>19 June 2014 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>7 December 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>10 May 2006 (me) Review posted live</div></li><li class="half_rhythm"><div>30 January 2006 (mm) Original submission</div></li></ul></div></div><div id="muenke.References"><h2 id="_muenke_References_">References</h2><div id="muenke.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.agochukwu.2013.453">Agochukwu NB, Solomon BD, Benson LJ, Muenke M. Talocalcaneal coalition in Muenke syndrome: report of a patient, review of the literature in FGFR-related craniosynostoses, and consideration of mechanism. <span><span class="ref-journal">Am J Med Genet A. </span>2013;<span class="ref-vol">161A</span>:453–60.</span> [<a href="/pmc/articles/PMC3581720/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3581720</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23378035" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23378035</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.agochukwu.2014a.135">Agochukwu NB, Solomon BD, Muenke M. Hearing loss in syndromic craniosynostoses: introduction and consideration of mechanisms. <span><span class="ref-journal">Am J Audiol. </span>2014a;<span class="ref-vol">23</span>:135–41.</span> [<a href="/pmc/articles/PMC4131981/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4131981</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24686979" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24686979</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.agochukwu.2014b.2037">Agochukwu NB, Solomon BD, Muenke M. Hearing loss in syndromic craniosynostoses: otologic manifestations and clinical findings. <span><span class="ref-journal">Int J Pediatr Otorhinolaryngol. </span>2014b;<span class="ref-vol">78</span>:2037–47.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25441602" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25441602</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.agochukwu.2012.1447">Agochukwu NB, Solomon BD, Muenke M. Impact of genetics on the diagnosis and clinical management of syndromic craniosynostoses. <span><span class="ref-journal">Childs Nerv Syst. </span>2012;<span class="ref-vol">28</span>:1447–63.</span> [<a href="/pmc/articles/PMC4101189/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4101189</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22872262" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22872262</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.arnaud.2002.6">Arnaud E, Meneses P, Lajeunie E, Thorne JA, Marchac D, Renier D. Postoperative mental and morphological outcome for nonsyndromic brachycephaly. <span><span class="ref-journal">Plast Reconstr Surg. </span>2002;<span class="ref-vol">110</span>:6–12.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12087222" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12087222</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.bannink.2011.233">Bannink N, Maliepaard M, Raat H, Joosten KF, Mathijssen IM. 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Timing, rates and spectra of human germline mutation. <span><span class="ref-journal">Nat Genet. </span>2016;<span class="ref-vol">48</span>:126–33.</span> [<a href="/pmc/articles/PMC4731925/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4731925</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26656846" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26656846</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.rannaneliya.2004.200">Rannan-Eliya SV, Taylor IB, De Heer IM, Van Den Ouweland AM, Wall SA, Wilkie AO. Paternal origin of FGFR3 mutations in Muenke-type craniosynostosis. <span><span class="ref-journal">Hum Genet. </span>2004;<span class="ref-vol">115</span>:200–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15241680" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15241680</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.renier.2000.631">Renier D, El-Ghouzzi V, Bonaventure J, Le Merrer M, Lajeunie E. Fibroblast growth factor receptor 3 mutation in nonsyndromic coronal synostosis: clinical spectrum, prevalence, and surgical outcome. <span><span class="ref-journal">J Neurosurg. </span>2000;<span class="ref-vol">92</span>:631–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10761652" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10761652</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.ridgway.2011.455">Ridgway EB, Wu JK, Sullivan SR, Vasudavan S, Padwa BL, Rogers GF, Mulliken JB. Craniofacial growth in patients with FGFR3 Pro250Arg mutation after fronto-orbital advancement in infancy. <span><span class="ref-journal">J Craniofac Surg. </span>2011;<span class="ref-vol">22</span>:455–61.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21403567" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21403567</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.robin.1999.1060">Robin NH. Molecular genetic advances in understanding craniosynostosis. <span><span class="ref-journal">Plast Reconstr Surg. </span>1999;<span class="ref-vol">103</span>:1060–70.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10077104" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10077104</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.robin.1998.296">Robin NH, Scott JA, Cohen AR, Goldstein JA. Nonpenetrance in FGFR3-associated coronal synostosis syndrome. <span><span class="ref-journal">Am J Med Genet. </span>1998;<span class="ref-vol">80</span>:296–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9843059" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9843059</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.rymer.2019.e656">Rymer K, Shiang R, Hsiung A, Pandya A, Bigdeli T, Webb BT, Rhodes J. Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans. <span><span class="ref-journal">Mol Genet Genomic Med. </span>2019;<span class="ref-vol">7</span>:e656. </span> [<a href="/pmc/articles/PMC6565579/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6565579</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31016899" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31016899</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.salokorpi.2021.3127">Salokorpi N, Satanin L, Teterin I, Sinikumpu JJ, Serlo W. Posterior vault distraction technique: how I do it. <span><span class="ref-journal">Childs Nerv Syst. </span>2021;<span class="ref-vol">37</span>:3127–36.</span> [<a href="/pmc/articles/PMC8510953/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8510953</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34032915" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34032915</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.schindler.2002.764">Schindler S, Friedrich M, Wagener H, Lorenz B, Preising MN. Heterozygous P250L mutation of fibroblast growth factor receptor 3 in a case of isolated craniosynostosis. <span><span class="ref-journal">J Med Genet. </span>2002;<span class="ref-vol">39</span>:764–6.</span> [<a href="/pmc/articles/PMC1734995/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1734995</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12362036" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12362036</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.shah.2006.2794">Shah PS, Siriwardena K, Taylor G, Steele L, Ray P, Blaser S, Chitayat D. Sudden infant death in a patient with FGFR3 P250R mutation. <span><span class="ref-journal">Am J Med Genet A. </span>2006;<span class="ref-vol">140</span>:2794–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17103449" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17103449</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.shaw.2011.770">Shaw A, Petersen OB, Chitty LS. Prenatal diagnosis of craniosynostosis: sonographic features of Muenke syndrome. <span><span class="ref-journal">J Obstet Gynaecol. </span>2011;<span class="ref-vol">31</span>:770–1.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22085076" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22085076</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.singh.2014.1230">Singh A, Goyal M, Kumar S, Kress W, Kapoor S. Phenotypic variability in two families of Muenke syndrome with FGFR3 mutation. <span><span class="ref-journal">Indian J Pediatr. </span>2014;<span class="ref-vol">81</span>:1230–2.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24705944" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24705944</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.thomas.2014.1721">Thomas GP, Wall SA, Jayamohan J, Magdum SA, Richards PG, Wiberg A, Johnson D. Lessons learned in posterior cranial vault distraction. <span><span class="ref-journal">J Craniofac Surg. </span>2014;<span class="ref-vol">25</span>:1721–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25162545" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25162545</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.thomas.2005.347">Thomas GP, Wilkie AO, Richards PG, Wall SA. FGFR3 P250R mutation increases the risk of reoperation in apparent "nonsyndromic" coronal craniosynostosis. <span><span class="ref-journal">J Craniofac Surg. </span>2005;<span class="ref-vol">16</span>:347–52.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15915095" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15915095</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.tonni.2011.909">Tonni G, Panteghini M, Rossi A, Baldi M, Magnani C, Ferrari B, Lituania M. Craniosynostosis: prenatal diagnosis by means of ultrasound and SSSE-MRI. Family series with report of neurodevelopmental outcome and review of the literature. <span><span class="ref-journal">Arch Gynecol Obstet. </span>2011;<span class="ref-vol">283</span>:909–16.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20811900" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20811900</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.trusen.2003.168">Trusen A, Beissert M, Collmann H, Darge K. The pattern of skeletal anomalies in the cervical spine, hands and feet in patients with Saethre-Chotzen syndrome and Muenke-type mutation. <span><span class="ref-journal">Pediatr Radiol. </span>2003;<span class="ref-vol">33</span>:168–72.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12612814" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12612814</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.van_der_meulen.2006.2493">van der Meulen J, van den Ouweland A, Hoogeboom J. Trigonocephaly in Muenke syndrome. <span><span class="ref-journal">Am J Med Genet A. </span>2006;<span class="ref-vol">140</span>:2493–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17036334" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17036334</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.wiberg.2012.799">Wiberg A, Magdum S, Richards PG, Jayamohan J, Wall SA, Johnson D. Posterior calvarial distraction in craniosynostosis - an evolving technique. <span><span class="ref-journal">J Craniomaxillofac Surg. </span>2012;<span class="ref-vol">40</span>:799–806.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22560871" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22560871</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.wilkie.2010.e391">Wilkie AO, Byren JC, Hurst JA, Jayamohan J, Johnson D, Knight SJ, Lester T, Richards PG, Twigg SR, Wall SA. Prevalence and complications of single gene and chromosomal disorders in craniosynostosis. <span><span class="ref-journal">Pediatrics. </span>2010;<span class="ref-vol">126</span>:e391–400.</span> [<a href="/pmc/articles/PMC3535761/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3535761</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20643727" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20643727</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.wilkie.1995.165">Wilkie AOM, Slaney SF, Oldridge M., Poole MD, Ashworth GJ, Hockley AD, Hayward RD, David DJ, Pulleyn LK, Rutland P, Malcolm S, Winter RM, Reardon W. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. <span><span class="ref-journal">Nat Genet. </span>1995;<span class="ref-vol">9</span>:165–72.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7719344" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7719344</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.yarnell.2015.428">Yarnell CM, Addissie YA, Hadley DW, Guillen Sacoto MJ, Agochukwu NB, Hart RA, Wiggs EA, Platte P, Paelecke Y, Collmann H, Schweitzer T, Kruszka P, Muenke M. Executive Function and Adaptive Behavior in Muenke Syndrome. <span><span class="ref-journal">J Pediatr. </span>2015;<span class="ref-vol">167</span>:428–34.</span> [<a href="/pmc/articles/PMC4516644/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4516644</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26028288" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26028288</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="muenke.REF.yu.2010.1086">Yu JE, Park DH, Yoon SH. A Korean family with the Muenke syndrome. <span><span class="ref-journal">J Korean Med Sci. </span>2010;<span class="ref-vol">25</span>:1086–9.</span> [<a href="/pmc/articles/PMC2890890/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2890890</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20592905" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20592905</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1415_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Paul Kruszka</span>, MD, MPH<div class="affiliation small">GeneDx, LLC<br />Gaithersburg, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.xdeneg@akzsurkp" class="oemail">moc.xdeneg@akzsurkp</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Myron Rolle</span>, MD<div class="affiliation small">Department of Neurosurgery<br />Massachusetts General Hospital<br />Boston, Massachusetts<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.srentrap@ellorm" class="oemail">gro.srentrap@ellorm</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Kristopher T Kahle</span>, MD, PhD<div class="affiliation small">Department of Neurosurgery<br />Massachusetts General Hospital<br />Boston, Massachusetts<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.dravrah.hgm@rehpotsirk.elhak" class="oemail">ude.dravrah.hgm@rehpotsirk.elhak</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Maximilian Muenke</span>, MD, FACMG<div class="affiliation small">National Human Genome Research Institute<br />National Institutes of Health<br />Bethesda, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.liamg@ekneumxam" class="oemail">moc.liamg@ekneumxam</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">May 10, 2006</span>; Last Update: <span itemprop="dateModified">March 30, 2023</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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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>Kruszka P, Rolle M, Kahle KT, et al. Muenke Syndrome. 2006 May 10 [Updated 2023 Mar 30]. 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/mps7/?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/mona/?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="figobmuenkeTmoleculargenetictestingused"><div id="muenke.T.molecular_genetic_testing_used" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Muenke Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1415/table/muenke.T.molecular_genetic_testing_used/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__muenke.T.molecular_genetic_testing_used_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_muenke.T.molecular_genetic_testing_used_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_muenke.T.molecular_genetic_testing_used_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_muenke.T.molecular_genetic_testing_used_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><br />Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_muenke.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FGFR3</i>
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</td><td headers="hd_h_muenke.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_muenke.T.molecular_genetic_testing_used_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <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="muenke.TF.1.1"><p class="no_margin">See <a href="/books/NBK1415/?report=reader#muenke.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="muenke.TF.1.2"><p class="no_margin">See <a href="#muenke.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="muenke.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="muenke.TF.1.4"><p class="no_margin">Muenke syndrome is defined by the specific pathogenic variant <a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">c.749C>G (p.Pro250Arg)</a> [<a class="bibr" href="#muenke.REF.bellus.1996.174" rid="muenke.REF.bellus.1996.174">Bellus et al 1996</a>].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmuenkeTmuenkesyndromefrequencyofse"><div id="muenke.T.muenke_syndrome_frequency_of_se" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Muenke Syndrome: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1415/table/muenke.T.muenke_syndrome_frequency_of_se/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__muenke.T.muenke_syndrome_frequency_of_se_lrgtbl__"><table><thead><tr><th id="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons<br />w/Feature</th><th id="hd_h_muenke.T.muenke_syndrome_frequency_of_se_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_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Coronal synostosis</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~85%</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Synostosis of other sutures</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~3</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing loss</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>70%</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental delay</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>60%</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intellectual disability</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>40%</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Behavioral issues</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~50%</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ocular anomalies</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>60%</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Strabismus in 39%-66%</td></tr><tr><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Limb findings</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~50%</td><td headers="hd_h_muenke.T.muenke_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobmuenkeTalleliccraniosynostosisdisord"><div id="muenke.T.allelic_craniosynostosis_disord" class="table"><h3><span class="label">Table 3a. </span></h3><div class="caption"><p>Allelic Craniosynostosis Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1415/table/muenke.T.allelic_craniosynostosis_disord/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__muenke.T.allelic_craniosynostosis_disord_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_muenke.T.allelic_craniosynostosis_disord_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_muenke.T.allelic_craniosynostosis_disord_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>FGFR3</i> Pathogenic Variants <sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_muenke.T.allelic_craniosynostosis_disord_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Isolated unilateral coronal synostosis</td><td headers="hd_h_muenke.T.allelic_craniosynostosis_disord_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobmuenkeTnotablefgfr3pathogenicvarian">c.749C>T (p.Pro250Leu)</a> reported in 1 family <sup>2</sup></td></tr><tr><td headers="hd_h_muenke.T.allelic_craniosynostosis_disord_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Crouzon syndrome w/acanthosis nigricans</td><td headers="hd_h_muenke.T.allelic_craniosynostosis_disord_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1172C>A (p.Ala391Glu) <sup>3</sup></td></tr><tr><td headers="hd_h_muenke.T.allelic_craniosynostosis_disord_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pfeiffer syndrome</td><td headers="hd_h_muenke.T.allelic_craniosynostosis_disord_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1172C>A (p.Ala391Glu) reported in 1 person w/Pfeiffer syndrome <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="muenke.TF.3a.1"><p class="no_margin">Reference sequences: <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000142.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000142<wbr style="display:inline-block"></wbr>​.5</a>; <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></p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="muenke.TF.3a.2"><p class="no_margin">
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<a class="bibr" href="#muenke.REF.schindler.2002.764" rid="muenke.REF.schindler.2002.764">Schindler et al [2002]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="muenke.TF.3a.3"><p class="no_margin">
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<a class="bibr" href="#muenke.REF.mulliken.1999.1603" rid="muenke.REF.mulliken.1999.1603">Mulliken et al [1999]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="muenke.TF.3a.4"><p class="no_margin">
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<a class="bibr" href="#muenke.REF.rymer.2019.e656" rid="muenke.REF.rymer.2019.e656">Rymer et al [2019]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmuenkeTotherclinicallydistinctallel"><div id="muenke.T.other_clinically_distinct_allel" class="table"><h3><span class="label">Table 3b. </span></h3><div class="caption"><p>Other Clinically Distinct Allelic Disorders and Associated <i>FGFR3</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1415/table/muenke.T.other_clinically_distinct_allel/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__muenke.T.other_clinically_distinct_allel_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Phenotype</th><th id="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>FGFR3</i> Pathogenic Variants <sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_muenke.T.other_clinically_distinct_allel_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_muenke.T.other_clinically_distinct_allel_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1138G>A (p.Gly380Arg) & c.1138G>C (p.Gly380Arg)</td></tr><tr><td headers="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Camptodactyly, tall stature, & hearing loss (CATSHL) syndrome (OMIM <a href="https://omim.org/entry/610474" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">610474</a>)</td><td headers="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD<br />AR</td><td headers="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1862G>A (p.Arg621His)</td></tr><tr><td headers="hd_h_muenke.T.other_clinically_distinct_allel_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_muenke.T.other_clinically_distinct_allel_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Common pathogenic variants are c.1620C>A (p.Asn540Lys) & c.1620C>G (p.Asn540Lys)</td></tr><tr><td headers="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lacrimoauriculodentodigital syndrome (OMIM <a href="https://omim.org/entry/149730" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">149730</a>)</td><td headers="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1537G>A (p.Asp513Asn)</td></tr><tr><td headers="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/td/?report=reader">Thanatophoric dysplasia</a> (TD)</td><td headers="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1948A>G (p.Lys650Glu) is identified in >99% of persons w/TD type II</td></tr><tr><td headers="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe achondroplasia w/developmental delay & acanthosis nigricans (SADDAN) syndrome (OMIM <a href="https://omim.org/entry/616482" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">616482</a>)</td><td headers="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_muenke.T.other_clinically_distinct_allel_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1949A>T (p.Lys650Met)</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; MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="muenke.TF.3b.1"><p class="no_margin">Reference sequences: <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000142.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000142<wbr style="display:inline-block"></wbr>​.5</a>; <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></p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmuenkeTcomparisonofmuenkesyndromew"><div id="muenke.T.comparison_of_muenke_syndrome_w" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Comparison of Muenke Syndrome with Other <i>FGFR</i>-Related Craniosynostosis Syndromes and Saethre-Chotzen Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1415/table/muenke.T.comparison_of_muenke_syndrome_w/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__muenke.T.comparison_of_muenke_syndrome_w_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_2" style="text-align:left;vertical-align:middle;">Syndrome</th><th id="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Features of Syndrome</th></tr><tr><th headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3" id="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/Muenke Syndrome</th><th headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3" id="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from Muenke Syndrome</th></tr></thead><tbody><tr><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FGFR1</i>
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<br />
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<i>FGFR2</i>
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<br />
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<i>FGFR3</i>
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</td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pfeiffer syndrome <sup>1</sup></td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3 hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Bilateral coronal synostosis</div></li><li class="half_rhythm"><div>Midface retrusion</div></li><li class="half_rhythm"><div>Widely spaced eyes</div></li><li class="half_rhythm"><div>Downslanted palpebral fissures</div></li><li class="half_rhythm"><div>Strabismus</div></li><li class="half_rhythm"><div>Highly arched palate</div></li><li class="half_rhythm"><div>Brachydactyly</div></li><li class="half_rhythm"><div>Normal intellect</div></li><li class="half_rhythm"><div>Broad thumbs & great toes</div></li><li class="half_rhythm"><div>Variable brachydactyly</div></li><li class="half_rhythm"><div>Ocular proptosis</div></li></ul>
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</td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3 hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Medial deviation of thumbs & great toes</div></li><li class="half_rhythm"><div>Lateral deviation of thumbs & great toes away from other digits</div></li><li class="half_rhythm"><div>Malformed & fused phalanges</div></li><li class="half_rhythm"><div>Symphalangism</div></li><li class="half_rhythm"><div>Mandibular prognathism</div></li></ul>
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</td></tr><tr><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FGFR2</i>
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</td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/apert/?report=reader">Apert syndrome</a>
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</td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3 hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Bilateral coronal synostosis</div></li><li class="half_rhythm"><div>Broad thumbs & great toes</div></li><li class="half_rhythm"><div>Widely spaced eyes</div></li><li class="half_rhythm"><div>Downslanted palpebral fissures</div></li><li class="half_rhythm"><div>Strabismus</div></li><li class="half_rhythm"><div>Highly arched palate</div></li><li class="half_rhythm"><div>Hearing loss</div></li><li class="half_rhythm"><div>Ocular proptosis</div></li></ul>
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</td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3 hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Disproportionately severe midface retrusion</div></li><li class="half_rhythm"><div>Severe, symmetric soft tissue / bony syndactyly of fingers & toes</div></li><li class="half_rhythm"><div>Lateral deviation of thumbs & great toes</div></li><li class="half_rhythm"><div>Acneiform eruptions</div></li></ul>
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</td></tr><tr><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Beare-Stevenson cutis gyrate <sup>1</sup></td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3 hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Bilateral coronal synostosis</div></li><li class="half_rhythm"><div>Normal extremities</div></li></ul>
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</td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3 hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Furrowed palms & soles</div></li><li class="half_rhythm"><div>Widespread cutis gyrata & acanthosis nigricans</div></li><li class="half_rhythm"><div>Prominent umbilicus</div></li><li class="half_rhythm"><div>Moderate intellectual disability</div></li></ul>
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</td></tr><tr><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Crouzon syndrome <sup>1</sup></td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3 hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Bilateral coronal synostosis</div></li><li class="half_rhythm"><div>Normal extremities</div></li><li class="half_rhythm"><div>Normal intellect</div></li><li class="half_rhythm"><div>Strabismus</div></li><li class="half_rhythm"><div>Widely spaced eyes</div></li><li class="half_rhythm"><div>Hearing deficit (conductive vs sensorineural in Muenke syndrome)</div></li></ul>
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</td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3 hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Significant proptosis</div></li><li class="half_rhythm"><div>Mandibular prognathism</div></li><li class="half_rhythm"><div>Convex nasal ridge</div></li><li class="half_rhythm"><div>Malar flattening</div></li><li class="half_rhythm"><div>Progressive hydrocephalus</div></li></ul>
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</td></tr><tr><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Jackson-Weiss syndrome <sup>1, 2</sup></td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3 hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Bilateral coronal synostosis</div></li><li class="half_rhythm"><div>Midface retrusion</div></li><li class="half_rhythm"><div>Tarsal fusions</div></li><li class="half_rhythm"><div>Broad great toes</div></li></ul>
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</td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3 hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Metatarsal fusions</div></li><li class="half_rhythm"><div>Abnormal tarsal bones</div></li><li class="half_rhythm"><div>Medial deviation of great toes</div></li></ul>
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</td></tr><tr><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>TWIST1</i>
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</td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/scs/?report=reader">Saethre-Chotzen syndrome</a>
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</td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3 hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Uni- or bilateral coronal synostosis</div></li><li class="half_rhythm"><div>Brachycephaly</div></li><li class="half_rhythm"><div>Facial asymmetry</div></li><li class="half_rhythm"><div>Midface retrusion</div></li><li class="half_rhythm"><div>Normal intellect or mild-to-moderate developmental delay</div></li><li class="half_rhythm"><div>Ptosis</div></li><li class="half_rhythm"><div>Widely spaced eyes</div></li><li class="half_rhythm"><div>Strabismus</div></li><li class="half_rhythm"><div>Downslanted palpebral fissures</div></li><li class="half_rhythm"><div>High-arched palate</div></li><li class="half_rhythm"><div>Brachydactyly</div></li></ul>
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</td><td headers="hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_1_3 hd_h_muenke.T.comparison_of_muenke_syndrome_w_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Small ear pinna w/prominent crus</div></li><li class="half_rhythm"><div>Syndactyly of fingers 2-3</div></li><li class="half_rhythm"><div>Low anterior hairline</div></li><li class="half_rhythm"><div>Duplication of the distal phalanx of the hallux</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="muenke.TF.4.1"><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>2. </dt><dd><div id="muenke.TF.4.2"><p class="no_margin">Jackson-Weiss syndrome is most likely limited to members of the original pedigree.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmuenkeTrecommendedevaluationsfollowi"><div id="muenke.T.recommended_evaluations_followi" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Muenke Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1415/table/muenke.T.recommended_evaluations_followi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__muenke.T.recommended_evaluations_followi_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_muenke.T.recommended_evaluations_followi_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_muenke.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Craniofacial</b>
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</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assessment of suture involvement by skull radiographs or preferably 3D skull CT</div></li><li class="half_rhythm"><div>Assessment for hydrocephalus w/brain CT or MRI</div></li></ul>
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</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_muenke.T.recommended_evaluations_followi_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_muenke.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiology assessment</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Development</b>
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</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To incl motor, adaptive, cognitive, & speech-language eval</div></li><li class="half_rhythm"><div>Eval for early intervention / special education</div></li></ul>
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</td></tr><tr><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Psychiatric/</b>
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<br />
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<b>Behavioral</b>
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</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropsychiatric eval</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For persons age >12 mos: screening for behavior concerns incl ADHD</td></tr><tr><td headers="hd_h_muenke.T.recommended_evaluations_followi_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_muenke.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider EEG if seizures are a concern.</td></tr><tr><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Eyes</b>
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</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment for exposure keratopathy</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic assessment</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for reduced vision, abnormal ocular movement, best corrected visual acuity, refractive errors, & strabismus</td></tr><tr><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Fundoscopy to assess for papilledema</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Papilledema is present when intracranial pressure is ↑.</td></tr><tr><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Genetic counseling</b>
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</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_muenke.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & their families re nature, MOI, & implications of Muenke syndrome to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_muenke.T.recommended_evaluations_followi_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>
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<br />
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<b>& resources</b>
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</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_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="#muenke.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>
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</td><td headers="hd_h_muenke.T.recommended_evaluations_followi_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">ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="muenke.TF.5.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmuenkeTrecommendedsurveillanceforin"><div id="muenke.T.recommended_surveillance_for_in" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Muenke Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1415/table/muenke.T.recommended_surveillance_for_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__muenke.T.recommended_surveillance_for_in_lrgtbl__"><table><thead><tr><th id="hd_h_muenke.T.recommended_surveillance_for_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_muenke.T.recommended_surveillance_for_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_muenke.T.recommended_surveillance_for_in_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_muenke.T.recommended_surveillance_for_in_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_muenke.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiology eval</td><td headers="hd_h_muenke.T.recommended_surveillance_for_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually or as indicated</td></tr><tr><td headers="hd_h_muenke.T.recommended_surveillance_for_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Development</b>
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</td><td headers="hd_h_muenke.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental progress & educational needs.</td><td headers="hd_h_muenke.T.recommended_surveillance_for_in_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_muenke.T.recommended_surveillance_for_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Psychiatric/</b>
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<br />
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<b>Behavioral</b>
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</td><td headers="hd_h_muenke.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Behavioral assessment</td></tr><tr><td headers="hd_h_muenke.T.recommended_surveillance_for_in_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_muenke.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Monitor those w/seizures as clinically indicated.</div></li><li class="half_rhythm"><div>Assess for new manifestations such as seizures, changes in tone, & movement disorders.</div></li></ul>
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</td></tr><tr><td headers="hd_h_muenke.T.recommended_surveillance_for_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Eyes</b>
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</td><td headers="hd_h_muenke.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmology assessment for strabismus</td><td headers="hd_h_muenke.T.recommended_surveillance_for_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually or as indicated</td></tr><tr><td headers="hd_h_muenke.T.recommended_surveillance_for_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Family/</b>
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<br />
|
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<b>Community</b>
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</td><td headers="hd_h_muenke.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess family need for social work support, care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).</td><td headers="hd_h_muenke.T.recommended_surveillance_for_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobmuenkemolgenTA"><div id="muenke.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Muenke Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1415/table/muenke.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__muenke.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_muenke.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_muenke.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_muenke.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_muenke.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_muenke.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_muenke.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_muenke.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/2261" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>FGFR3</i>
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</a>
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</td><td headers="hd_b_muenke.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=2261" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">4p16<wbr style="display:inline-block"></wbr>​.3</a>
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</td><td headers="hd_b_muenke.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/P22607" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Fibroblast growth factor receptor 3</a>
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</td><td headers="hd_b_muenke.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.lovd.nl/FGFR3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FGFR3 @ LOVD</a>
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</td><td headers="hd_b_muenke.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=FGFR3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FGFR3</a>
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</td><td headers="hd_b_muenke.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=FGFR3[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FGFR3</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="muenke.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
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chromosome locus from
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
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<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobmuenkemolgenTB"><div id="muenke.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Muenke Syndrome (<a href="/omim/134934,602849" 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/NBK1415/table/muenke.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__muenke.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/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;">
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<a href="/omim/602849" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">602849</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MUENKE SYNDROME; MNKES</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobmuenkeTnotablefgfr3pathogenicvarian"><div id="muenke.T.notable_fgfr3_pathogenic_varian" class="table"><h3><span class="label">Table 7. </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/NBK1415/table/muenke.T.notable_fgfr3_pathogenic_varian/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__muenke.T.notable_fgfr3_pathogenic_varian_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_muenke.T.notable_fgfr3_pathogenic_varian_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_muenke.T.notable_fgfr3_pathogenic_varian_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_muenke.T.notable_fgfr3_pathogenic_varian_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_muenke.T.notable_fgfr3_pathogenic_varian_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_muenke.T.notable_fgfr3_pathogenic_varian_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000142.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000142<wbr style="display:inline-block"></wbr>​.5</a>
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<br />
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<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>
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</td><td headers="hd_h_muenke.T.notable_fgfr3_pathogenic_varian_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.749C>G</td><td headers="hd_h_muenke.T.notable_fgfr3_pathogenic_varian_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Pro250Arg</td><td headers="hd_h_muenke.T.notable_fgfr3_pathogenic_varian_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pathogenic variant assoc w/Muenke syndrome</td></tr><tr><td headers="hd_h_muenke.T.notable_fgfr3_pathogenic_varian_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.749C>T</td><td headers="hd_h_muenke.T.notable_fgfr3_pathogenic_varian_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Pro250Leu</td><td headers="hd_h_muenke.T.notable_fgfr3_pathogenic_varian_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#muenke.Genetically_Related_Allelic_Disor">Genetically Related Disorders</a>.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>). See <a href="/books/n/gene/app3/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobmuenkeF1"><div id="muenke.F1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK1415/bin/muenke-Image001.jpg" alt="Figure 1. " /></div><h3><span class="label">Figure 1. </span></h3><div class="caption"><p>Schema of the FGFR3 protein</p><p>The loops represent the three immunoglobulin domains (left to right: IgI, IgII, IgIII). The p.Pro250Arg protein change (indicated with a black dot) is in the linker region between the second and third immunoglobulin domains. The grey boxes following the third immunoglobulin domain are (left to right): transmembrane domain (small grey box); first and second tyrosine kinase domains (2nd and 3rd dark grey boxes, respectively) [<a class="bibr" href="#muenke.REF.cunningham.2007.67" rid="muenke.REF.cunningham.2007.67">Cunningham et al 2007</a>].</p></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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