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<meta name="ncbi_db" content="books" /><meta name="ncbi_pdid" content="book-part" /><meta name="ncbi_acc" content="NBK425723" /><meta name="ncbi_domain" content="gene" /><meta name="ncbi_report" content="record" /><meta name="ncbi_type" content="fulltext" /><meta name="ncbi_objectid" content="" /><meta name="ncbi_pcid" content="/NBK425723/" /><meta name="ncbi_pagename" content="Myhre Syndrome - GeneReviews® - NCBI Bookshelf" /><meta name="ncbi_bookparttype" content="chapter" /><meta name="ncbi_app" content="bookshelf" />
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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Myhre Syndrome" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2024/12/12" /><meta name="citation_author" content="Angela E Lin" /><meta name="citation_author" content="Nicola Brunetti-Pierri" /><meta name="citation_author" content="Mark E Lindsay" /><meta name="citation_author" content="Lisa A Schimmenti" /><meta name="citation_author" content="Lois J Starr" /><meta name="citation_pmid" content="28406602" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK425723/" /><meta name="citation_keywords" content="Myhre-LAPS Syndrome" /><meta name="citation_keywords" content="Laryngotracheal Stenosis, Arthropathy, Prognathism, and Short Stature (LAPS) Syndrome" /><meta name="citation_keywords" content="Myhre-LAPS Syndrome" /><meta name="citation_keywords" content="Mothers against decapentaplegic homolog 4" /><meta name="citation_keywords" content="SMAD4" /><meta name="citation_keywords" content="Myhre Syndrome" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Myhre Syndrome" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Angela E Lin" /><meta name="DC.Contributor" content="Nicola Brunetti-Pierri" /><meta name="DC.Contributor" content="Mark E Lindsay" /><meta name="DC.Contributor" content="Lisa A Schimmenti" /><meta name="DC.Contributor" content="Lois J Starr" /><meta name="DC.Date" content="2024/12/12" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK425723/" /><meta name="description" content="Myhre syndrome is a multisystem progressive connective tissue disorder that often results in significant complications. The highly distinctive (and often severe) findings of joint stiffness, restrictive lung and cardiovascular disease, progressive and proliferative fibrosis, and thickening of the skin usually occur spontaneously. Some proliferation such as abnormal scarring or adhesions may follow trauma, invasive medical procedures, or surgery. Effusions of the heart, airways, lungs, uterus, and peritoneum may occur and can progress to fibrosis. Most affected individuals have characteristic facial features (short palpebral fissures, deeply set eyes, maxillary underdevelopment, short philtrum, thin vermilion of the upper lip, narrow mouth, and prognathism) and developmental delay / cognitive disability, typically in the mild-to-moderate range. Neurobehavioral issues may include autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and/or anxiety. Although immunoglobulin (Ig) G and IgA deficiency are rare, affected individuals can experience recurrent infections (including otitis media, sinusitis, mastoiditis, or croup). Hearing loss can progress over time. Growth may be impaired in early life. Most adolescents develop obesity. Eye findings can include refractive errors, astigmatism, corectopia, and optic nerve anomalies. Gastrointestinal (GI) issues may include gastroesophageal reflux disease, constipation, and encopresis. Less commonly, stenosis of the GI tract, Hirschsprung disease, and/or metabolic dysfunction-associated liver disease may be observed." /><meta name="og:title" content="Myhre Syndrome" /><meta name="og:type" content="book" /><meta name="og:description" content="Myhre syndrome is a multisystem progressive connective tissue disorder that often results in significant complications. The highly distinctive (and often severe) findings of joint stiffness, restrictive lung and cardiovascular disease, progressive and proliferative fibrosis, and thickening of the skin usually occur spontaneously. Some proliferation such as abnormal scarring or adhesions may follow trauma, invasive medical procedures, or surgery. Effusions of the heart, airways, lungs, uterus, and peritoneum may occur and can progress to fibrosis. Most affected individuals have characteristic facial features (short palpebral fissures, deeply set eyes, maxillary underdevelopment, short philtrum, thin vermilion of the upper lip, narrow mouth, and prognathism) and developmental delay / cognitive disability, typically in the mild-to-moderate range. Neurobehavioral issues may include autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and/or anxiety. Although immunoglobulin (Ig) G and IgA deficiency are rare, affected individuals can experience recurrent infections (including otitis media, sinusitis, mastoiditis, or croup). Hearing loss can progress over time. Growth may be impaired in early life. Most adolescents develop obesity. Eye findings can include refractive errors, astigmatism, corectopia, and optic nerve anomalies. Gastrointestinal (GI) issues may include gastroesophageal reflux disease, constipation, and encopresis. Less commonly, stenosis of the GI tract, Hirschsprung disease, and/or metabolic dysfunction-associated liver disease may be observed." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK425723/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/gene/myhre/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK425723/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script><meta name="book-collection" content="NONE" />
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK425723_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK425723_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/m-sulfatase-def/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/mfm/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK425723_"><span class="title" itemprop="name">Myhre Syndrome</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: Myhre-LAPS Syndrome</div><p class="contrib-group"><span itemprop="author">Angela E Lin</span>, MD, <span itemprop="author">Nicola Brunetti-Pierri</span>, MD, <span itemprop="author">Mark E Lindsay</span>, MD, PhD, <span itemprop="author">Lisa A Schimmenti</span>, MD, and <span itemprop="author">Lois J Starr</span>, MD, PhD.</p><a data-jig="ncbitoggler" href="#__NBK425723_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK425723_ai__"><div class="contrib half_rhythm"><span itemprop="author">Angela E Lin</span>, MD<div class="affiliation small">MassGeneral Hospital for Children<br />Boston, Massachusetts<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.bgm@nila" class="oemail">gro.bgm@nila</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Nicola Brunetti-Pierri</span>, MD<div class="affiliation small">Department of Translational Medicine<br />University of Naples "Federico II"<br />Naples, Italy<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ti.megit@ittenurb" class="oemail">ti.megit@ittenurb</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Mark E Lindsay</span>, MD, PhD<div class="affiliation small">MassGeneral Hospital for Children<br />Boston, Massachusetts<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.dravrah.hgm@kram.yasdnil" class="oemail">ude.dravrah.hgm@kram.yasdnil</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Lisa A Schimmenti</span>, MD<div class="affiliation small">Mayo Clinic<br />Rochester, Minnesota<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.oyam@asil.itnemmihcs" class="oemail">ude.oyam@asil.itnemmihcs</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Lois J Starr</span>, MD, PhD<div class="affiliation small">University of Nebraska Medical Center<br />Omaha, Nebraska<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.cmnu@rratsl" class="oemail">ude.cmnu@rratsl</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">April 13, 2017</span>; Last Update: <span itemprop="dateModified">December 12, 2024</span>.</p><p><em>Estimated reading time: 41 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="myhre.Summary" itemprop="description"><h2 id="_myhre_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Myhre syndrome is a multisystem progressive connective tissue disorder that often results in significant complications. The highly distinctive (and often severe) findings of joint stiffness, restrictive lung and cardiovascular disease, progressive and proliferative fibrosis, and thickening of the skin usually occur spontaneously. Some proliferation such as abnormal scarring or adhesions may follow trauma, invasive medical procedures, or surgery. Effusions of the heart, airways, lungs, uterus, and peritoneum may occur and can progress to fibrosis. Most affected individuals have characteristic facial features (short palpebral fissures, deeply set eyes, maxillary underdevelopment, short philtrum, thin vermilion of the upper lip, narrow mouth, and prognathism) and developmental delay / cognitive disability, typically in the mild-to-moderate range. Neurobehavioral issues may include autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and/or anxiety. Although immunoglobulin (Ig) G and IgA deficiency are rare, affected individuals can experience recurrent infections (including otitis media, sinusitis, mastoiditis, or croup). Hearing loss can progress over time. Growth may be impaired in early life. Most adolescents develop obesity. Eye findings can include refractive errors, astigmatism, corectopia, and optic nerve anomalies. Gastrointestinal (GI) issues may include gastroesophageal reflux disease, constipation, and encopresis. Less commonly, stenosis of the GI tract, Hirschsprung disease, and/or metabolic dysfunction-associated liver disease may be observed.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of Myhre syndrome is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with characteristic clinical findings and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> (typically recurrent) <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>SMAD4</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Feeding therapy for those with poor weight gain or feeding issues; gastrostomy tube placement may be required for persistent feeding issues; referral to nutrition for those who develop obesity; consideration of balloon dilation or long-term tracheostomy for those with complete or recurrent tracheal stenosis; use of smaller-size, uncuffed endotracheal tubes for anesthesia; intralesional steroids for some keloids; physical therapy for decreased range of motion of joints; orthotics for tiptoe walking; dietary management, stool softeners, prokinetics, osmotic agents, or laxatives for constipation; guarded treatment with minimal instrumentation of the GI tract for gastrointestinal stenosis. Standard treatment for orofacial clefting, velopharyngeal insufficiency, developmental delay / intellectual disability, cardiovascular disease including systemic/pulmonary hypertension, restrictive lung disease, sleep apnea, immunodeficiency, tethered spinal cord, frequent fractures, eye/vision issues, hearing loss, protein-losing enteropathy, liver dysfunction, diabetes mellitus, cryptorchidism, hypospadias, and epilepsy.</p><p><i>Prevention of secondary complications:</i> Limiting tissue trauma appears to be the single most important preventive measure. When possible, alternative noninvasive approaches should be pursued during diagnosis and management.</p><p><i>Surveillance:</i> At each visit, measure growth parameters; right upper arm blood pressure (if tolerated); monitor for evidence of respiratory insufficiency and obtain pulse oxygen measurement; evaluate for signs/symptoms of upper airway stenosis and sleep apnea; monitor for constipation and signs/symptoms of GI stenosis; monitor developmental progress and educational needs, including mobility and self-help skills; assess for signs/symptoms of anxiety, ASD, and ADHD; assess for signs/symptoms of frequent infections; monitor for premature puberty in childhood; encourage nonstrenuous exercise, healthy eating, and weight management. Annually (or as clinically indicated), pulmonary function studies or impulse oscillometry in children age six years and older, if able to cooperate with test maneuvers; ophthalmology evaluation; hearing evaluation; assessment for abnormal scarring. Every two years, echocardiogram (in an asymptomatic person with a normal echocardiogram at initial diagnosis). Every five to ten years starting in childhood (age 5-10 years), CT or MR angiogram of the aorta, the exact frequency of which is based on the presence and degree of aortic disease. The decision to use CT or MR depends on the age and behavior of individual, the imaging center, and the availability of supportive services ("Child Life") to accomplish without anesthesia. Starting in the second decade, low threshold for fasting blood sugar and hemoglobin A1c to assess for diabetes mellitus; periodic DXA scan to assess bone mineral density; monitor for heavy menses. As clinically indicated, more extensive cardiovascular imaging in persons with abnormal findings at initial diagnosis; renal bladder ultrasound, if there is intractable incontinence. As needed, in the third decade of life, coronary CT angiography; evaluation for sleep apnea and need for intervention.</p><p><i>Agents/circumstances to avoid:</i> Smoking; tissue trauma; elective tracheal surgery/intubation (if possible); tracheal resection; growth hormone therapy.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Myhre syndrome is an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> disorder typically caused by a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. <i>De novo SMAD4</i> pathogenic variants that have been evaluated for parent of origin to date have all been paternal and have been associated with advanced paternal age. A few individuals diagnosed with Myhre syndrome have the disorder as the result of a <i>SMAD4</i> pathogenic variant inherited from an affected parent. Each child of an individual with Myhre syndrome has a 50% chance of inheriting the <i>SMAD4</i> pathogenic variant. Once the <i>SMAD4</i> pathogenic variant has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p></div></div><div id="myhre.Diagnosis"><h2 id="_myhre_Diagnosis_">Diagnosis</h2><p>No consensus clinical diagnostic criteria for Myhre syndrome have been published.</p><div id="myhre.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Myhre syndrome <b>should be suspected</b> in individuals with the following clinical and imaging findings and family history. Although no single feature is pathognomonic, co-occurrence of some findings is highly suggestive of Myhre syndrome (see <a href="/books/NBK425723/table/myhre.T.myhre_syndrome_frequency_of_sele/?report=objectonly" target="object" rid-ob="figobmyhreTmyhresyndromefrequencyofsele">Table 2</a> for frequency of select features).</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Short stature (height is significantly less than predicted mid-parental height) with compact body habitus</div></li><li class="half_rhythm"><div>Characteristic facial features (See <a href="#myhre.Clinical_Description">Clinical Description</a>, <b>Craniofacial</b> and <a class="figpopup" href="/books/NBK425723/figure/myhre.F1/?report=objectonly" target="object" rid-figpopup="figmyhreF1" rid-ob="figobmyhreF1">Figures 1</a>, <a class="figpopup" href="/books/NBK425723/figure/myhre.F2/?report=objectonly" target="object" rid-figpopup="figmyhreF2" rid-ob="figobmyhreF2">2</a>, <a class="figpopup" href="/books/NBK425723/figure/myhre.F3/?report=objectonly" target="object" rid-figpopup="figmyhreF3" rid-ob="figobmyhreF3">3</a>, <a class="figpopup" href="/books/NBK425723/figure/myhre.F4/?report=objectonly" target="object" rid-figpopup="figmyhreF4" rid-ob="figobmyhreF4">4</a>, <a class="figpopup" href="/books/NBK425723/figure/myhre.F5/?report=objectonly" target="object" rid-figpopup="figmyhreF5" rid-ob="figobmyhreF5">5</a>, and <a class="figpopup" href="/books/NBK425723/figure/myhre.F6/?report=objectonly" target="object" rid-figpopup="figmyhreF6" rid-ob="figobmyhreF6">6</a>.)</div></li><li class="half_rhythm"><div>Conductive and mixed hearing loss</div></li><li class="half_rhythm"><div>Respiratory difficulties, usually due to restrictive thorax or, infrequently, multilevel airway stenosis (including choanal, subglottic, laryngotracheal, and/or bronchial)</div></li><li class="half_rhythm"><div>Progressively stiff, thickened skin and subcutaneous tissue</div></li><li class="half_rhythm"><div>Limited range of motion of the joints with occasional contractures</div></li><li class="half_rhythm"><div>Effusions involving the heart, airways, lungs, uterus, and peritoneum, which may progress to fibrosis</div></li><li class="half_rhythm"><div>Mild-to-moderate intellectual disability</div></li><li class="half_rhythm"><div>Autism spectrum disorder or neurodivergent behaviors</div></li><li class="half_rhythm"><div>Severe constipation and/or encopresis</div></li><li class="half_rhythm"><div>Premature puberty</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col fig" id="figmyhreF1" co-legend-rid="figlgndmyhreF1"><a href="/books/NBK425723/figure/myhre.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figmyhreF1" rid-ob="figobmyhreF1"><img class="small-thumb" src="/books/NBK425723/bin/myhre-Image001.gif" src-large="/books/NBK425723/bin/myhre-Image001.jpg" alt="Figure 1. . The same female with Myhre syndrome at ages seven months, four years, and 16 years (lateral and frontal views)." /></a><div class="icnblk_cntnt" id="figlgndmyhreF1"><h4 id="myhre.F1"><a href="/books/NBK425723/figure/myhre.F1/?report=objectonly" target="object" rid-ob="figobmyhreF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">The same female with Myhre syndrome at ages seven months, four years, and 16 years (lateral and frontal views). Note the short palpebral fissures, thin vermilion of the upper lip, and maxillary underdevelopment. She required tracheostomy at age 13 years <a href="/books/NBK425723/figure/myhre.F1/?report=objectonly" target="object" rid-ob="figobmyhreF1">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figmyhreF2" co-legend-rid="figlgndmyhreF2"><a href="/books/NBK425723/figure/myhre.F2/?report=objectonly" target="object" title="Figure 2. " class="img_link icnblk_img figpopup" rid-figpopup="figmyhreF2" rid-ob="figobmyhreF2"><img class="small-thumb" src="/books/NBK425723/bin/myhre-Image002.gif" src-large="/books/NBK425723/bin/myhre-Image002.jpg" alt="Figure 2. . The same female with Myhre syndrome as a newborn and at ages 12 months, 3." /></a><div class="icnblk_cntnt" id="figlgndmyhreF2"><h4 id="myhre.F2"><a href="/books/NBK425723/figure/myhre.F2/?report=objectonly" target="object" rid-ob="figobmyhreF2">Figure 2. </a></h4><p class="float-caption no_bottom_margin">The same female with Myhre syndrome as a newborn and at ages 12 months, 3.5 years, and seven years. Note the mild left-sided facial asymmetry (7th cranial nerve palsy), short palpebral fissures, thin vermilion of the upper lip, and progression of mild <a href="/books/NBK425723/figure/myhre.F2/?report=objectonly" target="object" rid-ob="figobmyhreF2">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figmyhreF3" co-legend-rid="figlgndmyhreF3"><a href="/books/NBK425723/figure/myhre.F3/?report=objectonly" target="object" title="Figure 3. " class="img_link icnblk_img figpopup" rid-figpopup="figmyhreF3" rid-ob="figobmyhreF3"><img class="small-thumb" src="/books/NBK425723/bin/myhre-Image003.gif" src-large="/books/NBK425723/bin/myhre-Image003.jpg" alt="Figure 3. . Male with Myhre syndrome at age 12 years with mild facial features (mild maxillary underdevelopment and thin vermilion of the upper lip) and finger contractures." /></a><div class="icnblk_cntnt" id="figlgndmyhreF3"><h4 id="myhre.F3"><a href="/books/NBK425723/figure/myhre.F3/?report=objectonly" target="object" rid-ob="figobmyhreF3">Figure 3. </a></h4><p class="float-caption no_bottom_margin">Male with Myhre syndrome at age 12 years with mild facial features (mild maxillary underdevelopment and thin vermilion of the upper lip) and finger contractures. Reported as Patient 4 in Starr et al [2015]</p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figmyhreF4" co-legend-rid="figlgndmyhreF4"><a href="/books/NBK425723/figure/myhre.F4/?report=objectonly" target="object" title="Figure 4. " class="img_link icnblk_img figpopup" rid-figpopup="figmyhreF4" rid-ob="figobmyhreF4"><img class="small-thumb" src="/books/NBK425723/bin/myhre-Image004.gif" src-large="/books/NBK425723/bin/myhre-Image004.jpg" alt="Figure 4. . Female with Myhre syndrome at age five years." /></a><div class="icnblk_cntnt" id="figlgndmyhreF4"><h4 id="myhre.F4"><a href="/books/NBK425723/figure/myhre.F4/?report=objectonly" target="object" rid-ob="figobmyhreF4">Figure 4. </a></h4><p class="float-caption no_bottom_margin">Female with Myhre syndrome at age five years. Note the short palpebral fissures, thin vermilion of the upper and lower lips, left-sided facial palsy, and brachydactyly, with otherwise mild features. Reported by Hawkes & Kini [2015]</p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figmyhreF5" co-legend-rid="figlgndmyhreF5"><a href="/books/NBK425723/figure/myhre.F5/?report=objectonly" target="object" title="Figure 5. " class="img_link icnblk_img figpopup" rid-figpopup="figmyhreF5" rid-ob="figobmyhreF5"><img class="small-thumb" src="/books/NBK425723/bin/myhre-Image005.gif" src-large="/books/NBK425723/bin/myhre-Image005.jpg" alt="Figure 5. . The same male with Myhre syndrome at various ages from toddlerhood (lower right corner) to age 19 years (upper left corner)." /></a><div class="icnblk_cntnt" id="figlgndmyhreF5"><h4 id="myhre.F5"><a href="/books/NBK425723/figure/myhre.F5/?report=objectonly" target="object" rid-ob="figobmyhreF5">Figure 5. </a></h4><p class="float-caption no_bottom_margin">The same male with Myhre syndrome at various ages from toddlerhood (lower right corner) to age 19 years (upper left corner). </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figmyhreF6" co-legend-rid="figlgndmyhreF6"><a href="/books/NBK425723/figure/myhre.F6/?report=objectonly" target="object" title="Figure 6. " class="img_link icnblk_img figpopup" rid-figpopup="figmyhreF6" rid-ob="figobmyhreF6"><img class="small-thumb" src="/books/NBK425723/bin/myhre-Image006.gif" src-large="/books/NBK425723/bin/myhre-Image006.jpg" alt="Figure 6. . Two different women with Myhre syndrome at ages 40 years (A) and 50 years (B)." /></a><div class="icnblk_cntnt" id="figlgndmyhreF6"><h4 id="myhre.F6"><a href="/books/NBK425723/figure/myhre.F6/?report=objectonly" target="object" rid-ob="figobmyhreF6">Figure 6. </a></h4><p class="float-caption no_bottom_margin">Two different women with Myhre syndrome at ages 40 years (A) and 50 years (B). The women are shown together in C. </p></div></div><p>
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<b>Imaging findings</b>
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</p><ul><li class="half_rhythm"><div>
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<b>Echocardiographic findings</b>
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</div><ul><li class="half_rhythm"><div>Aortic narrowing, such as typical juxtaductal aortic coarctation, diffuse long-segment aortic hypoplasia, or segmental stenosis (branch arteries)</div></li><li class="half_rhythm"><div>Congenital heart defects (See <a href="#myhre.Clinical_Description">Clinical Description</a>, <b>Cardiovascular</b>.)</div></li><li class="half_rhythm"><div>Pericardial involvement ranging from transient effusion to chronic severe constrictive pericarditis</div></li><li class="half_rhythm"><div>Restrictive cardiomyopathy and diastolic dysfunction</div></li><li class="half_rhythm"><div>Pulmonary hypertension</div></li></ul></li><li class="half_rhythm"><div><b>Skeletal radiographs</b> (See <a class="figpopup" href="/books/NBK425723/figure/myhre.F7/?report=objectonly" target="object" rid-figpopup="figmyhreF7" rid-ob="figobmyhreF7">Figure 7</a>.)</div><ul><li class="half_rhythm"><div>Thickened calvarium</div></li><li class="half_rhythm"><div>Shortened long bones</div></li><li class="half_rhythm"><div>Enlarged (tall) or flattened (platyspondyly) vertebrae with shortened pedicles</div></li><li class="half_rhythm"><div>Cervical vertebral fusion</div></li><li class="half_rhythm"><div>Hypoplastic iliac wings</div></li><li class="half_rhythm"><div>Absent or extra ribs</div></li><li class="half_rhythm"><div>Small exostoses and/or enostoses (bone islands)</div></li></ul></li></ul><div class="iconblock whole_rhythm clearfix ten_col fig" id="figmyhreF7" co-legend-rid="figlgndmyhreF7"><a href="/books/NBK425723/figure/myhre.F7/?report=objectonly" target="object" title="Figure 7. " class="img_link icnblk_img figpopup" rid-figpopup="figmyhreF7" rid-ob="figobmyhreF7"><img class="small-thumb" src="/books/NBK425723/bin/myhre-Image007.gif" src-large="/books/NBK425723/bin/myhre-Image007.jpg" alt="Figure 7. " /></a><div class="icnblk_cntnt" id="figlgndmyhreF7"><h4 id="myhre.F7"><a href="/books/NBK425723/figure/myhre.F7/?report=objectonly" target="object" rid-ob="figobmyhreF7">Figure 7. </a></h4><p class="float-caption no_bottom_margin">Radiographs of a female with Myhre syndrome at age 14 years A. Lateral cervical spine shows thickened calvaria and anterior cervical vertebral fusion (arrow) of C2 and C3.</p></div></div><p><b>Family history.</b> Because Myhre syndrome is typically caused by a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, most probands represent a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case (i.e., a single occurrence in a family). Infrequently, the family history may be consistent with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> inheritance (e.g., affected males and females in multiple generations) [<a class="bk_pop" href="#myhre.REF.meerschaut.2019.2494">Meerschaut et al 2019</a>, <a class="bk_pop" href="#myhre.REF.demir.2023.175">Demir et al 2023</a>, <a class="bk_pop" href="#myhre.REF.vanbelleghem.2024.1086">Vanbelleghem et al 2024</a>].</p></div><div id="myhre.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of Myhre syndrome <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with characteristic <a href="#myhre.Suggestive_Findings">clinical findings</a> and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> (typically recurrent) pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variant in <i>SMAD4</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK425723/table/myhre.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobmyhreTmoleculargenetictestingusedi">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "<a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bk_pop" href="#myhre.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>SMAD4</i> variant of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> does not establish or rule out the diagnosis. (3) Individuals described as having "Myhre-like syndrome" require genetic testing for confirmation.</p><p>Molecular genetic testing approaches can include a combination of <b><a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing</b> (single gene testing, <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>) and <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see <a href="#myhre.Option_1">Option 1</a>), whereas comprehensive genomic testing does not (see <a href="#myhre.Option_2">Option 2</a>).</p><div id="myhre.Option_1"><h4>Option 1</h4><p>When the phenotypic and imaging findings suggest the diagnosis of Myhre syndrome, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> approaches can include <b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b> or use of a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Sequence analysis of <i>SMAD4</i> may be performed first to detect the recurrent pathogenic <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants associated with Myhre syndrome.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>SMAD4</i> and other genes of interest (see <a href="#myhre.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul></div><div id="myhre.Option_2"><h4>Option 2</h4><p>When the diagnosis of Myhre syndrome has not been considered, <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing may be used. <b>Comprehensive</b>
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<b>genomic testing</b> does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> is likely involved. <b>Exome sequencing</b> is often used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible. ACMG recommends <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> and genome sequencing as first- or second-tier diagnostic testing for children with intellectual disability and/or multiple <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> anomalies [<a class="bk_pop" href="#myhre.REF.manickam.2021.2029">Manickam et al 2021</a>]. To date, all of the <i>SMAD4</i> pathogenic variants reported (<a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> pathogenic variants impacting amino acid positions 496 and 500 causing Myhre syndrome) are within the <a class="def" href="/books/n/gene/glossary/def-item/coding-region/">coding region</a> and are likely to be identified on <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="myhre.T.molecular_genetic_testing_used_i" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Myhre Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK425723/table/myhre.T.molecular_genetic_testing_used_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myhre.T.molecular_genetic_testing_used_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_myhre.T.molecular_genetic_testing_used_i_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_myhre.T.molecular_genetic_testing_used_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_myhre.T.molecular_genetic_testing_used_i_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_myhre.T.molecular_genetic_testing_used_i_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SMAD4</i>
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</td><td headers="hd_h_myhre.T.molecular_genetic_testing_used_i_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_myhre.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <sup>4</sup></td></tr><tr><td headers="hd_h_myhre.T.molecular_genetic_testing_used_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>5</sup></td><td headers="hd_h_myhre.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported <sup>6</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="myhre.TF.1.1"><p class="no_margin">See <a href="/books/NBK425723/#myhre.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="myhre.TF.1.2"><p class="no_margin">See <a href="#myhre.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="myhre.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants and small intragenic deletions/insertions; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="myhre.TF.1.4"><p class="no_margin"><a class="bk_pop" href="#myhre.REF.lin.2016.2617">Lin et al [2016]</a>, <a class="bk_pop" href="#myhre.REF.cappuccio.2021.702">Cappuccio et al [2021]</a>, <a class="bk_pop" href="#myhre.REF.yang.2022.304">Yang et al [2022]</a>, <a class="bk_pop" href="#myhre.REF.lin.2024.e63638">Lin et al [2024]</a></p></div></dd><dt>5. </dt><dd><div id="myhre.TF.1.5"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd><dt>6. </dt><dd><div id="myhre.TF.1.6"><p class="no_margin">No <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications have been reported. However, these are not expected to occur since all variants detected so far result in disease by a <a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a> mechanism (see <a href="#myhre.Molecular_Genetics">Molecular Genetics</a>).</p></div></dd></dl></div></div></div></div></div></div><div id="myhre.Clinical_Characteristics"><h2 id="_myhre_Clinical_Characteristics_">Clinical Characteristics</h2><div id="myhre.Clinical_Description"><h3>Clinical Description</h3><p>Myhre syndrome is a multisystem progressive connective tissue disorder that often results in significant complications. The highly distinctive (and often severe) findings of joint stiffness, restrictive lung and cardiovascular disease, progressive and proliferative fibrosis, and thickening of the skin may occur spontaneously or following trauma, invasive medical procedures, or surgery. In most, short stature and hearing loss also develop over time.</p><p>To date, more than 200 affected individuals with a molecularly confirmed diagnosis of Myhre syndrome have been reported [<a class="bk_pop" href="#myhre.REF.bassett.2016.54">Bassett et al 2016</a>, <a class="bk_pop" href="#myhre.REF.lin.2016.2617">Lin et al 2016</a>, <a class="bk_pop" href="#myhre.REF.lin.2020.328">Lin et al 2020</a>, <a class="bk_pop" href="#myhre.REF.cappuccio.2021.702">Cappuccio et al 2021</a>, <a class="bk_pop" href="#myhre.REF.cappuccio.2022.1384">Cappuccio et al 2022</a>, <a class="bk_pop" href="#myhre.REF.yang.2022.304">Yang et al 2022</a>, <a class="bk_pop" href="#myhre.REF.lin.2024.e63638">Lin et al 2024</a>, <a class="bk_pop" href="#myhre.REF.vanbelleghem.2024.1086">Vanbelleghem et al 2024</a>]. The following descriptions of the phenotypic features associated with Myhre syndrome are based on these reports, which will not be cited again unless there is specific or unique data pertaining to a particular citation.</p><div id="myhre.T.myhre_syndrome_frequency_of_sele" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Myhre Syndrome: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK425723/table/myhre.T.myhre_syndrome_frequency_of_sele/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myhre.T.myhre_syndrome_frequency_of_sele_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2" colspan="3" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Frequency</th><th id="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" style="text-align:left;vertical-align:middle;">Comments</th></tr><tr><th headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2" id="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Most<br />(>75%)</th><th headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2" id="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Common<br />(25%-75%)</th><th headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2" id="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Infrequent<br />(<25%)</th></tr></thead><tbody><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Characteristic facial features</b>
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</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">More apparent in older children & adults</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Developmental delays &/or cognitive disability</b>
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</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Typically mild to moderate</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Growth issues</b>
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</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Small for gestational age, intrauterine growth restriction, & short stature have been observed; <sup>1, 2</sup> many adults are overweight.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cardiovascular issues</b>
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</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl aortic hypoplasia & stenosis, <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart defects, pericardial involvement, restrictive cardiomyopathy</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Respiratory issues</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl reactive airway disease, <sup>3</sup> restrictive lung disease, <sup>4</sup> & rarely choanal stenosis, multisite airway stenosis, &/or sleep apnea</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Recurrent infections</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May incl otitis media, sinusitis, mastoiditis, or croup, w/resulting stridor; IgG & IgA deficiency is rare.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Skin issues</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Stiff & thickened skin is most common, although proliferative fibrosis &/or abnormal scarring (often after trauma) may be seen.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal findings</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl joint limitations, contractures, & stiff gait that often progresses w/age</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurobehavioral/psychiatric findings</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl ASD, ADHD, &/or anxiety; rarely, psychosis</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Abnormal sleep</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May incl obstructive sleep apnea</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Abnormal tone</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypertonia, hypotonia</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Eye findings</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Refractive error & astigmatism are more common, w/optic nerve abnormalities being less common, & corectopia rarer still.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hearing loss</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Typically conductive or mixed hearing loss; recurrent otitis media is common.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Oropharyngeal findings</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May incl small or widely spaced teeth, restricted mouth opening, VPI, & rarely cleft palate</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal issues</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May incl GERD, constipation, encopresis, or rarely stenosis of GI tract, HSCR, or metabolic dysfunction-assoc liver disease</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Endocrinologic issues</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Premature puberty &/or adult-onset diabetes mellitus</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genitourinary findings</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Impairment in balance</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_2 hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_myhre.T.myhre_syndrome_frequency_of_sele_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; GI = gastrointestinal; HSCR = Hirschsprung disease; Ig = immunoglobulin; VPI = velopharyngeal insufficiency</p></div></dd><dt>1. </dt><dd><div id="myhre.TF.2.1"><p class="no_margin">Length or height that is more than two standard deviations below the mean for age and sex.</p></div></dd><dt>2. </dt><dd><div id="myhre.TF.2.2"><p class="no_margin">Short stature is more common in those whose <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> involves codon 500 (see <a href="#myhre.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>).</p></div></dd><dt>3. </dt><dd><div id="myhre.TF.2.3"><p class="no_margin">Usually unresponsive to bronchodilator therapy</p></div></dd><dt>4. </dt><dd><div id="myhre.TF.2.4"><p class="no_margin">Typically due to a restrictive thorax</p></div></dd></dl></div></div></div><p><b>Craniofacial.</b> The craniofacial features of Myhre syndrome (see <a class="figpopup" href="/books/NBK425723/figure/myhre.F1/?report=objectonly" target="object" rid-figpopup="figmyhreF1" rid-ob="figobmyhreF1">Figures 1</a>, <a class="figpopup" href="/books/NBK425723/figure/myhre.F2/?report=objectonly" target="object" rid-figpopup="figmyhreF2" rid-ob="figobmyhreF2">2</a>, <a class="figpopup" href="/books/NBK425723/figure/myhre.F3/?report=objectonly" target="object" rid-figpopup="figmyhreF3" rid-ob="figobmyhreF3">3</a>, <a class="figpopup" href="/books/NBK425723/figure/myhre.F4/?report=objectonly" target="object" rid-figpopup="figmyhreF4" rid-ob="figobmyhreF4">4</a>, <a class="figpopup" href="/books/NBK425723/figure/myhre.F5/?report=objectonly" target="object" rid-figpopup="figmyhreF5" rid-ob="figobmyhreF5">5</a>, and <a class="figpopup" href="/books/NBK425723/figure/myhre.F6/?report=objectonly" target="object" rid-figpopup="figmyhreF6" rid-ob="figobmyhreF6">6</a>) can vary considerably and progress over time (see also Figure 5 in <a class="bk_pop" href="#myhre.REF.lin.2024.e63638">Lin et al [2024]</a>), which make the features more apparent in older individuals. Although classic coarsening of features is not present, mandibular prominence is notable and attributed to disharmonic maxillary/mandibular growth. Facial features typically also include:</p><ul><li class="half_rhythm"><div>Short palpebral fissures (See <a class="figpopup" href="/books/NBK425723/figure/myhre.F4/?report=objectonly" target="object" rid-figpopup="figmyhreF4" rid-ob="figobmyhreF4">Figure 4</a>.)</div></li><li class="half_rhythm"><div>Deeply set eyes</div></li><li class="half_rhythm"><div>Maxillary underdevelopment</div></li><li class="half_rhythm"><div>Short philtrum</div></li><li class="half_rhythm"><div>Narrow mouth</div></li><li class="half_rhythm"><div>Thin vermilion of the upper lip (See <a class="figpopup" href="/books/NBK425723/figure/myhre.F3/?report=objectonly" target="object" rid-figpopup="figmyhreF3" rid-ob="figobmyhreF3">Figure 3</a>.)</div></li><li class="half_rhythm"><div>Small and/or widely spaced teeth</div></li><li class="half_rhythm"><div>Prognathism</div></li></ul><p>While cleft lip and palate is rare, velopharyngeal insufficiency is common.</p><p><b>Developmental delay and intellectual disability.</b> Mild-to-moderate developmental delay and intellectual disability are common. Cognition can be within the normal range, although this is not the most common outcome. Delayed speech can be significant. Most affected individuals are ultimately verbal, using verbal communication as their primary means of communication, although some remain essentially nonverbal. Most affected individuals are supported by parents and under guardianship of their parents. Activities of daily living are achieved by many adults, although delayed toilet training and hygiene (e.g., bathing, dental care, menstrual assistance) can be a challenge to independence. Less commonly, affected individuals have attended college (generally smaller schools or two-year programs that provide accommodations for individuals with learning challenges). Several adults have been employed, have a partner, reproduced, and engaged in recreational activities such as musical theater, singing, and writing.</p><p>
|
||
<b>Other neurodevelopmental features</b>
|
||
</p><ul><li class="half_rhythm"><div><b>Abnormalities of tone</b> can include low truncal tone (hypotonia) transitioning to high tone (hypertonia).</div></li><li class="half_rhythm"><div><b>Tiptoe walking</b> is observed often, but not well understood. In many children, it is viewed as an autism spectrum disorder behavior. In a few affected individuals, MRI imaging shows a form of tethered cord (rarely, classic) for which surgery is performed (see <a href="#myhre.Management">Management</a>).</div></li><li class="half_rhythm"><div><b>Balance issues</b> are attributed to lack of general fitness and stiff joints.</div></li><li class="half_rhythm"><div><b>Epilepsy</b> is not common. Some affected individuals have had abnormal movements and staring spells, during which EEG was either not completed or was normal.</div></li></ul><p><b>Neurobehavioral/psychiatric.</b> Autism spectrum disorder (ASD) has been noted in 40%-70% of affected individuals and may range from mild social disability to severe autism. Attention-deficit/hyperactivity disorder (ADHD) and anxiety have also been observed in affected individuals. Psychosis has been rarely observed.</p><p><b>Neuroimaging.</b> When performed, brain MRI has commonly found white matter hyperintensities, which are better characterized as white matter injury related to intrinsic cerebral microvasculopathy and not true external injury or birth trauma.</p><p><b>Growth.</b> Intrauterine growth restriction (IUGR) has been found during the pregnancies of the majority of affected infants. Short stature with compact body habitus (with normal head circumference) becomes more apparent over time.</p><ul><li class="half_rhythm"><div>Most affected individuals have shortened long bones.</div></li><li class="half_rhythm"><div>Adult height is expected to be more than two standard deviations below what is predicted by parental heights in more than 80% of affected individuals, particularly in those who have a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> at codon position 500 (see <a href="#myhre.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>).</div></li><li class="half_rhythm"><div>Although head circumference is rarely greater than or equal to two standard deviations above the mean for age and sex, it is commonly proportionally greater than height ("relative macrocephaly").</div></li><li class="half_rhythm"><div>Although Myhre syndrome-specific growth charts have not been developed, growth is expected to be at the lower end or below the typical growth charts for weight and length/height for infants and children.</div></li><li class="half_rhythm"><div>Overweight (BMI >25, or >99th centile) may begin in adolescence and is found in most adults.</div></li></ul><p><b>Gastrointestinal/feeding.</b> Many infants and children have difficulty with poor feeding and weight gain and some may benefit from a feeding tube (see <b>Growth</b> in this section and <a href="#myhre.Management">Management</a>). Other gastrointestinal findings may include:</p><ul><li class="half_rhythm"><div>Choking, coughing, and/or dysphagia</div></li><li class="half_rhythm"><div>Mild-to-severe constipation</div></li><li class="half_rhythm"><div>Duodenal atresia</div></li><li class="half_rhythm"><div>Late-onset and <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> pyloric stenosis; less commonly stenosis may involve the duodenum, jejunum, and anus.</div></li><li class="half_rhythm"><div>Protein-losing enteropathy associated with right heart failure and restrictive cardiomyopathy (Patient 1 in <a class="bk_pop" href="#myhre.REF.lin.2016.2617">Lin et al [2016]</a>)</div></li><li class="half_rhythm"><div>Hirschsprung disease</div></li><li class="half_rhythm"><div>Abnormal liver function tests can suggest a pattern of metabolic dysfunction-associated steatotic liver disease (MASLD); however, this is an emerging observation.</div></li></ul><p><b>Cardiovascular.</b> Progressive cardiovascular issues can appear at any age; those with onset in childhood may worsen following instrumentation. Two affected individuals with restrictive cardiomyopathy (which is rare) who were treated with heart and heart/lung transplantation did not survive due to postoperative complications [<a class="bk_pop" href="#myhre.REF.starr.2015.2893">Starr et al 2015</a>], and thus, transplantation has not been used in other reported affected individuals.</p><p>In 47 individuals with confirmed Myhre syndrome evaluated at Massachusetts General Hospital [<a class="bk_pop" href="#myhre.REF.lin.2024.e63638">Lin et al 2024</a>], 77% had a cardiovascular abnormality including structural heart defects (47%), mild long-segment aorta hypoplasia (60%), systemic hypertension (38%), moderate-to-severe narrowing including coarctation (21%), additional arterial stenoses (13%), pericardial disease (13%), and restrictive cardiomyopathy (4%).</p><ul><li class="half_rhythm"><div><b>Congenital cardiovascular abnormalities</b> can include the following:</div><ul><li class="half_rhythm"><div>Atrial septal defect or ventricular septal defect</div></li><li class="half_rhythm"><div>Patent ductus arteriosus</div></li><li class="half_rhythm"><div>Tetralogy of Fallot</div></li><li class="half_rhythm"><div>Obstructive defects of the left heart, such as juxtaductal aortic coarctation, long-segment aortic narrowing, aortic valve stenosis, mitral valve stenosis, and multiple levels of obstruction. These are more common than obstructive defects of the right side, such as valvar and branch pulmonary artery stenosis.</div></li><li class="half_rhythm"><div>Visceral vascular stenoses (in celiac, superior mesenteric, inferior mesenteric, and/or renal arteries)</div></li></ul></li><li class="half_rhythm"><div><b>Pericardial disease</b> can present as short-term or recurrent effusions, or as chronic or progressive constrictive pericarditis that may require surgical intervention (see <a href="#myhre.Management">Management</a>).</div><ul><li class="half_rhythm"><div>Restrictive cardiomyopathy, a lethal condition, can be difficult to diagnose without cardiac catheterization to assess hemodynamics.</div></li><li class="half_rhythm"><div>While constrictive pericarditis and restrictive cardiomyopathy can present with similar hemodynamic impairment, they differ in their pathogenesis and treatment (see <a href="#myhre.Management">Management</a>).</div></li></ul></li><li class="half_rhythm"><div><b>Pulmonary hypertension,</b> either primary or as a result of left ventricular dysfunction, has been infrequently reported; however, this may reflect limited evaluation and/or bias toward ascertainment and/or reporting of younger affected individuals (as underlying causes of pulmonary hypertension resulting from involvement of the lungs and cardiovascular circulation may evolve with age). It is unknown how often this is secondary to right-sided cardiac dysfunction or severe left-sided obstruction, although both have been observed.</div></li></ul><p><b>Respiratory.</b> Respiratory findings are usually <a class="def" href="/books/n/gene/glossary/def-item/multifactorial/">multifactorial</a>. The cause of multilevel airway stenosis ranging from the choanae distally to include laryngotracheal narrowing, subglottic stenosis (ranging from mild to complete), and the bronchi is unknown. There may be a <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> predisposition, which is exacerbated by trauma or infection. However, many children have had numerous intubations without developing "traumatic" stenosis. There can be mild stridor and croup in childhood, which rarely progresses to a severe multilevel form. Upper airway obstruction caused by choanal stenosis progressing to atresia is rare and a dramatic manifestation of airway occlusion from the proliferative process.</p><p>Other findings can include the following:</p><ul><li class="half_rhythm"><div>Restrictive pulmonary disease, often associated with restrictive thorax</div></li><li class="half_rhythm"><div>"Asthma" that does not always respond to bronchodilator therapy, as in typical reactive airway disease</div></li><li class="half_rhythm"><div>Interstitial lung disease and severe pulmonary fibrosis on autopsy [<a class="bk_pop" href="#myhre.REF.starr.2022.611">Starr et al 2022</a>].</div></li><li class="half_rhythm"><div>Abnormal sleep, most often associated with autism. In some instances, a sleep study may reveal obstructive sleep apnea.</div></li><li class="half_rhythm"><div>Sleep apnea</div></li></ul><p><b>Immune system.</b> The precise immunologic profile in people with Myhre syndrome has not been fully studied. Increased frequency of infections involving the respiratory tract (including otitis media, sinusitis, mastoiditis, or croup) has been reported and may result from mechanical factors. For example, ear canals, sinuses, and mastoid cells may be opacified from proliferative debris. Compromised innate immunity originating from epithelial cells may contribute to increased susceptibility to upper respiratory tract infections [<a class="bk_pop" href="#myhre.REF.lindsay.2024">Lindsay et al 2024</a>]. Serum immunoglobulin (Ig) G and IgA deficiency have been noted in a small number of affected individuals [<a class="bk_pop" href="#myhre.REF.lin.2024.e63638">Lin et al 2024</a>]. Intravenous Ig was utilized with reported benefit in at least two affected individuals [<a class="bk_pop" href="#myhre.REF.lin.2024.e63638">Lin et al 2024</a>] (see <a href="#myhre.Management">Management</a>).</p><p><b>Cutaneous and serosal findings.</b> Thick, firm skin is seen in nearly all individuals with Myhre syndrome, and stiffness may progress in many adults. Various terms used to describe the skin include thick, stiff, firm, rough, hyperkeratotic, and inelastic. Skin changes may not be apparent in infancy; they are often first noted on the extensor surfaces, palms, and soles. The changes progress with age. Additional skin findings include minimal creasing of the facial skin and unusual white linear scars.</p><p>Proliferative fibrosis / abnormal scarring can occur following trauma or surgery. Some individuals develop hypertrophic, keloid-like scars. In addition to the skin, proliferation can also involve the large airways (trachea and bronchi) and the serosal surfaces of the heart, lungs, and peritoneum.</p><p><b>Musculoskeletal.</b> Reduced range of motion of large and small joints is characteristic of Myhre syndrome and is exacerbated with age. Posture may be distinct, with flexed elbows and bending forward at the hips (see <a class="bk_pop" href="#myhre.REF.ishibashi.2014.300">Ishibashi et al [2014]</a>, Figure 1). Other features that may be present include:</p><ul><li class="half_rhythm"><div>Small hands and feet with brachydactyly, found in most individuals (See <a class="figpopup" href="/books/NBK425723/figure/myhre.F3/?report=objectonly" target="object" rid-figpopup="figmyhreF3" rid-ob="figobmyhreF3">Figures 3</a> and <a class="figpopup" href="/books/NBK425723/figure/myhre.F4/?report=objectonly" target="object" rid-figpopup="figmyhreF4" rid-ob="figobmyhreF4">4</a>.)</div></li><li class="half_rhythm"><div>Clinodactyly</div></li><li class="half_rhythm"><div>Syndactyly of the toes, usually 2-3</div></li><li class="half_rhythm"><div>Scoliosis</div></li><li class="half_rhythm"><div>Absence of normal lumbar lordosis and straight spine</div></li><li class="half_rhythm"><div>Sacral dimple, sometimes associated with a tethered spinal cord</div></li><li class="half_rhythm"><div>Bony fractures, which may be associated with childhood activities and/or trauma</div></li><li class="half_rhythm"><div>Leg pain involving the calf, which can be severe. Pain is not relieved with standard analgesics and is poorly understood. It can be associated with lower spinal cord compression.</div></li></ul><p>Characteristic radiographic findings in affected individuals are listed in <a href="#myhre.Suggestive_Findings">Suggestive Findings</a>.</p><p><b>Ophthalmologic.</b> Refractive errors are common and usually include hyperopia with astigmatism. Other findings may include strabismus, cataracts, corectopia, and optic nerve anomalies. Nasolacrimal duct stenosis or atresia is common and may be difficult to manage due to recurrent stenosis related to progressive fibrosis.</p><p><b>Hearing.</b> Hearing loss is observed in most individuals with Myhre syndrome. Most newborns pass their neonatal hearing screen; hearing loss usually becomes evident in early childhood to late teens.</p><ul><li class="half_rhythm"><div>Hearing loss is predominantly conductive or mixed; affected individuals most often have a history of bilateral myringotomy tube placement.</div></li><li class="half_rhythm"><div>The underlying etiology of the hearing loss is often unclear or unknown and may require inner ear imaging to diagnose structural anomalies, although this is thought to be rare.</div></li></ul><p><b>Endocrine.</b> Endocrine findings may include premature puberty (reported in both sexes), early menarche, meno- or metrorrhagia, and macromastia, the latter prompting reduction mammoplasty in some. Both premature ovarian failure and secondary amenorrhea have been observed.</p><p>Glucose intolerance in adults may be more common than the few reports of diabetes. One teenage girl had hyperinsulinism and an impaired glucose tolerance test, which may indicate insulin resistance [<a class="bk_pop" href="#myhre.REF.kilci.2022.42">Kilci et al 2022</a>].</p><p><b>Genitourinary.</b> Genitourinary findings are infrequent but have included mild hypospadias and undescended testes in males.</p><p><b>Neoplasia.</b> Since a report of neoplasia in six individuals with Myhre syndrome (3 of whom were women with endometrial cancer) [<a class="bk_pop" href="#myhre.REF.lin.2020.328">Lin et al 2020</a>], there have been no additional reports of affected individuals with neoplasia. Anecdotally, there are additional cases, including one further person with endometrial cancer and two with hypothalamic hamartoma.</p></div><div id="myhre.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>Genotype-<a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> correlations are still emerging [<a class="bk_pop" href="#myhre.REF.yang.2022.304">Yang et al 2022</a>, <a class="bk_pop" href="#myhre.REF.lin.2024.e63638">Lin et al 2024</a>] with a detailed analysis in adults [<a class="bk_pop" href="#myhre.REF.vanbelleghem.2024.1086">Vanbelleghem et al 2024</a>].</p><p><a href="/books/NBK425723/table/myhre.T.smad4_pathogenic_variants_refere/?report=objectonly" target="object" rid-ob="figobmyhreTsmad4pathogenicvariantsrefere"><b>c.1498A>G (p.Ile500Val)</b></a><b>.</b> Based on limited data, individuals with the highly recurrent c.1498A>G (p.Ile500Val) <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> are more likely to have prenatal growth deficiency with postnatal short stature and severe aortic obstruction.</p><p><a href="/books/NBK425723/table/myhre.T.smad4_pathogenic_variants_refere/?report=objectonly" target="object" rid-ob="figobmyhreTsmad4pathogenicvariantsrefere"><b>c.1486C>T (p.Arg496Cys)</b></a><b>.</b> Individuals with the c.1486C>T (p.Arg496Cys) <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> are more likely to have a height within the normal range for age and sex. Females with this pathogenic variant are more likely to have premature puberty and heavy menses (see <a href="#myhre.Management">Management</a>). Of the six individuals reported with neoplasia, three were women with endometrial cancer, two of whom were <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for the c.1486C>T (p.Arg496Cys) pathogenic variant. To date, all known affected individuals who have developed seizures have had this specific pathogenic variant.</p></div><div id="myhre.Nomenclature"><h3>Nomenclature</h3><p>In the 2023 revision of the Nosology of Genetic Skeletal Disorders [<a class="bk_pop" href="#myhre.REF.unger.2023.1164">Unger et al 2023</a>], Myhre syndrome is referred to as <i>SMAD4</i>-related Myhre dysplasia and included in the acromelic dysplasias group [<a href="/books/NBK425723/table/myhre.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobmyhreTmoleculargenetictestingusedi">Table 1</a> in <a class="bk_pop" href="#myhre.REF.costantini.2023.225">Costantini et al 2023</a>].</p><p>LAPS (<i>l</i>aryngotracheal stenosis, <i>a</i>rthropathy, <i>p</i>rognathism, and <i>s</i>hort stature) syndrome was determined to be allelic to Myhre syndrome with pathogenic variants in the same codons [<a class="bk_pop" href="#myhre.REF.lindor.2012.1520">Lindor et al 2012</a>, <a class="bk_pop" href="#myhre.REF.picco.2013.1164">Picco et al 2013</a>, <a class="bk_pop" href="#myhre.REF.michot.2014.1272">Michot et al 2014</a>] (see <a href="#myhre.Genetically_Related_Allelic_Disord">Genetically Related Disorders</a>); the term is no longer in use.</p></div><div id="myhre.Prevalence"><h3>Prevalence</h3><p>The prevalence of Myhre syndrome is unknown. A rough estimate of the prevalence is 1:900,000 individuals.</p></div></div><div id="myhre.Genetically_Related_Allelic_Disord"><h2 id="_myhre_Genetically_Related_Allelic_Disord_">Genetically Related (Allelic) Disorders</h2><p>Other phenotypes known to be associated with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> pathogenic variants in <i>SMAD4</i> are listed in <a href="/books/NBK425723/table/myhre.T.smad4_allelic_disorders/?report=objectonly" target="object" rid-ob="figobmyhreTsmad4allelicdisorders">Table 3</a>.</p><div id="myhre.T.smad4_allelic_disorders" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p><i>SMAD4</i> Allelic Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK425723/table/myhre.T.smad4_allelic_disorders/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myhre.T.smad4_allelic_disorders_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_myhre.T.smad4_allelic_disorders_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_myhre.T.smad4_allelic_disorders_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_myhre.T.smad4_allelic_disorders_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Class of Variants</th></tr></thead><tbody><tr><td headers="hd_h_myhre.T.smad4_allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/jps/">Juvenile polyposis syndrome</a> (JPS)</td><td headers="hd_h_myhre.T.smad4_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_myhre.T.smad4_allelic_disorders_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Loss of function</td></tr><tr><td headers="hd_h_myhre.T.smad4_allelic_disorders_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/hht/">Hereditary hemorrhagic telangiectasia</a> (HHT) <sup>1</sup></td><td headers="hd_h_myhre.T.smad4_allelic_disorders_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_myhre.T.smad4_allelic_disorders_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Loss of function</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a></p></div></dd><dt>1. </dt><dd><div id="myhre.TF.3.1"><p class="no_margin">Hereditary hemorrhagic telangiectasia (HHT) and Myhre syndrome have opposing phenotypes consistent with <i>SMAD4</i> loss of function and gain of function, respectively [<a class="bk_pop" href="#myhre.REF.gheewalla.2022.3084">Gheewalla et al 2022</a>]. Telangiectasias and juvenile polyps, reported in heterozygotes for a <i>SMAD4</i> <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, have not been reported in people with Myhre syndrome.</p></div></dd></dl></div></div></div><p><b>Sporadic tumors</b> (including colorectal cancer and pancreatic tumors) occurring as single tumors in the absence of any other findings of Myhre syndrome frequently contain a somatic variant in <i>SMAD4</i> that is not present in the <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> [<a class="bk_pop" href="#myhre.REF.chen.2014.181">Chen et al 2014</a>]. In these circumstances predisposition to these tumors is not heritable. See <a href="#myhre.Molecular_Pathogenesis">Molecular Pathogenesis</a>, <b>Cancer and benign tumors</b>.</p></div><div id="myhre.Differential_Diagnosis"><h2 id="_myhre_Differential_Diagnosis_">Differential Diagnosis</h2><p>The disorders that most closely resemble Myhre syndrome are the other acromelic dysplasias – geleophysic dysplasia, acromicric dysplasia, and Weill-Marchesani syndrome – which share the findings of thickened skin, short stature, short hands, and stiff joints [<a class="bk_pop" href="#myhre.REF.costantini.2023.225">Costantini et al 2023</a>]. <a href="/books/NBK425723/table/myhre.T.disorders_of_interest_in_the_dif/?report=objectonly" target="object" rid-ob="figobmyhreTdisordersofinterestinthedif">Table 4</a> lists these and other syndromes that have more limited overlapping features.</p><div id="myhre.T.disorders_of_interest_in_the_dif" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Disorders of Interest in the Differential Diagnosis of Myhre Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK425723/table/myhre.T.disorders_of_interest_in_the_dif/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myhre.T.disorders_of_interest_in_the_dif_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_2" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Clinical Features of Disorder</th></tr><tr><th headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_4" id="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/Myhre syndrome</th><th headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_4" id="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from Myhre syndrome</th></tr></thead><tbody><tr><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ADAMTS10</i>
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<br />
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<i>ADAMTS17</i>
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<br />
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<i>FBN1</i>
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<br />
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<i>LTPBP2</i>
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</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/weill-ms/">Weill-Marchesani syndrome</a>
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</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />AD</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_4 hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>IUGR</div></li><li class="half_rhythm"><div>Short stature</div></li><li class="half_rhythm"><div>Brachydactyly</div></li><li class="half_rhythm"><div>Joint stiffness</div></li></ul>
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</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_4 hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Distinctive lens abnormalities <sup>1</sup></div></li><li class="half_rhythm"><div>No hearing loss</div></li></ul>
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</td></tr><tr><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ADAMTSL2</i>
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<br />
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<i>FBN1</i>
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<br />
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<i>LTBP3</i>
|
||
</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/geleophys-dysp/">Geleophysic dysplasia</a> <sup>2</sup></td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />AD</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_4 hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>IUGR</div></li><li class="half_rhythm"><div>Short stature</div></li><li class="half_rhythm"><div>Short hands & feet</div></li><li class="half_rhythm"><div>Progressive joint limitation & contractures</div></li><li class="half_rhythm"><div>Progressive cardiac valvar thickening</div></li><li class="half_rhythm"><div>Thickened skin</div></li></ul>
|
||
</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_4 hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hepatomegaly</div></li><li class="half_rhythm"><div>Distinctive facial features</div></li><li class="half_rhythm"><div>Delayed bone age</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>FBN1</i>
|
||
<br />
|
||
<i>LTBP3</i>
|
||
</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>FBN1-</i>related acromicric dysplasia (OMIM <a href="https://omim.org/entry/102370" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">102370</a>) & <i>LTBP3-</i>related acromicric dysplasia <sup>3</sup></td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_4 hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>IUGR</div></li><li class="half_rhythm"><div>Short stature</div></li><li class="half_rhythm"><div>Brachydactyly</div></li><li class="half_rhythm"><div>Joint stiffness</div></li><li class="half_rhythm"><div>Thickened skin</div></li></ul>
|
||
</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_4 hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Characteristic external notch of 5th metacarpal & internal notch of femoral head</div></li><li class="half_rhythm"><div>No hearing loss</div></li><li class="half_rhythm"><div>Less frequent <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> cardiac anomalies</div></li><li class="half_rhythm"><div>No calvarial thickening</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>FBN1</i>
|
||
</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Stiff skin syndrome (OMM <a href="https://omim.org/entry/184900" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">184900</a>)</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_4 hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Stiff skin</div></li><li class="half_rhythm"><div>Stiff joints</div></li></ul>
|
||
</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_4 hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Skin has rock-hard involvement.</div></li><li class="half_rhythm"><div>Not <a class="def" href="/books/n/gene/glossary/def-item/dysmorphic/">dysmorphic</a></div></li><li class="half_rhythm"><div>Few cardiovascular features</div></li><li class="half_rhythm"><div>No calvarial thickening</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TRIM37</i>
|
||
</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MULIBREY nanism (OMIM <a href="https://omim.org/entry/253250" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">253250</a>)</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_4 hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>IUGR</div></li><li class="half_rhythm"><div>Short stature</div></li><li class="half_rhythm"><div>Relatively large head</div></li><li class="half_rhythm"><div>Constrictive pericarditis</div></li><li class="half_rhythm"><div>Restrictive cardiomyopathy</div></li><li class="half_rhythm"><div>Hearing loss</div></li></ul>
|
||
</td><td headers="hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_1_4 hd_h_myhre.T.disorders_of_interest_in_the_dif_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Shorter stature</div></li><li class="half_rhythm"><div>Small tongue</div></li><li class="half_rhythm"><div>No calvarial thickening</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; IUGR = intrauterine growth restriction; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a></p></div></dd><dt>1. </dt><dd><div id="myhre.TF.4.1"><p class="no_margin">The ocular manifestations of Weill-Marchesani syndrome, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness.</p></div></dd><dt>2. </dt><dd><div id="myhre.TF.4.2"><p class="no_margin">Major findings are likely to be present in the first year of life. Cardiac, airway, and pulmonary involvement result in death before age five years in approximately 33% of individuals with geleophysic dysplasia.</p></div></dd><dt>3. </dt><dd><div id="myhre.TF.4.3"><p class="no_margin">
|
||
<a class="bk_pop" href="#myhre.REF.mcinerneyleo.2016.457">McInerney-Leo et al [2016]</a>
|
||
</p></div></dd></dl></div></div></div></div><div id="myhre.Management"><h2 id="_myhre_Management_">Management</h2><p>Although formal evidence-based clinical management guidelines for Myhre syndrome have not yet been published, expert consensus recommendations provide pragmatic clinical guidance (Table 5 in <a class="bk_pop" href="#myhre.REF.lin.2024.e63638">Lin et al [2024]</a> and Table 2 in <a class="bk_pop" href="#myhre.REF.vanbelleghem.2024.1086">Vanbelleghem et al [2024]</a>).</p><div id="myhre.Evaluations_Following_Initial_Diag"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with Myhre syndrome, the evaluations summarized in <a href="/books/NBK425723/table/myhre.T.myhre_syndrome_recommended_evalu/?report=objectonly" target="object" rid-ob="figobmyhreTmyhresyndromerecommendedevalu">Table 5</a> (if not completed previously as part of the diagnostic evaluation) are recommended.</p><div id="myhre.T.myhre_syndrome_recommended_evalu" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Myhre Syndrome: Recommended Evaluations Following Initial Diagnosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK425723/table/myhre.T.myhre_syndrome_recommended_evalu/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myhre.T.myhre_syndrome_recommended_evalu_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_myhre.T.myhre_syndrome_recommended_evalu_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_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Constitutional</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of growth parameters</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for short stature & either growth restriction in younger persons or obesity in older persons</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Craniofacial</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Physical exam for evidence of cleft lip & palate</div></li><li class="half_rhythm"><div>Assessment for velopharyngeal insufficiency</div></li></ul>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If present, consider referral to multidisciplinary craniofacial center, which may also evaluate progressive mandibular overgrowth ("prognathism").</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Developmental</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_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 evals</div></li><li class="half_rhythm"><div>Eval for early intervention / special education, ABA therapy</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurobehavioral/</b>
|
||
<br />
|
||
<b>Psychiatric</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider neuropsychologic & psychiatric assessments based on age.</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In persons age >12 months: screen for concerns incl sleep disturbances, anxiety, &/or findings suggestive of ASD; assessment for features of ADHD & psychiatric issues in older persons</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiovascular</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of upper & lower extremity blood pressure</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To assess for aortic obstruction & systemic hypertension</div></li><li class="half_rhythm"><div>Consider referral to nephrologist for those w/systemic hypertension.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">2D echocardiography w/Doppler</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for structural heart disease, vasculopathy, & cardiac function; if abnormal, refer to cardiologist.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">CT angiogram or MRA of aorta</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>In children who are able to complete procedure w/o anesthesia (age 5-10 yrs) or if there is hypertension</div></li><li class="half_rhythm"><div>Cardiac catheterization may be indicated to document characteristic hemodynamics of restrictive cardiomyopathy & pulmonary hypertension.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Respiratory</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for airway stenosis by least invasive means possible.</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Auscultation & observation w/ & w/o activity for signs of upper airway obstruction incl noisy breathing, work of breathing, & oxygen saturation.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Consider assessment of pulmonary function, oxygen saturation levels, 3- and 6-minute walk test, <sup>1</sup> & impulse oscillometry (when available).</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for obstructive &/or restrictive lung disease</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Consider polysomnography.</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For sleep disturbance & obstruction</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Immunologic</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Quantitative serum Ig to assess for Ig deficiency in those w/excessive infections or who are of school age or older</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If abnormal, consider referral to immunologist.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Integument</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dermatologic eval</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for hyperkeratosis pilaris & abnormal scarring.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics / physical medicine & rehab / PT & OT eval</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To include assessment of:
|
||
<ul><li class="half_rhythm"><div>Gross motor & fine motor skills</div></li><li class="half_rhythm"><div>↓ range of motion of joints (OT modifications may be indicated.)</div></li><li class="half_rhythm"><div>Mobility, ADL, & need for adaptive devices</div></li><li class="half_rhythm"><div>Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Consider skeletal survey.</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for bony anomalies</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Assess for history of frequent bony fractures.</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to orthopedist &/or endocrinologist.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Eyes</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic eval</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To assess for strabismus, refractive error, & cataracts</div></li><li class="half_rhythm"><div>Give special attention to optic nerve.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hearing</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologic eval</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assess for degree & type of hearing loss.</div></li><li class="half_rhythm"><div>Newborn hearing screen may be normal; low threshold for repeat testing.</div></li><li class="half_rhythm"><div>Consider inner ear imaging for those w/hearing loss.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment for recurrent vomiting & chronic constipation</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low threshold to image for concern of pyloric or other stenosis of GI tract. <sup>2, 3</sup></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Assessment for signs/symptoms of protein-losing enteropathy & metabolic dysfunction-assoc liver disease</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Obtain baseline serum laboratory tests. <sup>4</sup></div></li><li class="half_rhythm"><div>Consider standard coagulation tests.</div></li><li class="half_rhythm"><div>Evaluate cardiovascular hemodynamics under care of cardiologist & liver specialist.</div></li><li class="half_rhythm"><div>Consider referral to GI specialist.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Endocrinologic</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluate for pubertal status in children & adolescents, & for signs/symptoms of menstrual irregularities & macromastia in females.</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for premature puberty (in both sexes), premature ovarian failure, menorrhagia, & secondary amenorrhea</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Assess for signs/symptoms of insulin-dependent diabetes. <sup>5</sup></td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">More common in older adults</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Monitor onset of menses & assess for dysfunctional uterine bleeding. <sup>6</sup></td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/endocrinologist & gynecologist</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genitourinary</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical exam for cryptorchidism & hypospadias in males</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to urologist.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Renal ultrasound w/Doppler <sup>7</sup></td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for renal anomalies & renal artery stenosis</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider brain MRI & EEG if seizures are a concern.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic</b>
|
||
<br />
|
||
<b>counseling</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>8</sup></td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To obtain a <a class="def" href="/books/n/gene/glossary/def-item/pedigree/">pedigree</a> & inform affected persons & their families re nature, MOI, & implications of Myhre syndrome to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family support</b>
|
||
<br />
|
||
<b>& resources</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Myhre Syndrome Foundation (MSF)</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_evalu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assess need for social work involvement for parental support.</div></li><li class="half_rhythm"><div>Consider palliative care counseling to support family & affected person when there are serious complications (e.g., cardiopulmonary, airway, or neoplastic involvement).</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ABA = applied behavior analysis; ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; GI = gastrointestinal; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; MRA = magnetic resonance angiography; OT = occupational therapy; PT = physical therapy</p></div></dd><dt>1. </dt><dd><div id="myhre.TF.5.1"><p class="no_margin">When a person is old enough to cooperate with this evaluation.</p></div></dd><dt>2. </dt><dd><div id="myhre.TF.5.2"><p class="no_margin">Intestinal obstruction may contribute to constipation.</p></div></dd><dt>3. </dt><dd><div id="myhre.TF.5.3"><p class="no_margin">Hirschsprung disease has been reported.</p></div></dd><dt>4. </dt><dd><div id="myhre.TF.5.4"><p class="no_margin">Basic chemistry and liver function tests (AST, ALT, etc.), with consideration of adding albumin and total protein in those who have protein-losing enteropathy</p></div></dd><dt>5. </dt><dd><div id="myhre.TF.5.5"><p class="no_margin">Consider obtaining a hemoglobin A1c in those with suggestive signs/symptoms or as a baseline in adolescents and adults.</p></div></dd><dt>6. </dt><dd><div id="myhre.TF.5.6"><p class="no_margin">Which could suggest endometrial cancer</p></div></dd><dt>7. </dt><dd><div id="myhre.TF.5.7"><p class="no_margin">Consider obtaining kidney function tests, such as electrolytes, blood urea nitrogen, creatinine, and cystatin C in those with hypertension or renal artery stenosis.</p></div></dd><dt>8. </dt><dd><div id="myhre.TF.5.8"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="myhre.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>There is no cure for Myhre syndrome. Supportive care to improve quality of life, maximize function, and reduce complications is recommended, ideally involving multidisciplinary care by specialists in relevant fields (see <a href="/books/NBK425723/table/myhre.T.myhre_syndrome_treatment_of_mani/?report=objectonly" target="object" rid-ob="figobmyhreTmyhresyndrometreatmentofmani">Table 6</a>).</p><div id="myhre.T.myhre_syndrome_treatment_of_mani" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Myhre Syndrome: Treatment of Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK425723/table/myhre.T.myhre_syndrome_treatment_of_mani/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myhre.T.myhre_syndrome_treatment_of_mani_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Poor weight gain /</b>
|
||
<br />
|
||
<b>Feeding difficulties</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Feeding therapy</div></li><li class="half_rhythm"><div>Gastrostomy tube placement may be required for persistent feeding issues.</div></li></ul>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs/symptoms of dysphagia</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Obesity</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to nutritionist for interventions.</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May be difficult to manage</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Orofacial clefting /</b>
|
||
<br />
|
||
<b>Velopharyngeal</b>
|
||
<br />
|
||
<b>insufficiency</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment, ideally by craniofacial team</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multidisciplinary teams may incl surgical team (craniofacial surgeon), clinical geneticist, otolaryngologist, pediatrician, radiologist, psychologist, multiple dental specialists, audiologist, speech therapist, & social worker.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Short stature</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Growth hormone therapy is <b>not</b> currently recommended.</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">There is no systematic study of growth hormone treatment in Myhre syndrome. <sup>1</sup></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Developmental delay /</b>
|
||
<br />
|
||
<b>Intellectual disability /</b>
|
||
<br />
|
||
<b>Neurobehavioral issues</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#myhre.Developmental_Delay__Intellectual">Developmental Delay / Intellectual Disability Management Issues</a>.</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Congenital heart defects / Pericardial disease / Myocardial disease</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment by cardiologist trained in <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> heart disease, pericardial disease, & restrictive cardiomyopathy <sup>2</sup></td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Avoid any unnecessary instrumentation, as assoc tissue trauma may induce stenosis & scarring-type tissue response.</div></li><li class="half_rhythm"><div>Affected persons who are in heart failure should be under care of cardiovascular specialist w/access to transplant center. Cardiac & lung transplantation are assoc w/high risk of mortality.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Systemic/pulmonary hypertension</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Medical therapy based on underlying cause</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Complete or recurrent tracheal stenosis</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider balloon dilation; long-term tracheostomy can also be considered. <sup>3</sup></td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Tracheal resection is contraindicated. <sup>4</sup></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Anesthesia</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To avoid traumatic intubation, consider using smaller-size, uncuffed endotracheal tube.</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Elective tracheal surgery/intubation should be avoided but can be managed w/preoperative multidisciplinary discussion when necessary (see <a href="#myhre.AgentsCircumstances_to_Avoid">Agents/Circumstances to Avoid</a>).</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Restrictive lung disease</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Symptomatic & standard treatment per pulmonologist</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Oxygen supplementation as necessary</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Sleep apnea</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment per sleep specialist</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May incl use of CPAP, BiPAP, or oxygen supplementation</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Immunodeficiency</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per immunologist</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May incl IVIG therapy <sup>5</sup></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Keloids</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Some keloids can be treated w/intralesional steroids.</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Minimal invasiveness for lesion removal</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Decreased range of motion of joints</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical therapy</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">It is not known if passive range of motion exercises help maintain flexibility; however, physical activity to maintain conditioning is encouraged.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Tiptoe walking</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthotics may be recommended by orthopedic consultants, but adherence is not always achieved.</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For those w/o tethered cord</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Tethered spinal cord</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per neurosurgeon</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Frequent fractures</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per orthopedist</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No special treatment or preventive therapy is currently known to be effective.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Strabismus / Refractive error / Cataracts</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment(s) as recommended by ophthalmologist</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Optic nerve abnormalities</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmic subspecialist may be appropriate.</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Low vision services</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Children: through early intervention programs &/or school district</div></li><li class="half_rhythm"><div>Adults: low vision clinic &/or community vision services / OT / mobility services</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hearing loss</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing aids may be helpful, per audiologist/otolaryngologist.</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Community hearing services through early intervention or school district</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Persistent middle ear effusions</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per otolaryngologist</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May incl myringotomy tubes & cerumen removal</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Constipation</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Aggressive mgmt incl diet mgmt, stool softeners, prokinetics, osmotic agents, or laxatives as needed</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>GI stenosis</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Guarded treatment per gastroenterologist</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Minimal instrumentation of GI tract is advised because postoperative adhesions can be fatal. <sup>6</sup></div></li><li class="half_rhythm"><div>Approach endoscopy w/caution to avoid airway manipulation, which ↑ risk for tracheal/laryngeal scarring/stenosis. <sup>4</sup></div></li><li class="half_rhythm"><div>Noninvasive 3D imaging may be preferred.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Protein-losing enteropathy & liver dysfunction</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per gastroenterologist &/or hepatologist</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Diabetes mellitus</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment & monitoring by endocrinologist</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May be difficult to manage & require insulin pumps</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Premature ovarian failure / Secondary amenorrhea / Menstrual irregularities</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per gynecologist &/or endocrinologist</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cryptorchidism &/or hypospadias</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per urologist</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Epilepsy</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standardized treatment w/ASM by experienced neurologist</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family/Community</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ensure appropriate social work involvement to connect families w/local resources, respite, & support.</div></li><li class="half_rhythm"><div>Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.</div></li></ul>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_treatment_of_mani_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ongoing assessment of need for palliative care involvement &/or home nursing</div></li><li class="half_rhythm"><div>Consider involvement in adaptive sports or <a href="https://www.specialolympics.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Special Olympics</a>.</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">CPAP = continuous positive airway pressure; BiPAP = bilevel positive airway pressure; GI = gastrointestinal; IVIG = intravenous immunoglobulin; PT = physical therapy</p></div></dd><dt>1. </dt><dd><div id="myhre.TF.6.1"><p class="no_margin">Growth hormone therapy is not endorsed because its anabolic action may interact with the activating <i>SMAD4</i> action.</p></div></dd><dt>2. </dt><dd><div id="myhre.TF.6.2"><p class="no_margin">All individuals with Myhre syndrome should be under the care of a cardiologist.</p></div></dd><dt>3. </dt><dd><div id="myhre.TF.6.3"><p class="no_margin"><a class="bk_pop" href="#myhre.REF.mcgowan.2011.e553">McGowan et al [2011]</a>, <a class="bk_pop" href="#myhre.REF.oldenburg.2015.636">Oldenburg et al [2015]</a>, <a class="bk_pop" href="#myhre.REF.starr.2015.2893">Starr et al [2015]</a></p></div></dd><dt>4. </dt><dd><div id="myhre.TF.6.4"><p class="no_margin">
|
||
<a class="bk_pop" href="#myhre.REF.oldenburg.2015.636">Oldenburg et al [2015]</a>
|
||
</p></div></dd><dt>5. </dt><dd><div id="myhre.TF.6.5"><p class="no_margin">
|
||
<a class="bk_pop" href="#myhre.REF.starr.2015.2893">Starr et al [2015]</a>
|
||
</p></div></dd><dt>6. </dt><dd><div id="myhre.TF.6.6"><p class="no_margin">
|
||
<a class="bk_pop" href="#myhre.REF.lindor.2012.1520">Lindor et al [2012]</a>
|
||
</p></div></dd></dl></div></div></div><div id="myhre.Developmental_Delay__Intellectual"><h4>Developmental Delay / Intellectual Disability Management Issues</h4><p>The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.</p><p><b>Ages 0-3 years.</b> Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.</p><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:</p><ul><li class="half_rhythm"><div>IEP services:</div><ul><li class="half_rhythm"><div>An IEP provides specially designed instruction and related services to children who qualify.</div></li><li class="half_rhythm"><div>IEP services will be reviewed annually to determine whether any changes are needed.</div></li><li class="half_rhythm"><div>Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.</div></li><li class="half_rhythm"><div>Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.</div></li><li class="half_rhythm"><div>PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</div></li><li class="half_rhythm"><div>As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.</div></li></ul></li><li class="half_rhythm"><div>A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, and modified assignments.</div></li><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div><div id="myhre.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p>
|
||
<b>Gross motor dysfunction</b>
|
||
</p><ul><li class="half_rhythm"><div>Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g. contractures).</div></li><li class="half_rhythm"><div>Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).</div></li></ul><p><b>Fine motor dysfunction.</b> Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.</p><p><b>Oral motor dysfunction</b> should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety.</p><p><b>Communication issues.</b> Consider evaluation for alternative means of communication (e.g., <a href="https://www.asha.org/NJC/AAC/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">augmentative and alternative communication</a> [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development. Also consider using American Sign Language (ASL) for those with hearing loss and minimal expressive language.</p></div><div id="myhre.SocialBehavioral_Concerns"><h4>Social/Behavioral Concerns</h4><p>Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.</p></div></div><div id="myhre.Prevention_of_Secondary_Complicati"><h3>Prevention of Secondary Complications</h3><p>Limiting tissue trauma appears to be the single most important preventive measure. When possible, alternative noninvasive approaches should be pursued during diagnosis and management [<a class="bk_pop" href="#myhre.REF.oldenburg.2015.636">Oldenburg et al 2015</a>, <a class="bk_pop" href="#myhre.REF.starr.2015.2893">Starr et al 2015</a>].</p><ul><li class="half_rhythm"><div>Extreme care with intubation and use of an endotracheal tube without a cuff (or careful monitoring of pressures with a cuff) may help prevent airway stenosis [<a class="bk_pop" href="#myhre.REF.oldenburg.2015.636">Oldenburg et al 2015</a>].</div></li><li class="half_rhythm"><div>Minimize abdominal and pelvic procedures as extensive adhesions may develop postoperatively [<a class="bk_pop" href="#myhre.REF.lindor.2012.1520">Lindor et al 2012</a>].</div></li><li class="half_rhythm"><div>Hysterectomy should be an option of last resort for treatment of menorrhagia as postsurgical fibrosis can occur.</div></li><li class="half_rhythm"><div>Recognize risk of thickened scars or keloids with ear or other piercings.</div></li><li class="half_rhythm"><div>Use of orthodontic braces may stimulate gum hypertrophy.</div></li></ul></div><div id="myhre.Surveillance"><h3>Surveillance</h3><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in <a href="/books/NBK425723/table/myhre.T.myhre_syndrome_recommended_surve/?report=objectonly" target="object" rid-ob="figobmyhreTmyhresyndromerecommendedsurve">Table 7</a> are recommended.</p><div id="myhre.T.myhre_syndrome_recommended_surve" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Myhre Syndrome: Recommended Surveillance</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK425723/table/myhre.T.myhre_syndrome_recommended_surve/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myhre.T.myhre_syndrome_recommended_surve_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_myhre.T.myhre_syndrome_recommended_surve_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_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Growth</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of growth parameters</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" rowspan="5" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Cardiovascular <sup>1</sup></b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In asymptomatic persons w/normal echocardiogram at <a href="#myhre.Evaluations_Following_Initial_Diag">initial diagnosis</a>, repeat echocardiogram.</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 2 yrs</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">In persons w/abnormal findings at <a href="#myhre.Evaluations_Following_Initial_Diag">initial diagnosis</a>, more extensive imaging may be indicated given progressive nature of disorder.</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As clinically indicated</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Right upper arm blood pressure measurement (if tolerated)</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">CT angiogram or MRA of aorta <sup>2</sup></td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 5-10 yrs starting in childhood (age 5-10 yrs) <sup>3</sup></td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Coronary CT angiogram</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As needed in 3rd decade of life</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Respiratory</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pulmonary function studies or impulse oscillometry in children age >6 yrs, if able to cooperate w/test maneuvers</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Eval for sleep apnea & need for intervention</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As needed in 3rd decade of life</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Monitor for evidence of respiratory insufficiency & obtain pulse oxygen measurement.</div></li><li class="half_rhythm"><div>Evaluate for signs/symptoms of upper airway stenosis & sleep apnea.</div></li></ul>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="7" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor for constipation & signs/symptoms of GI stenosis.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Developmental</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental progress & educational needs.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurobehavioral/</b>
|
||
<br />
|
||
<b>Psychiatric</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment for anxiety, ASD, & ADHD</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical medicine, OT/PT, mobility assessment, self-help skills</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Immunologic</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment of signs/symptoms of frequent infections</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family/</b>
|
||
<br />
|
||
<b>Community</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) & care coordination.</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Eyes</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologist eval</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Annually or as clinically indicated</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hearing</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologist eval</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Integument</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment for abnormal scarring</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Endocrinologic</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Low threshold for fasting blood sugar & hemoglobin A1c to assess for diabetes mellitus</div></li><li class="half_rhythm"><div>Periodic DXA scan to assess bone mineral density</div></li></ul>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Starting in 2nd decade</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Monitor for premature puberty. <sup>4</sup></td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit in childhood</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Postpubertal women: monitor for heavy menses. <sup>4</sup></td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Starting in 2nd decade</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genitourinary</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Renal/bladder ultrasound</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If there is intractable incontinence</td></tr><tr><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Lifestyle</b>
|
||
</td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Encourage nonstrenuous exercise, healthy eating, & weight mgmt.. <sup>5</sup></td><td headers="hd_h_myhre.T.myhre_syndrome_recommended_surve_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DXA = dual-energy x-ray absorptiometry; GI = gastrointestinal; MRA = magnetic resonance angiography; OT = occupational therapy; PT = physical therapy</p></div></dd><dt>1. </dt><dd><div id="myhre.TF.7.1"><p class="no_margin">Note that pericardial effusion and restrictive cardiomyopathy may occur at any age and may be clinically asymptomatic [<a class="bk_pop" href="#myhre.REF.starr.2015.2893">Starr et al 2015</a>, <a class="bk_pop" href="#myhre.REF.garavelli.2016.1307">Garavelli et al 2016</a>, <a class="bk_pop" href="#myhre.REF.lin.2016.2617">Lin et al 2016</a>].</p></div></dd><dt>2. </dt><dd><div id="myhre.TF.7.2"><p class="no_margin">The decision to use CT angiogram or MRA depends on the age and behavior of individual, the imaging center, and the availability of supportive services ("Child Life") to accomplish without anesthesia.</p></div></dd><dt>3. </dt><dd><div id="myhre.TF.7.3"><p class="no_margin">The exact frequency is based on the presence and degree of aortic disease.</p></div></dd><dt>4. </dt><dd><div id="myhre.TF.7.4"><p class="no_margin">These findings are more common in those with the <a href="/books/NBK425723/table/myhre.T.smad4_pathogenic_variants_refere/?report=objectonly" target="object" rid-ob="figobmyhreTsmad4pathogenicvariantsrefere">c.1486C>T (p.Arg496Cys)</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div></dd><dt>5. </dt><dd><div id="myhre.TF.7.5"><p class="no_margin">Vaccines are endorsed.</p></div></dd></dl></div></div></div></div><div id="myhre.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Affected individuals should be aggressively counseled not to smoke.</p><p>Limiting tissue trauma (injury) appears to be the single most important preventive concept in this disorder to communicate to all health care providers involved in an individual's care (see <a href="#myhre.Prevention_of_Secondary_Complicati">Prevention of Secondary Complications</a>). Decision making with affected individuals and their families should include nonintervention as an option in, for example, ear piercing, orthodontic braces, exploratory procedures, or surgical repair of velopharyngeal insufficiency.</p><p>Elective tracheal surgery/intubation should be avoided when possible. Tracheal resection is contraindicated.</p><p>Growth hormone therapy is <b>not</b> currently recommended for affected individuals with short stature.</p></div><div id="myhre.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#myhre.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="myhre.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>The antihypertensive drug losartan is an angiotensin II type 1 receptor blocker. Through this mechanism, it also indirectly antagonizes transforming growth factor beta (TGF-β) signaling. In Myhre syndrome fibroblasts, losartan corrected an extracellular matrix deposition defect [<a class="bk_pop" href="#myhre.REF.piccolo.2014.988">Piccolo et al 2014</a>]. Thus, in a small uncontrolled open-label pilot study, three individuals with Myhre syndrome were treated with losartan. Improvements in skin thickness, joint range of motion, and myocardial strain were observed [<a class="bk_pop" href="#myhre.REF.cappuccio.2021.702">Cappuccio et al 2021</a>]. However, long-term controlled clinical trials with a larger number of affected individuals are needed to establish the efficacy of losartan on skin, joint, and heart abnormalities in Myhre syndrome.</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="myhre.Genetic_Counseling"><h2 id="_myhre_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="myhre.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Myhre syndrome is an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> disorder typically caused by a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div><div id="myhre.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>Most individuals diagnosed with Myhre syndrome have the disorder as the result of a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
|
||
<i>SMAD4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> [<a class="bk_pop" href="#myhre.REF.lin.2016.2617">Lin et al 2016</a>]. <i>De novo</i>
|
||
<i>SMAD4</i> pathogenic variants that have been evaluated for parent of origin to date have all been paternal and have been associated with advanced paternal age [<a class="bk_pop" href="#myhre.REF.wood.2024.1953">Wood et al 2024</a>].</div></li><li class="half_rhythm"><div>A few individuals diagnosed with Myhre syndrome have the disorder as the result of a <i>SMAD4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> inherited from an affected parent. Transmission from an affected mother to two affected children has been reported in three families segregating the <a href="/books/NBK425723/table/myhre.T.smad4_pathogenic_variants_refere/?report=objectonly" target="object" rid-ob="figobmyhreTsmad4pathogenicvariantsrefere">p.Arg496Cys</a>
|
||
<i>SMAD4</i> pathogenic variant [<a class="bk_pop" href="#myhre.REF.meerschaut.2019.2494">Meerschaut et al 2019</a>, <a class="bk_pop" href="#myhre.REF.demir.2023.175">Demir et al 2023</a>, <a class="bk_pop" href="#myhre.REF.vanbelleghem.2024.1086">Vanbelleghem et al 2024</a>].</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> appears to be the only affected family member (i.e., a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case), <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> is recommended for the parents of the proband to evaluate their genetic status and inform <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> assessment.</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> inherited a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> from a parent with gonadal (or somatic and gonadal) <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a>. Note: Testing of parental leukocyte DNA may not detect all instances of <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a> and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.</div></li></ul></li></ul><p><b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The risk to the sibs of the proband depends on the genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is affected and/or is known to have the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.</div></li><li class="half_rhythm"><div>If the <i>SMAD4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> cannot be detected in the leukocyte DNA of either parent, the <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> to sibs is estimated to be 1% because of the possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/gonadal-mosaicism/">gonadal mosaicism</a> [<a class="bk_pop" href="#myhre.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>SMAD4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> but are clinically unaffected, the risk to the sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for Myhre syndrome because of the possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/gonadal-mosaicism/">gonadal mosaicism</a>.</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Each child of an individual with Myhre syndrome has a 50% chance of inheriting the <i>SMAD4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents: if a parent has the <i>SMAD4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the parent's family members may be at risk.</p></div><div id="myhre.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.</div></li></ul></div><div id="myhre.Prenatal_Testing_and_Preimplantati"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>SMAD4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> for Myhre syndrome are possible.</p><p>Note: Severe features (e.g., tetralogy of Fallot with pulmonary atresia, severe growth restriction) have been reported in prenatally diagnosed fetuses not known to be at increased risk of Myhre syndrome [<a class="bk_pop" href="#myhre.REF.hui.2023.1366">Hui et al 2023</a>, <a class="bk_pop" href="#myhre.REF.jury.2024.1268">Jury et al 2024</a>].</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a>. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="myhre.Resources"><h2 id="_myhre_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>Myhre Syndrome Foundation</b>
|
||
</div><div>
|
||
<a href="https://www.myhresyndrome.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">myhresyndrome.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Alexander Graham Bell Association for the Deaf and Hard of Hearing</b>
|
||
</div><div><b>Phone:</b> 866-337-5220 (toll-free); 202-337-5221 (TTY)</div><div><b>Fax:</b> 202-337-8314</div><div><b>Email:</b> info@agbell.org</div><div>
|
||
<a href="https://www.agbell.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Listening and Spoken Language Knowledge Center</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>American Society for Deaf Children</b>
|
||
</div><div><b>Phone:</b> 800-942-2732 (ASDC)</div><div><b>Email:</b> info@deafchildren.org</div><div>
|
||
<a href="https://deafchildren.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">deafchildren.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>National Association of the Deaf</b>
|
||
</div><div><b>Phone:</b> 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)</div><div><b>Fax:</b> 301-587-1791</div><div><b>Email:</b> nad.info@nad.org</div><div>
|
||
<a href="https://www.nad.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">nad.org</a>
|
||
</div></li></ul>
|
||
</div><div id="myhre.Molecular_Genetics"><h2 id="_myhre_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="myhre.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Myhre Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK425723/table/myhre.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myhre.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_myhre.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_myhre.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_myhre.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_myhre.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_myhre.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_myhre.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_myhre.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/4089" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>SMAD4</i>
|
||
</a>
|
||
</td><td headers="hd_b_myhre.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=4089" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">18q21<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_b_myhre.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q13485" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Mothers against decapentaplegic homolog 4</a>
|
||
</td><td headers="hd_b_myhre.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://databases.lovd.nl/shared/genes/SMAD4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SMAD4 database</a>
|
||
</td><td headers="hd_b_myhre.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=SMAD4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SMAD4</a>
|
||
</td><td headers="hd_b_myhre.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=SMAD4[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SMAD4</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="myhre.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="myhre.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Myhre Syndrome (<a href="/omim/139210,600993" 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/NBK425723/table/myhre.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myhre.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/139210" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">139210</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MYHRE SYNDROME; MYHRS</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/600993" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">600993</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SMAD FAMILY MEMBER 4; SMAD4</td></tr></tbody></table></div></div><div id="myhre.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>SMAD4</i> encodes mothers against decapentaplegic homolog 4 (SMAD4), signal transduction protein that has roles in many diverse signaling pathways including canonical transforming growth factor beta (TGF-β), bone morphogenetic protein (BMP), and activin signaling. Heterozygous <b><a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a></b> pathogenic variants in <i>SMAD4</i> that cause Myhre syndrome have been thought to confer stability of the resulting abnormal protein due to an apparent decrease in monoubiquitination. The <i>SMAD4</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> <a href="/books/NBK425723/table/myhre.T.smad4_pathogenic_variants_refere/?report=objectonly" target="object" rid-ob="figobmyhreTsmad4pathogenicvariantsrefere">p.Ile500Val</a> increases stability of the SMAD3/SMAD4 transcriptional complex [<a class="bk_pop" href="#myhre.REF.lindsay.2024">Lindsay et al 2024</a>]. Both of these biochemical activities may be at play, as they would both affect the TGF-β signaling pathway, altering expression of downstream target genes. Signaling perturbations result in altered development of the axial and appendicular skeleton, cardiac muscle, and central nervous system during development and abnormal extracellular matrix deposition during early development and adulthood [<a class="bk_pop" href="#myhre.REF.caputo.2012.161">Caputo et al 2012</a>, <a class="bk_pop" href="#myhre.REF.le_goff.2014.503">Le Goff et al 2014</a>, <a class="bk_pop" href="#myhre.REF.piccolo.2014.988">Piccolo et al 2014</a>].</p><p>In contrast, <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <b><a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a></b>
|
||
<i>SMAD4</i> pathogenic variants have been well established as the cause of a spectrum of acquired cardiac and neoplastic diseases, including arteriovenous malformations, aortopathies, pulmonary artery hypertension, and colon cancer susceptibility in the context of <a href="/books/n/gene/jps/">juvenile polyposis</a> and <a href="/books/n/gene/hht/">hereditary hemorrhagic telangiectasia</a> syndromes [<a class="bk_pop" href="#myhre.REF.andrabi.2011.1165">Andrabi et al 2011</a>, <a class="bk_pop" href="#myhre.REF.nasim.2011.1385">Nasim et al 2011</a>, <a class="bk_pop" href="#myhre.REF.heald.2015.1758">Heald et al 2015</a>].</p><p><b>Mechanism of disease causation.</b> Gain of function (increased TGF-β signaling potency) has been demonstrated in some studies [<a class="bk_pop" href="#myhre.REF.lindsay.2024">Lindsay et al 2024</a>]; however, other research suggests a <a class="def" href="/books/n/gene/glossary/def-item/dominant-negative/">dominant-negative</a> mechanism causing an interruption of typical TGF-β and BMP signaling [<a class="bk_pop" href="#myhre.REF.alankarage.2022.1">Alankarage et al 2022</a>]. Resolution of the observed differences is still outstanding.</p><div id="myhre.T.smad4_pathogenic_variants_refere" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p><i>SMAD4 </i>Pathogenic Variants Referenced in This <i>GeneReview</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK425723/table/myhre.T.smad4_pathogenic_variants_refere/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__myhre.T.smad4_pathogenic_variants_refere_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_myhre.T.smad4_pathogenic_variants_refere_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_myhre.T.smad4_pathogenic_variants_refere_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_myhre.T.smad4_pathogenic_variants_refere_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_myhre.T.smad4_pathogenic_variants_refere_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_myhre.T.smad4_pathogenic_variants_refere_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_005359.6" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_005359<wbr style="display:inline-block"></wbr>.6</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_005350.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_005350<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td><td headers="hd_h_myhre.T.smad4_pathogenic_variants_refere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1486C>T</td><td headers="hd_h_myhre.T.smad4_pathogenic_variants_refere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg496Cys</td><td headers="hd_h_myhre.T.smad4_pathogenic_variants_refere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Persons w/this variant are typically not as short in stature.</div></li><li class="half_rhythm"><div>3 affected women w/this variant developed endometrial cancer [<a class="bk_pop" href="#myhre.REF.lin.2020.328">Lin et al 2020</a>]. <sup>1</sup></div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_myhre.T.smad4_pathogenic_variants_refere_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1498A>G</td><td headers="hd_h_myhre.T.smad4_pathogenic_variants_refere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ile500Val</td><td headers="hd_h_myhre.T.smad4_pathogenic_variants_refere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Highly recurrent <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a></div></li><li class="half_rhythm"><div>This variant may be assoc w/↑ risk for pre- & postnatal growth deficiency.</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><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><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/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd><dt>1. </dt><dd><div id="myhre.TF.8.1"><p class="no_margin">It remains unclear if this specific <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is associated with an increased risk of developing neoplasia (see <a href="#myhre.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>).</p></div></dd></dl></div></div></div><p><b>Cancer and benign tumors.</b> Although <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <i>SMAD4</i> <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> (<a class="def" href="/books/n/gene/glossary/def-item/inactivating/">inactivating</a>) pathogenic variants predispose to hamartomatous polyps in the gastrointestinal tract (see <a href="/books/n/gene/jps/">Juvenile Polyposis Syndrome</a>), the <a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a> pathogenic variants associated with Myhre syndrome show no such associations (see <a href="#myhre.Clinical_Description">Clinical Description</a>, <b>Neoplasia</b>).</p><p>Note that somatic inactivation of <i>SMAD4</i>, a gastrointestinal malignancy-specific tumor suppressor <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>, is found in one third of colorectal cancer specimens and half of pancreatic tumors [<a class="bk_pop" href="#myhre.REF.chen.2014.181">Chen et al 2014</a>].</p></div></div><div id="myhre.Chapter_Notes"><h2 id="_myhre_Chapter_Notes_">Chapter Notes</h2><div id="myhre.Author_Notes"><h3>Author Notes</h3><p><a href="https://www.massgeneral.org/children/myhre-syndrome" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Myhre Syndrome Clinic</a> at Massachusetts General Hospital</p><p><a href="https://lindsaylab.mgh.harvard.edu/publications/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Lindsay Lab</a> at Massachusetts General Hospital</p></div><div id="myhre.Acknowledgments"><h3>Acknowledgments</h3><p>The authors are indebted to the people living with Myhre syndrome and their families who have provided consent, motivation, contributions, and advocacy.</p></div><div id="myhre.Author_History"><h3>Author History</h3><p>Nicola Brunetti-Pierri, MD (2022-present)<br />Angela E Lin, MD (2017-present)<br />Noralane M Lindor, MD; Mayo Clinic (2017-2022)<br />Mark E Lindsay, MD, PhD (2022-present)<br />Lisa A Schimmenti, MD (2022-present)<br />Lois J Starr, MD, PhD (2017-present)</p></div><div id="myhre.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>12 December 2024 (ma) Comprehensive update posted live</div></li><li class="half_rhythm"><div>24 November 2022 (ma) Comprehensive update posted live</div></li><li class="half_rhythm"><div>13 April 2017 (bp) Review posted live</div></li><li class="half_rhythm"><div>11 July 2016 (ljs) Original submission</div></li></ul></div></div><div id="myhre.References"><h2 id="_myhre_References_">References</h2><div id="myhre.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.alankarage.2022.1">Alankarage
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D, Enriquez
|
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A, Steiner
|
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RD, Raggio
|
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C, Higgins
|
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M, Milnes
|
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D, Humphreys
|
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DT, Duncan
|
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EL, Sparrow
|
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DB, Giampietro
|
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PF, Chapman
|
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G, Dunwoodie
|
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SL. Myhre syndrome is caused by dominant-negative dysregulation of <em>SMAD4</em> and other co-factors.
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Differentiation.
|
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2022;128:1-12.
|
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[<a href="/pmc/articles/PMC10442510/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10442510</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/36194927" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36194927</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.andrabi.2011.1165">Andrabi
|
||
S, Bekheirnia
|
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MR, Robbins-Furman
|
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P, Lewis
|
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RA, Prior
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TW, Potocki
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L. SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/21465659" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21465659</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.bassett.2016.54">Bassett
|
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JK, Douzgou
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S, Kerr
|
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B. Severe constipation in a patient with Myhre syndrome: a case report.
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Clin Dysmorph.
|
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2016;25:54-7.
|
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[<a href="https://pubmed.ncbi.nlm.nih.gov/26636501" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26636501</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.cappuccio.2022.1384">Cappuccio
|
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G, Brunetti-Pierri
|
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N, Clift
|
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P, Learn
|
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C, Dykes
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JC, Mercer
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CL, Callewaert
|
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B, Meerschaut
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I, Spinelli
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AM, Bruno
|
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I, Gillespie
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MJ, Dorfman
|
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AT, Grimberg
|
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A, Lindsay
|
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ME, Lin
|
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AE. Expanded cardiovascular phenotype of Myhre syndrome includes tetralogy of Fallot suggesting a role for SMAD4 in human neural crest defects.
|
||
Am J Med Genet A.
|
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2022;188:1384-95.
|
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[<a href="https://pubmed.ncbi.nlm.nih.gov/35025139" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35025139</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.cappuccio.2021.702">Cappuccio
|
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G, Caiazza
|
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M, Roca
|
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A, Melis
|
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D, Iuliano
|
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A, Matyas
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G, Rubino
|
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M, Limongelli
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G, Brunetti-Pierri
|
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N.
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A pilot clinical trial with losartan in Myhre syndrome.
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Am J Med Genet A.
|
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2021;185:702-9.
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[<a href="/pmc/articles/PMC7898344/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7898344</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33369056" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33369056</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.caputo.2012.161">Caputo
|
||
V, Cianetti
|
||
L, Niceta
|
||
M, Carta
|
||
C, Ciolfi
|
||
A, Bocchinfuso
|
||
G, Carrani
|
||
E, Dentici
|
||
ML, Biamino
|
||
E, Belligni
|
||
E, Garavelli
|
||
L, Boccone
|
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L, Melis
|
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D, Andria
|
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G, Gelb
|
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BD, Stella
|
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L, Silengo
|
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M, Dallapiccola
|
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B, Tartaglia
|
||
M. A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome.
|
||
Am J Hum Genet.
|
||
2012;90:161-9.
|
||
[<a href="/pmc/articles/PMC3257749/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3257749</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22243968" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22243968</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.chen.2014.181">Chen
|
||
YW, Hsiao
|
||
PJ, Weng
|
||
CC, Kuo
|
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KK, Kuo
|
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TL, Wu
|
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DC, Hung
|
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WC, Cheng
|
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KH. SMAD4 loss triggers the phenotypic changes of pancreatic ductal adenocarcinoma cells.
|
||
BMC Cancer.
|
||
2014;14:181.
|
||
[<a href="/pmc/articles/PMC4007528/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4007528</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24625091" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24625091</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.costantini.2023.225">Costantini
|
||
A, Guasto
|
||
A, Cormier-Daire
|
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V.
|
||
TGF-β and BMP signaling pathways in skeletal dysplasia with short and tall stature.
|
||
Annu Rev Genomics Hum Genet.
|
||
2023;24:225-53.
|
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[<a href="https://pubmed.ncbi.nlm.nih.gov/37624666" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 37624666</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.demir.2023.175">Demir
|
||
Ş, Alavanda
|
||
C, Yeşil
|
||
G, Aslanger
|
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AD, Ateş
|
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EA. A second family with Myhre syndrome caused by the same recurrent SMAD4 pathogenic variation (p.Arg496Cys).
|
||
Mol Syndromol.
|
||
2023;14:175-80.
|
||
[<a href="/pmc/articles/PMC10090971/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10090971</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/37064342" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 37064342</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.garavelli.2016.1307">Garavelli
|
||
L
|
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Maini
|
||
I, Baccilieri
|
||
F, Ivanovski
|
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I, Pollazzon
|
||
M, Rosato
|
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S, Iughetti
|
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L, Unger
|
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|
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|
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M. Natural history and life-threatening complications in Myhre syndrome and review of the literature.
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|
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2016;175:1307-15.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/27562837" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27562837</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.gheewalla.2022.3084">Gheewalla
|
||
GM, Luther
|
||
J, Das
|
||
S, Kreher
|
||
JB, Scimone
|
||
ER, Wong
|
||
AW, Lindsay
|
||
ME, Lin
|
||
AE. An additional patient with SMAD4-juvenile polyposis-hereditary hemorrhagic telangiectasia and connective tissue abnormalities: SMAD4 loss-of-function and gain-of-function pathogenic variants result in contrasting phenotypes.
|
||
Am J Med Genet A.
|
||
2022;188:3084-8.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/36120950" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36120950</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.unger.2023.1164">Unger
|
||
S, Ferreira
|
||
CR, Mortier
|
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GR, Ali
|
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H, Bertola
|
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DR, Calder
|
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A, Cohn
|
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DH, Cormier-Daire
|
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V, Girisha
|
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KM, Hall
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C, Krakow
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D, Makitie
|
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O, Mundlos
|
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S, Nishimura
|
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G, Robertson
|
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SP, Savarirayan
|
||
R, Sillence
|
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D, Simon
|
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M, Sutton
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VR, Warman
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ML, Superti-Furga
|
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A. Nosology of genetic skeletal disorders: 2023 revision.
|
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Am J Med Genet A.
|
||
2023;191:1164-209.
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[<a href="/pmc/articles/PMC10081954/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10081954</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/36779427" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36779427</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.vanbelleghem.2024.1086">Vanbelleghem
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E, Van Damme
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T, Beyens
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A, Symoens
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S, Claes
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K, De Backer
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J, Meerschaut
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I, Vanommeslaeghe
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F, Delanghe
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SE, van den Ende
|
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J, Beyltjens
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T, Scimone
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ER, Lindsay
|
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ME, Schimmenti
|
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LA, Hinze
|
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AM, Dunn
|
||
E, Gomez-Ospina
|
||
N, Vandernoot
|
||
I, Delguste
|
||
T, Coppens
|
||
S, Cormier-Daire
|
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V, Tartaglia
|
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M, Garavelli
|
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L, Shieh
|
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J, Demir
|
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Ş, Arslan Ateş
|
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E, Zenker
|
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M, Rohanizadegan
|
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M, Rivera-Cruz
|
||
G, Douzgou
|
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S, Lin
|
||
AE, Callewaert
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B, et al.
|
||
Myhre syndrome in adulthood: clinical variability and emerging genotype-phenotype correlations.
|
||
Eur J Hum Genet.
|
||
2024;32:1086-94.
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||
[<a href="/pmc/articles/PMC11369149/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC11369149</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/38997468" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 38997468</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.wood.2024.1953">Wood
|
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KA, Tong
|
||
RS, Motta
|
||
M, Cordeddu
|
||
V, Scimone
|
||
ER, Bush
|
||
SJ, Maxwell
|
||
DW, Giannoulatou
|
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E, Caputo
|
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V, Traversa
|
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A, Mancini
|
||
C, Ferrero
|
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GB, Benedicenti
|
||
F, Grammatico
|
||
P, Melis
|
||
D, Steindl
|
||
K, Brunetti-Pierri
|
||
N, Trevisson
|
||
E, Wilkie
|
||
AO, Lin
|
||
AE, Cormier-Daire
|
||
V, Twigg
|
||
SR, Tartaglia
|
||
M, Goriely
|
||
A. SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline.
|
||
Am J Hum Genet.
|
||
2024;111:1953-69.
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||
[<a href="/pmc/articles/PMC11444041/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC11444041</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/39116879" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 39116879</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="myhre.REF.yang.2022.304">Yang
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||
DD, Rio
|
||
M, Michot
|
||
C, Boddaert
|
||
N, Yacoub
|
||
W, Garcelon
|
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N, Thierry
|
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B, Bonnet
|
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D, Rondeau
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S, Herve
|
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D, Guey
|
||
S, Angoulvant
|
||
F, Cormier-Daire
|
||
V. Natural history of Myhre syndrome.
|
||
Orphanet J Rare Dis.
|
||
2022;17:304.
|
||
[<a href="/pmc/articles/PMC9338657/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9338657</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35907855" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35907855</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK425723/?report=reader">PubReader</a></li><li><a href="/books/NBK425723/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK425723" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK425723" style="display:none" title="Cite this Page"><div class="bk_tt">Lin AE, Brunetti-Pierri N, Lindsay ME, et al. Myhre Syndrome. 2017 Apr 13 [Updated 2024 Dec 12]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK425723/pdf/Bookshelf_NBK425723.pdf">PDF version of this page</a> (3.0M)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this GeneReview</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#myhre.Summary" ref="log$=inpage&link_id=inpage">Summary</a></li><li><a href="#myhre.Diagnosis" ref="log$=inpage&link_id=inpage">Diagnosis</a></li><li><a href="#myhre.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#myhre.Genetically_Related_Allelic_Disord" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#myhre.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#myhre.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#myhre.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#myhre.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#myhre.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#myhre.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li><li><a href="#myhre.References" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/ca/84/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download GeneReviews data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>GeneReviews Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/gene/advanced/"><i>GeneReviews</i> Advanced Search</a></li><li><a href="/books/n/gene/glossary/"><i>GeneReviews</i> Glossary</a></li><li><a href="/books/n/gene/resource_mats/">Resource Materials</a> <span class="bk_hlight1">NEW FEATURE</span></li><li><a href="/books/n/gene/updates/">New in <i>GeneReviews</i></a></li><li><a href="/books/n/gene/authors/">Author List</a></li><li><a href="/books/n/gene/prospective_authors/">For Current/Prospective Authors</a></li><li><a href="/books/n/gene/GRpersonnel/"><i>GeneReviews</i> Personnel</a></li><li><a href="/books/n/gene/howto_linkin/">Download/Link to <i>GeneReviews</i></a></li><li><a href="/books/n/gene/contact_us/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Tests in GTR by Gene</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
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xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Phelan-McDermid Syndrome-SHANK3 Related.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Phelan-McDermid Syndrome-SHANK3 Related.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Phelan K, Rogers RC, Boccuto L. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/39083629" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> NFIX-Related Malan Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> NFIX-Related Malan Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Priolo M. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301510" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FBN1-Related Marfan Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Dietz H. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/29023086" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> SATB2-Associated Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> SATB2-Associated Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Zarate YA, Bosanko K, Fish J. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301570" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Alpha-Mannosidosis.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span 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</div>
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</div><!-- /.twelve_col -->
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<span class="PAFAppResources"></span>
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<span id="portal-csrf-token" style="display:none" data-token="CE8B5AF87C7FFCB1_0191SID"></span>
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<script type="text/javascript" src="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/js/3879255/4121861/3501987/4008961/3893018/3821238/4062932/4209313/4212053/4076480/3921943/3400083/3426610.js" snapshot="books"></script></body>
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</html> |