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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Legius Syndrome" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2020/08/06" /><meta name="citation_author" content="Eric Legius" /><meta name="citation_author" content="David Stevenson" /><meta name="citation_pmid" content="20945555" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK47312/" /><meta name="citation_keywords" content="Neurofibromatosis Type 1-Like Syndrome" /><meta name="citation_keywords" content="Neurofibromatosis Type 1-Like Syndrome" /><meta name="citation_keywords" content="Sprouty-related, EVH1 domain-containing protein 1" /><meta name="citation_keywords" content="SPRED1" /><meta name="citation_keywords" content="Legius Syndrome" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Legius Syndrome" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Eric Legius" /><meta name="DC.Contributor" content="David Stevenson" /><meta name="DC.Date" content="2020/08/06" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK47312/" /><meta name="description" content="Legius syndrome is characterized by multiple café au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 (NF1). Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities / attention-deficit/hyperactivity disorder (ADHD) / developmental delays. Current knowledge of the natural history of Legius syndrome is based on the clinical manifestations of fewer than 300 individuals with a molecularly confirmed diagnosis; better delineation of the clinical manifestations and natural history of Legius syndrome will likely occur as more affected individuals are identified." /><meta name="og:title" content="Legius Syndrome" /><meta name="og:type" content="book" /><meta name="og:description" content="Legius syndrome is characterized by multiple café au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 (NF1). 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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="#__NBK47312_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK47312_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/lhon/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/lenz/" 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="_NBK47312_"><span class="title" itemprop="name">Legius Syndrome</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: Neurofibromatosis Type 1-Like Syndrome</div><p class="contrib-group"><span itemprop="author">Eric Legius</span>, MD, PhD and <span itemprop="author">David Stevenson</span>, MD.</p><a data-jig="ncbitoggler" href="#__NBK47312_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK47312_ai__"><div class="contrib half_rhythm"><span itemprop="author">Eric Legius</span>, MD, PhD<div class="affiliation small">University of Leuven
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Leuven, Belgium<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="eb.nevuelzu@suigel.cire" class="oemail">eb.nevuelzu@suigel.cire</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">David Stevenson</span>, MD<div class="affiliation small">Stanford University
|
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Stanford, California<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.drofnats@nevetsad" class="oemail">ude.drofnats@nevetsad</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">October 14, 2010</span>; Last Update: <span itemprop="dateModified">August 6, 2020</span>.</p><p><em>Estimated reading time: 21 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="legius.Summary" itemprop="description"><h2 id="_legius_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Legius syndrome is characterized by multiple café au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 (NF1). Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities / attention-deficit/hyperactivity disorder (ADHD) / developmental delays. Current knowledge of the natural history of Legius syndrome is based on the clinical manifestations of fewer than 300 individuals with a molecularly confirmed diagnosis; better delineation of the clinical manifestations and natural history of Legius syndrome will likely occur as more affected individuals are identified.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of Legius syndrome is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with suggestive findings and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>SPRED1</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> Consideration of behavioral modification and/or pharmacologic therapy for those with ADHD; physical, speech, and occupational therapy for those with identified developmental delays; and individualized education plans for those with learning disorders.</p><p><i>Surveillance:</i> Routine screening for developmental delays and behavioral and learning problems.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Legius syndrome is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner. Many affected individuals have an affected parent. Each child of an individual with Legius syndrome has a 50% chance of inheriting the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and developing clinical features of the disorder. Preimplantation genetic testing or <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for pregnancies at increased risk is possible if the <i>SPRED1</i> pathogenic variant has been identified in an affected family member.</p></div></div><div id="legius.Diagnosis"><h2 id="_legius_Diagnosis_">Diagnosis</h2><div id="legius.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Legius syndrome <b>should be suspected</b> in an individual who:</p><ul><li class="half_rhythm"><div>Has pigmentary dysplasia consisting of café au lait macules, with or without intertriginous freckling; and</div></li><li class="half_rhythm"><div>Lacks the nonpigmentary clinical diagnostic manifestations of <a href="/books/n/gene/nf1/">neurofibromatosis type 1</a> (NF1) (e.g., Lisch nodules, neurofibromas, optic pathway glioma, sphenoid wing dysplasia, long bone dysplasia).</div></li></ul></div><div id="legius.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnostic criteria for Legius syndrome are met if at least two of the following criteria are present:</p><ul><li class="half_rhythm"><div>Five or more café au lait macules bilaterally distributed and no other NF1-related diagnostic criteria except for axillary or inguinal freckling</div></li><li class="half_rhythm"><div>A <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variant in <i>SPRED1</i> in 100% of cells from unaffected tissue (see <a href="/books/NBK47312/table/legius.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figoblegiusTmoleculargenetictestingused">Table 1</a>)</div></li><li class="half_rhythm"><div>A parent with the diagnosis of Legius syndrome by the above criteria</div></li></ul><p>Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>SPRED1</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 of this disorder.</p><p><b>Molecular testing approaches</b> can include:</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>SPRED1</i> to detect small intragenic deletions/insertions and <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. Note: Depending on the sequencing method used, single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a>, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> to detect exon and whole-gene deletions or duplications.</div></li><li class="half_rhythm"><div class="half_rhythm">A <b>multigene pane</b>l that includes <i>SPRED1</i> and other genes of interest (see <a href="#legius.Differential_Diagnosis">Differential Diagnosis</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>; thus, clinicians need to determine which <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</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>. (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><p>Note: Opinions differ on the appropriate approach when clinical information and family history cannot distinguish between NF1 and Legius syndrome. This is the case in individuals with only café au lait macules with or without freckling but no other signs of NF1. The assessment of pros and cons of molecular testing requires consideration of the circumstances unique to each individual, including (but not limited to) the following:</p><ul><li class="half_rhythm"><div>Clinical findings and family history</div></li><li class="half_rhythm"><div>Age of the individual</div></li><li class="half_rhythm"><div>Differences in recommended clinical management when the diagnosis of NF1 or Legius syndrome is established with certainty vs when the diagnosis of neither can be established with confidence</div></li><li class="half_rhythm"><div>Psychological burden of a diagnosis or lack thereof</div></li><li class="half_rhythm"><div>Costs of testing and surveillance</div></li><li class="half_rhythm"><div>Odds of identifying a diagnosis of NF1 vs Legius syndrome in those with <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> limited to pigmentary findings</div></li></ul><p>For various approaches, see <a class="bk_pop" href="#legius.REF.messiaen.2009.2111">Messiaen et al [2009]</a>, <a class="bk_pop" href="#legius.REF.pasmant.2009.1131">Pasmant et al [2009]</a>, <a class="bk_pop" href="#legius.REF.stevenson.2009.2150">Stevenson & Viskochil [2009]</a>, <a class="bk_pop" href="#legius.REF.muramzborovski.2010.1203">Muram-Zborovski et al [2010]</a>, <a class="bk_pop" href="#legius.REF.denayer.2011a.e1985">Denayer et al [2011a]</a>, <a class="bk_pop" href="#legius.REF.brems.2012.1538">Brems et al [2012]</a>, <a class="bk_pop" href="#legius.REF.evans.2016.212">Evans et al [2016]</a>, and <a class="bk_pop" href="#legius.REF.castellanos.2020.264">Castellanos et al [2020]</a>.</p><div id="legius.T.molecular_genetic_testing_used" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Legius Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47312/table/legius.T.molecular_genetic_testing_used/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__legius.T.molecular_genetic_testing_used_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_legius.T.molecular_genetic_testing_used_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_legius.T.molecular_genetic_testing_used_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_legius.T.molecular_genetic_testing_used_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_legius.T.molecular_genetic_testing_used_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SPRED1</i>
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</td><td headers="hd_h_legius.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_legius.T.molecular_genetic_testing_used_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">89% <sup>4</sup></td></tr><tr><td headers="hd_h_legius.T.molecular_genetic_testing_used_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Deletion/<a class="def" href="/books/n/gene/glossary/def-item/duplication/">duplication</a> analysis <sup>5</sup></td><td headers="hd_h_legius.T.molecular_genetic_testing_used_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10% <sup>6</sup></td></tr><tr><td headers="hd_h_legius.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown <sup>7</sup></td><td headers="hd_h_legius.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NA</td><td headers="hd_h_legius.T.molecular_genetic_testing_used_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~1%</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="legius.TF.1.1"><p class="no_margin">See <a href="/books/NBK47312/#legius.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="legius.TF.1.2"><p class="no_margin">See <a href="#legius.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="legius.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 small intragenic deletions/insertions and <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; 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="legius.TF.1.4"><p class="no_margin">Of individuals evaluated for NF1 without an identifiable <i>NF1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, 3%-25% had an identifiable <i>SPRED1</i> pathogenic variant [<a class="bk_pop" href="#legius.REF.brems.2007.1120">Brems et al 2007</a>, <a class="bk_pop" href="#legius.REF.messiaen.2009.2111">Messiaen et al 2009</a>, <a class="bk_pop" href="#legius.REF.pasmant.2009.1131">Pasmant et al 2009</a>, <a class="bk_pop" href="#legius.REF.spurlock.2009.431">Spurlock et al 2009</a>]. Sequence analysis should identify the majority of individuals without whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions, although it is estimated that approximately 1%-2% could have deep <a class="def" href="/books/n/gene/glossary/def-item/intronic/">intronic</a> variants which could be missed; however, this has not been reported.</p></div></dd><dt>5. </dt><dd><div id="legius.TF.1.5"><p class="no_margin">Testing that identifies <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 not detectable by <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> of the coding and flanking <a class="def" href="/books/n/gene/glossary/def-item/intronic/">intronic</a> regions of <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> DNA. 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 class="def" href="/books/n/gene/glossary/def-item/chromosomal-microarray/">chromosomal microarray</a> (CMA) that includes this gene/<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> segment.</p></div></dd><dt>6. </dt><dd><div id="legius.TF.1.6"><p class="no_margin"><a class="bk_pop" href="#legius.REF.spencer.2011.1352">Spencer et al [2011]</a> report that deletions comprise approximately 10% of <i>SPRED1</i> pathogenic variants and include multiexon deletions and whole <i>SPRED1</i> <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions</p></div></dd><dt>7. </dt><dd><div id="legius.TF.1.7"><p class="no_margin">Sequence analysis in combination with <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> should identify the majority of individuals, although it is estimated that approximately 1% could have deep <a class="def" href="/books/n/gene/glossary/def-item/intronic/">intronic</a> variants that could be missed; however, this has not been reported.</p></div></dd></dl></div></div></div></div></div><div id="legius.Clinical_Characteristics"><h2 id="_legius_Clinical_Characteristics_">Clinical Characteristics</h2><div id="legius.Clinical_Description"><h3>Clinical Description</h3><p>Of note, the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of Legius syndrome is based on the reports of relatively few (<300) individuals, in which the primary focus was on individuals with the overlapping pigmentary manifestations of <a href="/books/n/gene/nf1/">neurofibromatosis type 1</a> (NF1).</p><div id="legius.T.legius_syndrome_frequency_of_se" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Legius Syndrome: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47312/table/legius.T.legius_syndrome_frequency_of_se/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__legius.T.legius_syndrome_frequency_of_se_lrgtbl__"><table><thead><tr><th id="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons with Feature</th><th id="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Café au lait macules</b>
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</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>99%</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Skin freckling</b>
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</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">30%-50%</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Age dependent</td></tr><tr><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Macrocephaly</b>
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</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">20%</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Short stature</b>
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</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12%</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurobehavioral/developmental issues</b>
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</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">30%</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Multiple lipomas</b>
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</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">18%</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In adults</td></tr><tr><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Pectus deformity</b>
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</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12%</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/noonan/">
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<b>Noonan</b>
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</a>
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<b>-like facial features</b>
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</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15%</td><td headers="hd_h_legius.T.legius_syndrome_frequency_of_se_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div></div><p><b>Skin findings.</b> Almost invariably, individuals with Legius syndrome present with café au lait macules. In some instances, freckling of the axillary/groin region is present. Two individuals (a male age 60 years and a child age 2 years), each with a presumed pathogenic <i>SPRED1</i> variant, have been reported with no café au lait macules or freckling [<a class="bk_pop" href="#legius.REF.brems.2007.1120">Brems et al 2007</a>, <a class="bk_pop" href="#legius.REF.messiaen.2009.2111">Messiaen et al 2009</a>]. The lack of pigmentary manifestations in the child was possibly a result of the child's young age. It is known that café au lait macules can fade away in older individuals with NF1. The number of café au lait macules increases with age in infants, similar to what is observed in NF1 [Author, personal observation].</p><p><b>Macrocephaly.</b> Absolute or relative macrocephaly has been seen in children and adults with Legius syndrome. However, the frequency of macrocephaly varied in different reports: head circumference was at or above the 97th centile in approximately 40% of individuals in one cohort [<a class="bk_pop" href="#legius.REF.brems.2007.1120">Brems et al 2007</a>] but above the 95th centile in only one of 18 individuals in another cohort [<a class="bk_pop" href="#legius.REF.pasmant.2009.1131">Pasmant et al 2009</a>].</p><p><b>Stature.</b> Absolute short stature has not been frequently noted in most series (although <a class="bk_pop" href="#legius.REF.denayer.2011a.e1985">Denayer et al [2011a]</a> reported it in 31%). <a class="bk_pop" href="#legius.REF.brems.2007.1120">Brems et al [2007]</a> reported that in 52% of individuals, height was greater than the 50th centile. Growth charts for Legius syndrome have not been published.</p><p><b>Neurobehavioral and developmental problems</b> are observed in individuals with Legius syndrome, but in many instances detailed descriptions are lacking. <a class="bk_pop" href="#legius.REF.messiaen.2009.2111">Messiaen et al [2009]</a> reported three individuals who had hyperactivity and two who had attention deficits. Of the six individuals with developmental abnormalities described by <a class="bk_pop" href="#legius.REF.messiaen.2009.2111">Messiaen et al [2009]</a>, all had speech and/or language delays as the primary or only delay. In the 12 individuals with Legius syndrome described by <a class="bk_pop" href="#legius.REF.spurlock.2009.431">Spurlock et al [2009]</a>, no learning or developmental problems were noted in the probands. <a class="bk_pop" href="#legius.REF.denayer.2011a.e1985">Denayer et al [2011a]</a> described five children with motor delay and five with speech delay, three individuals with ADHD, and 14 of 25 individuals with learning difficulties. Learning disabilities were further reported by <a class="bk_pop" href="#legius.REF.benelli.2015.8">Benelli et al [2015]</a>, <a class="bk_pop" href="#legius.REF.sakai.2015.703">Sakai et al [2015]</a>, <a class="bk_pop" href="#legius.REF.sekelska.2017.205">Sekelska et al [2017]</a>, and <a class="bk_pop" href="#legius.REF.witkowski.2020.e1180">Witkowski et al [2020]</a> in five individuals.</p><p>The cognitive issues in individuals with Legius syndrome are likely milder than those observed in NF1. A study of 15 individuals with Legius syndrome by <a class="bk_pop" href="#legius.REF.denayer.2011b.123">Denayer et al [2011b]</a> showed a lower performance IQ in children with Legius syndrome compared to their unaffected family members, although the full-scale IQ did not differ. <a class="bk_pop" href="#legius.REF.laycockvan_spyk.2011.93">Laycock-van Spyk et al [2011]</a> reported one individual with cognitive impairment with an IQ of 68.</p><p><b>Brain imaging.</b> Two individuals had T<sub>2</sub>-weighted hyperintense lesions on brain imaging; thus, the presence of such lesions cannot be used to differentiate between Legius syndrome and NF1 [<a class="bk_pop" href="#legius.REF.denayer.2011a.e1985">Denayer et al 2011a</a>].</p><p><b>Vascular anomalies.</b> A small number of vascular anomalies have been reported, but the descriptions are incomplete and different in each instance. The vascular abnormalities were listed as "tuberous hemangioma," "inguinal hemangioma," "large right temporal venous anomaly in brain," and "vascular anomaly left lower leg." Additional data are needed to determine if these reported vascular anomalies are tumors or malformations, and whether there is an increase of vascular anomalies in individuals with Legius syndrome.</p><p><b>Rare features</b> reported in more than one individual:</p><ul><li class="half_rhythm"><div>Hearing loss in four individuals [<a class="bk_pop" href="#legius.REF.messiaen.2009.2111">Messiaen et al 2009</a>, <a class="bk_pop" href="#legius.REF.denayer.2011a.e1985">Denayer et al 2011a</a>]</div></li><li class="half_rhythm"><div>Seizures in six individuals [<a class="bk_pop" href="#legius.REF.messiaen.2009.2111">Messiaen et al 2009</a>, <a class="bk_pop" href="#legius.REF.denayer.2011a.e1985">Denayer et al 2011a</a>, <a class="bk_pop" href="#legius.REF.laycockvan_spyk.2011.93">Laycock-van Spyk et al 2011</a>, <a class="bk_pop" href="#legius.REF.benelli.2015.8">Benelli et al 2015</a>, <a class="bk_pop" href="#legius.REF.sakai.2015.703">Sakai et al 2015</a>]</div></li><li class="half_rhythm"><div>Polydactyly in three individuals [<a class="bk_pop" href="#legius.REF.messiaen.2009.2111">Messiaen et al 2009</a>, <a class="bk_pop" href="#legius.REF.denayer.2011a.e1985">Denayer et al 2011a</a>]</div></li><li class="half_rhythm"><div>Scoliosis in five individuals [<a class="bk_pop" href="#legius.REF.denayer.2011a.e1985">Denayer et al 2011a</a>, <a class="bk_pop" href="#legius.REF.laycockvan_spyk.2011.93">Laycock-van Spyk et al 2011</a>]</div></li><li class="half_rhythm"><div>Pulmonic valve stenosis in three individuals [<a class="bk_pop" href="#legius.REF.brems.2007.1120">Brems et al 2007</a>, <a class="bk_pop" href="#legius.REF.messiaen.2009.2111">Messiaen et al 2009</a>, <a class="bk_pop" href="#legius.REF.witkowski.2020.e1180">Witkowski et al 2020</a>]</div></li></ul><p><b>Other.</b> Examples of other findings reported in isolated or only a few individuals include fifth finger clinodactyly, Chiari I malformation, hypotonia, cataract, nephrolithiasis, urethral meatal stenosis, mitral valve prolapse, paroxysmal atrial tachycardia, tubular colonic adenoma, progressive dystonia, xanthelasmas, desmoid tumor, vestibular schwannoma, tenosynovial giant cell tumor, dermoid tumor of the ovary, non-small-cell lung cancer, Wilms tumor, and monoblastic acute leukemia. Observations of clinical findings in a single individual should be taken with caution because chance occurrence cannot be distinguished from specific disease associations.</p><p><b>Tumor risk.</b> Legius syndrome in general lacks the tumor manifestations typically observed in NF1 (i.e., Lisch nodules, neurofibromas, and central nervous system tumors). One group has suggested that individuals with Legius syndrome are at an increased risk for leukemia [<a class="bk_pop" href="#legius.REF.pasmant.2009.1131">Pasmant et al 2009</a>, <a class="bk_pop" href="#legius.REF.pasmant.2015a.631">Pasmant et al 2015a</a>]. There has been a report of acute myeloblastic leukemia in one individual by <a class="bk_pop" href="#legius.REF.pasmant.2009.1131">Pasmant et al [2009]</a>, and this group subsequently screened 230 pediatric lymphoblastic and acute myeloblastic leukemias and found a <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> frameshift <i>SPRED1</i> variant in an individual with Legius syndrome [<a class="bk_pop" href="#legius.REF.pasmant.2015a.631">Pasmant et al 2015a</a>]. Further studies are needed to assess the potential risk for cancers in Legius syndrome, particularly given that <i>SPRED1</i> is part of the RAS-MAPK signal transduction pathway, a pathway involved in several neoplasms.</p></div><div id="legius.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a> have been identified.</p></div><div id="legius.Penetrance"><h3>Penetrance</h3><p>The vast majority of individuals with <i>SPRED1</i> pathogenic variants have café au lait macules and/or freckling; however, the age of pigment <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> is not established. Only two individuals (a male age 60 years and a child age 2 years), each with a presumed <i>SPRED1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, were reported not to have café au lait macules or freckling [<a class="bk_pop" href="#legius.REF.brems.2007.1120">Brems et al 2007</a>, <a class="bk_pop" href="#legius.REF.messiaen.2009.2111">Messiaen et al 2009</a>].</p><p>Some very young children may not have developed café au lait macules yet, and in older individuals the café au lait macules may have faded away. Some adolescents or young adults show only two or three café au lait macules, and the syndrome may be underdiagnosed.</p></div><div id="legius.Nomenclature"><h3>Nomenclature</h3><p>The majority of individuals with <i>SPRED1</i> pathogenic variants share the pigmentary manifestations but lack the tumor findings associated with NF1. It is not a form of neurofibromatosis because no neurofibromas have been reported. To clearly delineate this point in counseling sessions and to avoid confusion between NF1 and NF1-like syndrome, the name "Legius syndrome" was chosen and fulfills its purpose.</p></div><div id="legius.Prevalence"><h3>Prevalence</h3><p>The prevalence of Legius syndrome is estimated at 1:46,000-1:75,000 based on the fraction of children with a <i>SPRED1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in cohorts of children followed at NF clinics [<a class="bk_pop" href="#legius.REF.messiaen.2009.2111">Messiaen et al 2009</a>, <a class="bk_pop" href="#legius.REF.pasmant.2015b.596">Pasmant et al 2015b</a>, <a class="bk_pop" href="#legius.REF.evans.2016.212">Evans et al 2016</a>, <a class="bk_pop" href="#legius.REF.giugliano.2019.580">Giugliano et al 2019</a>].</p></div></div><div id="legius.Genetically_Related_Allelic_Disor"><h2 id="_legius_Genetically_Related_Allelic_Disor_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> pathogenic variants in <i>SPRED1.</i></p><p><b>Sporadic tumors</b> (including mucosal and acral melanomas) occurring as single tumors in the absence of any other findings of Legius syndrome frequently harbor somatic variants in <i>SPRED1</i> that are <b>not</b> present in the <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> [<a class="bk_pop" href="#legius.REF.ablain.2018.1055">Ablain et al 2018</a>, <a class="bk_pop" href="#legius.REF.newell.2019.3163">Newell et al 2019</a>, <a class="bk_pop" href="#legius.REF.yeh.2019.1068">Yeh et al 2019</a>]. In these circumstances predisposition to these tumors is not heritable.</p></div><div id="legius.Differential_Diagnosis"><h2 id="_legius_Differential_Diagnosis_">Differential Diagnosis</h2><p>Of primary importance in the clinical delineation of Legius syndrome is establishing the absence of other manifestations associated with the large number of other syndromes with multiple café au lait macules (most notably <a href="/books/n/gene/nf1/">neurofibromatosis type 1</a>; see also <a href="/books/NBK47312/table/legius.T.disorders_with_multiple_caf_au/?report=objectonly" target="object" rid-ob="figoblegiusTdisorderswithmultiplecafau">Table 3</a>). Although the diagnosis of Legius syndrome is difficult to make clinically with certainty without identification of a <i>SPRED1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the lack of additional clinical features, especially in older individuals, can help to differentiate Legius syndrome from other conditions. The surveillance in neurofibromatosis type 1 is very different from the surveillance in Legius syndrome, stressing the importance of a correct diagnosis.</p><p><b>Neurofibromatosis type 1 (NF1)</b> is most frequently confused with Legius syndrome, as some individuals with Legius syndrome fulfill the clinical diagnostic criteria for NF1 [<a class="bk_pop" href="#legius.REF.nih.1988.172">NIH 1988</a>, <a class="bk_pop" href="#legius.REF.gutmann.1997.51">Gutmann et al 1997</a>]. About 8% of children with six or more café au lait spots and no other clinical features of NF1 have Legius syndrome [<a class="bk_pop" href="#legius.REF.evans.2016.212">Evans et al 2016</a>]. Distinguishing Legius syndrome from NF1 is sometimes impossible on the basis of clinical features alone in a young child because the multiple cutaneous neurofibromas and Lisch nodules characteristic of NF1 do not usually arise until later in childhood or adolescence. Examination of the parents for signs of Legius syndrome or NF1 may distinguish the two conditions, but in <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases reevaluation of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> after adolescence or molecular testing may be necessary to establish the diagnosis. The phenotypes associated with specific <i>NF1</i> pathogenic variants are similar to Legius syndrome in some instances. A described <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a>-<a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> correlation with the <i>NF1</i> 3-bp <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> resulting in removal of a methionine residue (c.2970_2972delAAT) [<a class="bk_pop" href="#legius.REF.koczkowska.2019.867">Koczkowska et al 2019</a>] and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants of p.Arg1809 [<a class="bk_pop" href="#legius.REF.rojnueangnit.2015.1052">Rojnueangnit et al 2015</a>] result in an attenuated NF1 phenotype with relative lack of neurofibromas.</p><div id="legius.T.disorders_with_multiple_caf_au" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Disorders with Multiple Café au Lait Macules of Interest in the Differential Diagnosis of Legius Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47312/table/legius.T.disorders_with_multiple_caf_au/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__legius.T.disorders_with_multiple_caf_au_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Additional Clinical Features Not Associated w/Legius Syndrome</th></tr></thead><tbody><tr><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>BLM</i>
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</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/bloom/">Bloom syndrome</a>
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</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pre- & postnatal severe growth retardation, susceptibility to infections, high incidence of hematological malignancies</td></tr><tr><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;"><i>BRAF</i><br /><i>HRAS</i><br /><i>KRAS</i><br /><i>LZTR1</i><br /><i>MAP2K1</i><br /><i>NRAS</i><br /><i>PTPN11</i><br /><i>RAF1</i><br /><i>RAF1</i><br /><i>RIT1</i><br /><i>SOS1</i> <sup>1</sup></td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/costello/">Costello syndrome</a>
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</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Coarse facial features, ulnar deviation of wrist & fingers, ↑ incidence of cardiomyopathy, arrhythmia, rhabdomyosarcoma, neuroblastoma, bladder transitional cell carcinoma</td></tr><tr><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/noonan/">Noonan syndrome</a> <sup>2</sup></td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD<br />(AR) <sup>3</sup></td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypertrophic cardiomyopathy</td></tr><tr><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/leopard/">Noonan syndrome w/multiple lentigines</a>
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</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lentigines, hypertrophic cardiomyopathy</td></tr><tr><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/cfc/">Cardiofaciocutaneous syndrome</a>
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</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Moderate to severe intellectual disability, skin abnormalities (hyperkeratosis), sparse hair</td></tr><tr><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>BRCA2</i><br /><i>BRIP1</i><br /><i>FANCA</i><br /><i>FANCB</i><br /><i>FANCC</i><br /><i>FANCD2</i><br /><i>FANCE</i><br /><i>FANCF</i><br /><i>FANCG</i><br /><i>FANCI</i><br />(21 genes) <sup>4</sup></td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/fa/">Fanconi anemia</a>
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</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />AD<br />XL</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bone marrow failure, skeletal limb malformations, microcephaly, malignancies</td></tr><tr><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GNAS</i>
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</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/mccune-albright/">Fibrous dysplasia/McCune-Albright syndrome</a>
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</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 5.</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fibrous bone dysplasia, precocious puberty, hyperpigmentation w/irregular borders</td></tr><tr><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MLH1</i>
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<br />
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<i>MSH2</i>
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<br />
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<i>MSH6</i>
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<br />
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<i>PMS2</i>
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</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CMMRD (See <a href="/books/n/gene/hnpcc/">Lynch Syndrome</a>.)</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">High frequency of childhood malignancies, pilomatricomas</td></tr><tr><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>NF1</i>
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</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/nf1/">Neurofibromatosis 1</a>
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</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Optic pathway & other brain glioma, Lisch nodules, choroidal abnormalities, neurofibromas, <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> bowing of limbs, pseudarthrosis, sphenoid bone dysplasia</td></tr><tr><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>PTEN</i>
|
||
</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bannayan-Riley-Ruvalcaba syndrome (See <a href="/books/n/gene/phts/"><i>PTEN</i> Hamartoma Tumor Syndrome</a>.)</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Extreme macrocephaly, ↑ risk for cancer & benign skin tumors, hamartomatous polyps</td></tr><tr><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TSC1</i>
|
||
<br />
|
||
<i>TSC2</i>
|
||
</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/tuberous-sclerosis/">Tuberous sclerosis complex</a>
|
||
</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_legius.T.disorders_with_multiple_caf_au_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Angiofibromas, shagreen patches, ungual fibromas, brain abnormalities (nodules, dysplasia, astrocytomas), renal angiomyolipomas, cardiac rhabdomyomas</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>; CMMRD = constitutional <a class="def" href="/books/n/gene/glossary/def-item/mismatch-repair/">mismatch repair</a> deficiency; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; XL = <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a></p></div></dd><dt>1. </dt><dd><div id="legius.TF.3.1"><p class="no_margin">Genes associated with RASopathies are grouped together in this table to avoid redundancy. See the linked <i>GeneReviews</i> for specific <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-<a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> relationships.</p></div></dd><dt>2. </dt><dd><div id="legius.TF.3.2"><p class="no_margin">At least one individual with Legius syndrome was previously diagnosed as having Noonan syndrome [<a class="bk_pop" href="#legius.REF.brems.2007.1120">Brems et al 2007</a>].</p></div></dd><dt>3. </dt><dd><div id="legius.TF.3.3"><p class="no_margin">Noonan syndrome is most often inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner. Noonan syndrome caused by pathogenic variants in <i>LZTR1</i> can be inherited in either an autosomal dominant or an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div></dd><dt>4. </dt><dd><div id="legius.TF.3.4"><p class="no_margin">Listed genes represent the most common genetic causes; see <a href="/books/n/gene/fa/">Fanconi Anemia</a> for additional associated genes.</p></div></dd><dt>5. </dt><dd><div id="legius.TF.3.5"><p class="no_margin"><a href="/books/n/gene/mccune-albright/">Fibrous dysplasia/McCune-Albright syndrome</a>, a sporadically occurring disorder, is caused by an early embryonic <a class="def" href="/books/n/gene/glossary/def-item/postzygotic/">postzygotic</a> somatic activating (<a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a>) <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>GNAS</i> (encoding the cAMP pathway-associated G-protein, Gsα).</p></div></dd></dl></div></div></div><p>
|
||
<b>Other disorders with multiple café au lait macules</b>
|
||
</p><ul><li class="half_rhythm"><div><a href="/books/n/gene/rss/"><b>Silver-Russell syndrome</b></a><b>.</b> Additional clinical features include marked prenatal and postnatal growth restriction and body asymmetry.</div></li><li class="half_rhythm"><div><b>Autosomal dominant café au lait spots</b> (OMIM <a href="https://omim.org/entry/114030" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">114030</a>). Several families with multiple café au lait macules inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> pattern have been described. It is possible that some of these families harbor a <i>SPRED1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, although this <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> in at least one family did not segregate with markers within the <i>SPRED1</i> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> [<a class="bk_pop" href="#legius.REF.nystr_m.2009.693">Nyström et al 2009</a>].</div></li></ul></div><div id="legius.Management"><h2 id="_legius_Management_">Management</h2><div id="legius.Evaluations_Following_Initial_Dia"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs of an individual with Legius syndrome, the evaluations summarized in <a href="/books/NBK47312/table/legius.T.recommended_evaluations_followi/?report=objectonly" target="object" rid-ob="figoblegiusTrecommendedevaluationsfollowi">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="legius.T.recommended_evaluations_followi" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Legius Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47312/table/legius.T.recommended_evaluations_followi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__legius.T.recommended_evaluations_followi_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_legius.T.recommended_evaluations_followi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_legius.T.recommended_evaluations_followi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_legius.T.recommended_evaluations_followi_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_legius.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Development</b>
|
||
</td><td headers="hd_h_legius.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_legius.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Incl motor, adaptive, cognitive, & speech/language eval</div></li><li class="half_rhythm"><div>Eval for early intervention / special education</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_legius.T.recommended_evaluations_followi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Psychiatric/</b>
|
||
<br />
|
||
<b>Behavioral</b>
|
||
</td><td headers="hd_h_legius.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropsychiatric eval</td><td headers="hd_h_legius.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Persons age >12 mos: screening for behavior concerns incl ADHD</td></tr><tr><td headers="hd_h_legius.T.recommended_evaluations_followi_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_legius.T.recommended_evaluations_followi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_legius.T.recommended_evaluations_followi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & their families re nature, MOI, & implications of Legius syndrome to facilitate medical & personal decision making</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; 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="legius.TF.4.1"><p class="no_margin">Geneticist, certified genetic counselor, or certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="legius.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div id="legius.T.treatment_of_manifestations_in" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Legius Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47312/table/legius.T.treatment_of_manifestations_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__legius.T.treatment_of_manifestations_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_legius.T.treatment_of_manifestations_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_legius.T.treatment_of_manifestations_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th></tr></thead><tbody><tr><td headers="hd_h_legius.T.treatment_of_manifestations_in_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>
|
||
</td><td headers="hd_h_legius.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified developmental delays</div></li><li class="half_rhythm"><div>Individualized education plans for learning disorders & school performance issues</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_legius.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Psychiatric/Behavioral</b>
|
||
</td><td headers="hd_h_legius.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consideration of behavioral modification or pharmacologic adjuvant therapy for individuals w/ADHD</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; OT = occupational therapy; PT = physical therapy</p></div></dd></dl></div></div></div></div><div id="legius.Surveillance"><h3>Surveillance</h3><div id="legius.T.recommended_surveillance_for_in" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Legius Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47312/table/legius.T.recommended_surveillance_for_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__legius.T.recommended_surveillance_for_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_legius.T.recommended_surveillance_for_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_legius.T.recommended_surveillance_for_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_legius.T.recommended_surveillance_for_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_legius.T.recommended_surveillance_for_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Development</b>
|
||
</td><td headers="hd_h_legius.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental progress & educational needs.</td><td headers="hd_h_legius.T.recommended_surveillance_for_in_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_legius.T.recommended_surveillance_for_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Psychiatric/Behavioral</b>
|
||
</td><td headers="hd_h_legius.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Behavioral assessment for ADHD</td></tr><tr><td headers="hd_h_legius.T.recommended_surveillance_for_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Vascular anomalies <sup>1</sup></b>
|
||
</td><td headers="hd_h_legius.T.recommended_surveillance_for_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Blood pressure assessment</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</p></div></dd><dt>1. </dt><dd><div id="legius.TF.6.1"><p class="no_margin">Although vascular abnormalities have been reported in a few individuals with Legius syndrome, hypertension has not been reported. However, given the prevalence of vascular abnormalities and hypertension in NF1, it would seem appropriate to have regular blood pressure monitoring at each physician visit.</p></div></dd></dl></div></div></div></div><div id="legius.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#legius.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="legius.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="legius.Genetic_Counseling"><h2 id="_legius_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="legius.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Legius syndrome is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p></div><div id="legius.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 class="half_rhythm">Many individuals diagnosed with Legius syndrome have an affected parent.</div></li><li class="half_rhythm"><div class="half_rhythm">Some individuals diagnosed with Legius 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> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>; the proportion of individuals with Legius syndrome caused by a <i>de novo</i> pathogenic variant is unknown. One report stated that six of 23 probands with <i>SPRED1</i> pathogenic variants in a clinical cohort had <i>de novo</i> variants [<a class="bk_pop" href="#legius.REF.messiaen.2009.2111">Messiaen et al 2009</a>].</div></li><li class="half_rhythm"><div class="half_rhythm">Molecular genetic testing is recommended for the parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with an apparent <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.e., a proband who appears to be the only affected family member).</div></li><li class="half_rhythm"><div class="half_rhythm">If the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> found 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, possible explanations include a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> pathogenic variant in the proband or <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> in a parent.* Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported.</div><div class="half_rhythm">* Misattributed parentage can also be explored as an alternative explanation for an apparent <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 class="half_rhythm">The family history of some individuals diagnosed with Legius syndrome may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> has demonstrated that neither parent is <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for the <i>SPRED1</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>.</div><div class="half_rhythm">Note: If the parent is the individual in whom the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> first occurred, the parent may have somatic/<a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> for the pathogenic variant and may be mildly/minimally affected. (Segmental distribution of café au lait macules as a result of <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a> for a <i>SPRED1</i> pathogenic variant has been observed in two individuals but is very rare [<a class="bk_pop" href="#legius.REF.jobling.2017.1077">Jobling et al 2017</a>; Author, unpublished data].)</div></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>All sibs who inherit a pathogenic <i>SPRED1</i> variant will develop some clinical features of Legius syndrome, but there is a high variability in the number and age of onset of café au lait macules (see <a href="#legius.Penetrance">Penetrance</a>).</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a known <i>SPRED1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> that 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/germline-mosaicism/">germline mosaicism</a> [<a class="bk_pop" href="#legius.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>SPRED1</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 Legius syndrome because of the possibility of reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> in a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parent or the theoretic possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline 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 Legius syndrome has a 50% chance of inheriting the <i>SPRED1</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>SPRED1</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="legius.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 young adults who are affected or at risk.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).</p></div><div id="legius.Prenatal_Testing_and_Preimplantat"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>SPRED1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> for Legius syndrome are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="legius.Resources"><h2 id="_legius_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>RASopathies Network</b>
|
||
</div><div><b>Email:</b> info@rasopathiesnet.org</div><div>
|
||
<a href="http://rasopathiesnet.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.rasopathiesnet.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Children's Tumor Foundation</b>
|
||
</div><div><b>Phone:</b> 800-323-7938</div><div><b>Email:</b> info@ctf.org</div><div>
|
||
<a href="http://www.ctf.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.ctf.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Nerve Tumours UK</b>
|
||
</div><div>United Kingdom</div><div>
|
||
<a href="https://nervetumours.org.uk/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.nervetumours.org.uk</a>
|
||
</div></li></ul>
|
||
</div><div id="legius.Molecular_Genetics"><h2 id="_legius_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="legius.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Legius Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47312/table/legius.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__legius.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_legius.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_legius.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_legius.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_legius.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_legius.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_legius.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_legius.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/161742" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>SPRED1</i>
|
||
</a>
|
||
</td><td headers="hd_b_legius.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=161742" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">15q14</a>
|
||
</td><td headers="hd_b_legius.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q7Z699" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Sprouty-related, EVH1 domain-containing protein 1</a>
|
||
</td><td headers="hd_b_legius.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.arup.utah.edu/database/SPRED1/SPRED1_welcome.php" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Legius Syndrome and SPRED1</a>
|
||
<br />
|
||
<a href="http://www.lovd.nl/SPRED1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SPRED1 @ LOVD</a>
|
||
<br />
|
||
<a href="http://databases.lovd.nl/shared/genes/SPRED1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SPRED1 database</a>
|
||
</td><td headers="hd_b_legius.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=SPRED1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SPRED1</a>
|
||
</td><td headers="hd_b_legius.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=SPRED1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SPRED1</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="legius.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="legius.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Legius Syndrome (<a href="/omim/609291,611431" 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/NBK47312/table/legius.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__legius.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/609291" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">609291</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SPROUTY-RELATED EVH1 DOMAIN-CONTAINING PROTEIN 1; SPRED1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/611431" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">611431</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LEGIUS SYNDROME; LGSS</td></tr></tbody></table></div></div><div id="legius.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>SPRED1</i> encodes Spred1, a protein that negatively regulates Ras-MAPK signaling. Spred1 functional domains include:</p><ul><li class="half_rhythm"><div>N-terminal EVH-1 <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a></div></li><li class="half_rhythm"><div>Central KIT binding <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a></div></li><li class="half_rhythm"><div>C-terminal SPRY <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a></div></li></ul><p>Spred1 belongs to a family of proteins that are negative regulators of the Ras/ERK pathway. Spred1 negatively regulates the Ras/ERK pathway by inhibiting Raf1 kinase activation [<a class="bk_pop" href="#legius.REF.wakioka.2001.647">Wakioka et al 2001</a>, <a class="bk_pop" href="#legius.REF.tidyman.2009.230">Tidyman & Rauen 2009</a>]. Spred1 has also been shown to interact with neurofibromin to bring it to plasma membrane-bound Ras peptides [<a class="bk_pop" href="#legius.REF.stowe.2012.1421">Stowe et al 2012</a>]. Specific interacting domains in SPRED1 and neurofibromin have been identified [<a class="bk_pop" href="#legius.REF.dunzendorfermatt.2016.7497">Dunzendorfer-Matt et al 2016</a>, <a class="bk_pop" href="#legius.REF.hirata.2016.3124">Hirata et al 2016</a>].</p><p>Disease-associated variants result in Spred1 proteins incapable of inhibiting Raf1 kinase activation, resulting in attenuated inhibition of downstream Raf-MEK-ERK signaling [<a class="bk_pop" href="#legius.REF.brems.2007.1120">Brems et al 2007</a>]. This uninhibited signaling and consequent increase in Ras signal propagation is similar to that observed in NF1 and likely results in the clinical overlap of these two conditions.</p><p><b>Mechanism of disease causation.</b> Loss of function</p></div></div><div id="legius.Chapter_Notes"><h2 id="_legius_Chapter_Notes_">Chapter Notes</h2><div id="legius.Acknowledgments"><h3>Acknowledgments</h3><p>John Carey, MD<br />Ludwine Messiaen, PhD<br />Talia Muram, MD</p></div><div id="legius.Author_History"><h3>Author History</h3><p>Eric Legius, MD, PhD (2020-present)<br />Rong Mao, MD; University of Utah (2010-2020)<br />Talia Muram-Zborovski, MD, University of Utah (2010-2015)<br />David Stevenson, MD (2010-present)<br />David Viskochil, MD, PhD; University of Utah (2010-2020)</p></div><div id="legius.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>6 August 2020 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>15 January 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>12 May 2011 (cd) Revision: Testing Strategy</div></li><li class="half_rhythm"><div>14 October 2010 (me) Review posted live</div></li><li class="half_rhythm"><div>29 April 2010 (ds) Original submission</div></li></ul></div></div><div id="legius.References"><h2 id="_legius_References_">References</h2><div id="legius.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="legius.REF.ablain.2018.1055">Ablain J, Xu M, Rothschild H, Jordan RC, Mito JK, Daniels BH, Bell CF, Joseph NM, Wu H, Bastian BC, Zon LI, Yeh I. Human tumor genomics and zebrafish modeling identify <em>SPRED1</em> loss as a driver of mucosal melanoma. <span><span class="ref-journal">Science. </span>2018;<span class="ref-vol">362</span>:1055–60.</span> [<a href="/pmc/articles/PMC6475924/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6475924</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30385465" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30385465</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.benelli.2015.8">Benelli E, Bruno I, Belcaro C, Ventura A, Berti I. Legius syndrome: case report and review of literature. <span><span class="ref-journal">Ital J Pediatr. </span>2015;<span class="ref-vol">41</span>:8.</span> [<a href="/pmc/articles/PMC4323213/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4323213</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25883013" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25883013</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.brems.2007.1120">Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R, Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimura A, Legius E. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. <span><span class="ref-journal">Nat Genet. </span>2007;<span class="ref-vol">39</span>:1120–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17704776" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17704776</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.brems.2012.1538">Brems H, Pasmant E, Van Minkelen R, Wimmer K, Upadhyaya M, Legius E, Messiaen L. Review and update of SPRED1 mutations causing Legius syndrome. <span><span class="ref-journal">Hum Mutat. </span>2012;<span class="ref-vol">33</span>:1538–46.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22753041" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22753041</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.castellanos.2020.264">Castellanos E, Rosas I, Negro A, Gel B, Alibés A, Baena N, Pineda M, Pi G, Pintos G, Salvador H, Lázaro C, Blanco I, Vilageliu L, Brems H, Grinberg D, Legius E, Serra E. Mutational spectrum by phenotype: panel-based NGS testing of patients with clinical suspicion of RASopathy and children with multiple café-au-lait macules. <span><span class="ref-journal">Clin Genet. </span>2020;<span class="ref-vol">97</span>:264–75.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31573083" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31573083</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.denayer.2011a.e1985">Denayer E, Chmara M, Brems H, Kievit AM, van Bever Y, Van den Ouweland AM, Van Minkelen R, de Goede-Bolder A, Oostenbrink R, Lakeman P, Beert E, Ishizaki T, Mori T, Keymolen K, Van den Ende J, Mangold E, Peltonen S, Brice G, Rankin J, Van Spaendonck-Zwarts KY, Yoshimura A, Legius E. Legius syndrome in fourteen families. <span><span class="ref-journal">Hum Mutat. </span>2011a;<span class="ref-vol">32</span>:E1985–98.</span> [<a href="/pmc/articles/PMC3038325/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3038325</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21089071" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21089071</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.denayer.2011b.123">Denayer E, Descheemaeker MJ, Stewart DR, Keymolen K, Plasschaert E, Ruppert SL, Snow J, Thurm AE, Joseph LA, Fryns JP, Legius E. Observations on intelligence and behavior in 15 patients with Legius syndrome. <span><span class="ref-journal">Am J Med Genet C Semin Med Genet. </span>2011b;<span class="ref-vol">157C</span>:123–8.</span> [<a href="/pmc/articles/PMC3081633/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3081633</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21495177" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21495177</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.dunzendorfermatt.2016.7497">Dunzendorfer-Matt T, Mercado EL, Maly K, McCormick F, Scheffzek K. The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2016;<span class="ref-vol">113</span>:7497–502.</span> [<a href="/pmc/articles/PMC4941445/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4941445</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27313208" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27313208</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.evans.2016.212">Evans DG, Bowers N, Burkitt-Wright E, Miles E, Garg S, Scott-Kitching V, Penman-Splitt M, Dobbie A, Howard E, Ealing J, Vassalo G, Wallace AJ, Newman W, Huson SM, et al. Comprehensive RNA analysis of the NF1 gene in classically affected NF1 affected individuals meeting NIH criteria has high sensitivity and mutation negative testing is reassuring in isolated cases with pigmentary features only. <span><span class="ref-journal">EBioMedicine. </span>2016;<span class="ref-vol">7</span>:212–20.</span> [<a href="/pmc/articles/PMC4909377/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4909377</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27322474" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27322474</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.giugliano.2019.580">Giugliano T, Santoro C, Torella A, Del Vecchio Blanco F, Grandone A, Onore ME, Melone MAB, Straccia G, Melis D, Piccolo V, Limongelli G, Buono S, Perrotta S, Nigro V, Piluso G. Clinical and genetic findings in children with neurofibromatosis type 1, Legius syndrome, and other related neurocutaneous disorders. <span><span class="ref-journal">Genes (Basel). </span>2019;<span class="ref-vol">10</span>:580.</span> [<a href="/pmc/articles/PMC6722641/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6722641</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31370276" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31370276</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.gutmann.1997.51">Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. <span><span class="ref-journal">JAMA. </span>1997;<span class="ref-vol">278</span>:51–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9207339" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9207339</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.hirata.2016.3124">Hirata Y, Brems H, Suzuki M, Kanamori M, Okada M, Morita R, Llano-Rivas I, Ose T, Messiaen L, Legius E, Yoshimura A. Interaction between a domain of the negative regulator of the Ras-ERK pathway, SPRED1 protein, and the GTPase-activating protein-related domain of neurofibromin is implicated in Legius syndrome and neurofibromatosis type 1. <span><span class="ref-journal">J Biol Chem. </span>2016;<span class="ref-vol">291</span>:3124–34.</span> [<a href="/pmc/articles/PMC4751360/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4751360</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26635368" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26635368</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.jobling.2017.1077">Jobling RK, Lara-Corrales I, Hsiao MC, Shugar A, Hedges S, Messiaen L, Kannu P. Mosaicism for a SPRED1 deletion revealed in a patient with clinically suspected mosaic neurofibromatosis. <span><span class="ref-journal">Br J Dermatol. </span>2017;<span class="ref-vol">176</span>:1077–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27423141" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27423141</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.koczkowska.2019.867">Koczkowska M, Callens T, Gomes A, Sharp A, Chen Y, Hicks AD, Aylsworth AS, Azizi AA, Basel DG, Bellus G, Bird LM, Blazo MA, Burke LW, Cannon A, Collins F, DeFilippo C, Denayer E, Digilio MC, Dills SK, Dosa L, Greenwood RS, Griffis C, Gupta P, Hachen RK, Hernández-Chico C, Janssens S, Jones KJ, Jordan JT, Kannu P, Korf BR, Lewis AM, Listernick RH, Lonardo F, Mahoney MJ, Ojeda MM, McDonald MT, McDougall C, Mendelsohn N, Miller DT, Mori M, Oostenbrink R, Perreault S, Pierpont ME, Piscopo C, Pond DA, Randolph LM, Rauen KA, Rednam S, Rutledge SL, Saletti V, Schaefer GB, Schorry EK, Scott DA, Shugar A, Siqveland E, Starr LJ, Syed A, Trapane PL, Ullrich NJ, Wakefield EG, Walsh LE, Wangler MF, Zackai E, Claes KBM, Wimmer K, van Minkelen R, De Luca A, Martin Y, Legius E, Messiaen LM. Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation. <span><span class="ref-journal">Genet Med. </span>2019;<span class="ref-vol">21</span>:867–76.</span> [<a href="/pmc/articles/PMC6752285/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6752285</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30190611" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30190611</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.laycockvan_spyk.2011.93">Laycock-van Spyk S, Jim HP, Thomas L, Spurlock G, Fares L, Palmer-Smith S, Kini U, Saggar A, Patton M, Mautner V, Pilz DT, Upadhyaya M. 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Expanding the Noonan spectrum/RASopathy NGS panel: Benefits of adding NF1 and SPRED1. <span><span class="ref-journal">Mol Genet Genomic Med. </span>2020;<span class="ref-vol">8</span>:e1180. </span> [<a href="/pmc/articles/PMC7196473/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7196473</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32107864" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32107864</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="legius.REF.yeh.2019.1068">Yeh I, Jorgenson E, Shen L, Xu M, North JP, Shain AH, Reuss D, Wu H, Robinson WA, Olshen A, von Deimling A, Kwok PY, Bastian BC, Asgari MM. 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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/NBK47312/?report=reader">PubReader</a></li><li><a href="/books/NBK47312/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK47312" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK47312" style="display:none" title="Cite this Page"><div class="bk_tt">Legius E, Stevenson D. Legius Syndrome. 2010 Oct 14 [Updated 2020 Aug 6]. 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/NBK47312/pdf/Bookshelf_NBK47312.pdf">PDF version of this page</a> (492K)</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="#legius.Summary" ref="log$=inpage&link_id=inpage">Summary</a></li><li><a href="#legius.Diagnosis" ref="log$=inpage&link_id=inpage">Diagnosis</a></li><li><a href="#legius.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#legius.Genetically_Related_Allelic_Disor" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#legius.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#legius.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#legius.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#legius.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#legius.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#legius.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li><li><a href="#legius.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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</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=medgen&DbFrom=books&Cmd=Link&LinkName=books_medgen&IdsFromResult=2337840" ref="log$=recordlinks">MedGen</a><div class="brieflinkpop offscreen_noflow">Related information in MedGen</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=omim&DbFrom=books&Cmd=Link&LinkName=books_omim&IdsFromResult=2337840" ref="log$=recordlinks">OMIM</a><div class="brieflinkpop offscreen_noflow">Related OMIM records</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=2337840" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=2337840" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=gene&DbFrom=books&Cmd=Link&LinkName=books_gene&IdsFromResult=2337840" ref="log$=recordlinks">Gene</a><div class="brieflinkpop offscreen_noflow">Locus Links</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301377" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Phelan-McDermid Syndrome-SHANK3 Related.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Phelan-McDermid Syndrome-SHANK3 Related.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Phelan K, Rogers RC, Boccuto L. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301625" ref="ordinalpos=1&linkpos=2&log$=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> Retinoblastoma.</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> Retinoblastoma.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Lohmann DR, Gallie BL. </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/24006547" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Ornithine Transcarbamylase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Ornithine Transcarbamylase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Lichter-Konecki U, Caldovic L, Morizono H, Simpson K, Ah Mew N, MacLeod E. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301288" ref="ordinalpos=1&linkpos=4&log$=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> Neurofibromatosis 1.</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> Neurofibromatosis 1.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Friedman JM. </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/20301744" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span 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