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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Noonan Syndrome with Multiple Lentigines - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
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<meta name="citation_title" content="Noonan Syndrome with Multiple Lentigines">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2022/06/30">
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<meta name="citation_author" content="Bruce D Gelb">
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<meta name="citation_author" content="Marco Tartaglia">
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<meta name="citation_keywords" content="LEOPARD Syndrome">
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<meta name="citation_keywords" content="Multiple Lentigines Syndrome">
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<meta name="citation_keywords" content="Multiple Lentigines Syndrome">
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<meta name="citation_keywords" content="LEOPARD Syndrome">
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<meta name="citation_keywords" content="Dual specificity mitogen-activated protein kinase kinase 1">
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<meta name="citation_keywords" content="RAF proto-oncogene serine/threonine-protein kinase">
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<meta name="citation_keywords" content="Serine/threonine-protein kinase B-raf">
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<meta name="citation_keywords" content="Tyrosine-protein phosphatase non-receptor type 11">
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<meta name="citation_keywords" content="BRAF">
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<meta name="citation_keywords" content="MAP2K1">
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<meta name="citation_keywords" content="PTPN11">
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<meta name="citation_keywords" content="Noonan Syndrome with Multiple Lentigines">
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<meta name="DC.Title" content="Noonan Syndrome with Multiple Lentigines">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Bruce D Gelb">
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<meta name="DC.Contributor" content="Marco Tartaglia">
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<meta name="DC.Date" content="2022/06/30">
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<meta name="description" content="Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth restriction resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th centile for age. Sensorineural hearing deficits, present in approximately 20% of affected individuals, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.">
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<meta name="og:title" content="Noonan Syndrome with Multiple Lentigines">
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<meta name="og:description" content="Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth restriction resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th centile for age. Sensorineural hearing deficits, present in approximately 20% of affected individuals, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.">
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class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK1383_"><span class="title" itemprop="name">Noonan Syndrome with Multiple Lentigines</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: LEOPARD Syndrome, Multiple Lentigines Syndrome</div><p class="contribs">Gelb BD, Tartaglia M.</p><p class="fm-aai"><a href="#_NBK1383_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 29 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="leopard.Summary" itemprop="description"><h2 id="_leopard_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth restriction resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th centile for age. Sensorineural hearing deficits, present in approximately 20% of affected individuals, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The clinical diagnosis of Noonan syndrome with multiple lentigines can be established in a proband with multiple lentigines plus two other cardinal features (cardiac abnormalities; poor linear growth / short stature; pectus deformity; and dysmorphic facial features including widely spaced eyes and ptosis) OR, in the absence of lentigines, three of the other cardinal manifestations plus an affected first-degree relative. The molecular diagnosis can be established in a proband with suggestive findings and a heterozygous pathogenic variant in one of four genes (<i>BRAF</i>, <i>MAP2K1</i>, <i>PTPN11</i>, and <i>RAF1</i>).</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Standard treatment of hypertrophic cardiomyopathy, structural heart defects, eye anomalies / eye movement abnormalities, seizures, cryptorchidism, and developmental issues. Hearing aids may be helpful if hearing loss is present. Growth hormone treatment may be considered for those with short stature, but data on use in NSML are lacking, and growth hormone therapy may be contraindicated in those with hypertrophic cardiomyopathy.</p><p><i>Surveillance:</i> Measurement of growth parameters; cardiac auscultation to assess for new heart murmur; clinical assessment for new neurologic manifestations such as seizures; and monitoring of developmental progress and educational needs at each visit. Annual echocardiogram until age three years and then at ages five years and ten years, or as clinically indicated. Audiology evaluation at least annually in infancy and childhood, or as clinically indicated. Ophthalmology evaluation if eye anomalies or eye movement issues are noted.</p><p><i>Agents/circumstances to avoid</i>: For individuals with hypertrophic cardiomyopathy, treatment with growth hormone must be undertaken with great caution (if at all) to avoid exacerbating a cardiac condition, and certain physical activities may be curtailed in order to reduce the risk of sudden cardiac death.</p><p><i>Evaluation of relatives at risk</i>: If the <i>BRAF</i>, <i>MAP2K1</i>, <i>PTPN11</i>, or <i>RAF1</i> pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives; if the pathogenic variant in the family is not known, a thorough physical examination with particular attention to the features of NSML may clarify the disease status of at-risk relatives. If NSML is suspected a cardiology evaluation with echocardiogram is recommended.</p><p><i>Pregnancy management</i>: For affected women, cardiac status should be monitored during pregnancy. Those with hypertrophic cardiomyopathy or valve dysfunction may be at risk for the development or exacerbation of heart failure during pregnancy, especially during the second and third trimesters.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>NSML is inherited in an autosomal dominant manner. A proband with NSML may have the disorder as the result of a <i>de novo</i> pathogenic variant; the proportion of cases caused by <i>de novo</i> pathogenic variants is unknown. Each child of an individual with NSML has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for a pregnancy at increased risk is possible if the pathogenic variant in an affected family member is known.</p></div></div><div id="leopard.Diagnosis"><h2 id="_leopard_Diagnosis_">Diagnosis</h2><p>Suggested clinical diagnostic criteria for Noonan syndrome with multiple lentigines (NSML) have been published [<a class="bibr" href="#leopard.REF.voron.1976.447" rid="leopard.REF.voron.1976.447">Voron et al 1976</a>, <a class="bibr" href="#leopard.REF.sarkozy.2008.13" rid="leopard.REF.sarkozy.2008.13">Sarkozy et al 2008</a>].</p><div id="leopard.Suggestive_Findings"><h3>Suggestive Findings</h3><p>NSML <b>should be suspected</b> in individuals with one or more of the following cardinal features:</p><ul><li class="half_rhythm"><div>Lentigines</div></li><li class="half_rhythm"><div>Cardiac abnormalities, particularly hypertrophic cardiomyopathy</div></li><li class="half_rhythm"><div>Poor linear growth / short stature</div></li><li class="half_rhythm"><div>Pectus deformity</div></li><li class="half_rhythm"><div>Dysmorphic facial features including widely spaced eyes and ptosis</div></li></ul><p>Additional features occurring frequently in NSML:</p><ul><li class="half_rhythm"><div class="half_rhythm">Variable degree of cognitive deficits</div></li><li class="half_rhythm"><div class="half_rhythm">Sensorineural hearing loss</div></li><li class="half_rhythm"><div class="half_rhythm">Cryptorchidism</div></li><li class="half_rhythm"><div class="half_rhythm">Skeletal anomalies</div></li><li class="half_rhythm"><div class="half_rhythm">Café au lait macules</div></li><li class="half_rhythm"><div class="half_rhythm">Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations)</div><div class="half_rhythm">Note: Absence of a known family history does not preclude the diagnosis.</div></li></ul></div><div id="leopard.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The clinical diagnosis of NSML can be established in a proband based on clinical criteria [<a class="bibr" href="#leopard.REF.voron.1976.447" rid="leopard.REF.voron.1976.447">Voron et al 1976</a>, <a class="bibr" href="#leopard.REF.sarkozy.2008.13" rid="leopard.REF.sarkozy.2008.13">Sarkozy et al 2008</a>], or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in one of four genes (<i>BRAF</i>, <i>MAP2K1</i>, <i>PTPN11</i>, and <i>RAF1)</i> listed in <a href="/books/NBK1383/table/leopard.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobleopardTmoleculargenetictestingused">Table 1</a>.</p><p>
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<b>Clinical diagnosis</b>
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</p><ul><li class="half_rhythm"><div>Multiple lentigines plus two of the other <a href="#leopard.Suggestive_Findings">cardinal features</a>, OR</div></li><li class="half_rhythm"><div>In the absence of lentigines, three of the other cardinal features plus a first-degree relative with NSML [<a class="bibr" href="#leopard.REF.sarkozy.2008.13" rid="leopard.REF.sarkozy.2008.13">Sarkozy et al 2008</a>]</div></li></ul><p><b>Molecular diagnosis.</b> The molecular diagnosis of NSML <b>is established</b> in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in <a href="/books/NBK1383/table/leopard.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobleopardTmoleculargenetictestingused">Table 1</a> identified by molecular genetic testing.</p><p>Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance in one of the genes listed in <a href="/books/NBK1383/table/leopard.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobleopardTmoleculargenetictestingused">Table 1</a> does not establish or rule out the diagnosis of this disorder.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, genome sequencing) depending on the phenotype.</p><p>Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in <a href="#leopard.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#leopard.Option_1">Option 1</a>), whereas those in whom the diagnosis of NSML has not been considered are more likely to be diagnosed using genomic testing (see <a href="#leopard.Option_2">Option 2</a>).</p><div id="leopard.Option_1"><h4>Option 1</h4><p>When the phenotypic and family history findings suggest the diagnosis of NSML, molecular genetic testing approaches can include use of a <b>multigene panel.</b> Serial single-gene genetic testing is not frequently used.</p><p><b>A Noonan syndrome, RASopathy, or hypertrophic cardiomyopathy</b>
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<b>multigene panel</b> that includes <i>BRAF</i>, <i>MAP2K1</i>, <i>PTPN11</i>, <i>RAF1</i>, and other genes of interest (see <a href="#leopard.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</p><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</p></div><div id="leopard.Option_2"><h4>Option 2</h4><p>When the diagnosis of NSML has not been considered because an individual has atypical phenotypic features, <b>comprehensive genomic testing</b> may be considered. Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figleopardTmoleculargenetictestingused"><a href="/books/NBK1383/table/leopard.T.molecular_genetic_testing_used/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobleopardTmoleculargenetictestingused"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="leopard.T.molecular_genetic_testing_used"><a href="/books/NBK1383/table/leopard.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobleopardTmoleculargenetictestingused">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Noonan Syndrome with Multiple Lentigines </p></div></div></div></div></div><div id="leopard.Clinical_Characteristics"><h2 id="_leopard_Clinical_Characteristics_">Clinical Characteristics</h2><div id="leopard.Clinical_Description"><h3>Clinical Description</h3><p>To date, more than 150 individuals with Noonan syndrome with multiple lentigines (NSML) have been reported.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figleopardTnoonansyndromewithmultiple"><a href="/books/NBK1383/table/leopard.T.noonan_syndrome_with_multiple/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobleopardTnoonansyndromewithmultiple"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="leopard.T.noonan_syndrome_with_multiple"><a href="/books/NBK1383/table/leopard.T.noonan_syndrome_with_multiple/?report=objectonly" target="object" rid-ob="figobleopardTnoonansyndromewithmultiple">Table 2. </a></h4><p class="float-caption no_bottom_margin">Noonan Syndrome with Multiple Lentigines: Frequency of Select Features </p></div></div><p><b>Dermatologic.</b> Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase into the thousands by puberty [<a class="bibr" href="#leopard.REF.coppin.1997.582" rid="leopard.REF.coppin.1997.582">Coppin & Temple 1997</a>]. Some individuals with NSML do not exhibit lentigines.</p><ul><li class="half_rhythm"><div>Café au lait macules are also observed in up to 70%-80% of affected individuals [<a class="bibr" href="#leopard.REF.digilio.2006.740" rid="leopard.REF.digilio.2006.740">Digilio et al 2006</a>], usually preceding the appearance of lentigines.</div></li><li class="half_rhythm"><div>Skin hyperelasticity has also been described.</div></li><li class="half_rhythm"><div>Neurofibromas have been described but are rare.</div></li></ul><p><b>Cardiovascular.</b> Approximately 85% of affected individuals have heart defects similar to those observed in <a href="/books/n/gene/noonan/?report=reader">Noonan syndrome</a> (NS) but with different frequencies [<a class="bibr" href="#leopard.REF.limongelli.2007.736" rid="leopard.REF.limongelli.2007.736">Limongelli et al 2007</a>]:</p><ul><li class="half_rhythm"><div>Hypertrophic cardiomyopathy is detected in up to 70% of individuals with heart defects (compared to 25% in NS). It most commonly appears during infancy and can be progressive.</div></li><li class="half_rhythm"><div>Pulmonary valve stenosis is noted in approximately 25% of affected individuals. Abnormalities of the aortic and mitral valves are also observed in a minority of persons with NSML.</div></li><li class="half_rhythm"><div>EKG abnormalities, aside from those typically associated with hypertrophic cardiomyopathy, include conduction defects (23%).</div></li></ul><p><b>Facial features.</b> Dysmorphic facial features are similar to those seen in Noonan syndrome, although usually milder [<a class="bibr" href="#leopard.REF.digilio.2006.740" rid="leopard.REF.digilio.2006.740">Digilio et al 2006</a>]. Features include inverted triangular-shaped face, downslanted palpebral fissures, low-set posteriorly rotated ears with thickened helices, and widely spaced eyes. The neck can be short with excess nuchal skin and a low posterior hairline. As in Noonan syndrome, facial features may be less evident or more subtle in adults.</p><p><b>Hearing.</b> Sensorineural hearing deficits are present in approximately 20% of persons with NSML. Minimal information is available about the progression of deafness in those with milder degrees of hearing impairment.</p><p><b>Growth.</b> Birth weight is usually normal but may be above the 97th centile. Postnatal growth restriction resulting in short stature is noted in fewer than 50% of affected individuals, although in most, height is less than the 25th centile for age. Adult height and response to growth hormone therapy have not been studied in this disorder.</p><p><b>Musculoskeletal.</b> Pectus anomalies (either excavatum or carinatum), present in 50% or more of affected individuals, are most often of cosmetic concern only and rarely require medical intervention.</p><p><b>Psychomotor development.</b> Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML. Specific information concerning the deficits typically found in these children is not available.</p><p><b>Genitourinary.</b> Cryptorchidism, unilateral or bilateral, is present in approximately one third of affected males. Other abnormalities including hypospadias, urinary tract defects, and ovarian abnormalities are observed infrequently. Renal anomalies have also (rarely) been reported [<a class="bibr" href="#leopard.REF.digilio.2006.740" rid="leopard.REF.digilio.2006.740">Digilio et al 2006</a>].</p><p><b>Eyes.</b> Ophthalmologic involvement in NSML is rare. Described issues include colobomata, stereopsis, and abnormal eye movements [<a class="bibr" href="#leopard.REF.alfieri.2008.335" rid="leopard.REF.alfieri.2008.335">Alfieri et al 2008</a>, <a class="bibr" href="#leopard.REF.watanabe.2011.576" rid="leopard.REF.watanabe.2011.576">Watanabe et al 2011</a>, <a class="bibr" href="#leopard.REF.van_den_heurck.2021" rid="leopard.REF.van_den_heurck.2021">Van den Heurck et al 2021</a>].</p><p><b>Neurologic.</b> Hypotonia is common in newborns and is associated with psychomotor delays. Seizures and autism spectrum disorder are uncommon manifestations in NSML.</p><p>
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<b>Rare features</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Craniosynostosis.</b> An anecdotal association has been reported between NSML and craniosynostosis, although it is unclear whether this represents a true association or whether the reported individuals had co-occurrence of two conditions. However, it has been postulated that an increased risk of craniosynostosis may be related to the functional link between FGF signaling and the RAS-MAPK pathway [<a class="bibr" href="#leopard.REF.mcdonald.2018.357" rid="leopard.REF.mcdonald.2018.357">McDonald et al 2018</a>, <a class="bibr" href="#leopard.REF.rodr_guez.2019.1598" rid="leopard.REF.rodr_guez.2019.1598">Rodríguez et al 2019</a>].</div><ul><li class="half_rhythm"><div>One reported individual with NSML, who had a pathogenic variant in <i>PTPN11</i>, had sagittal synostosis that required surgical correction as a result of increased intracranial pressure [<a class="bibr" href="#leopard.REF.mcdonald.2018.357" rid="leopard.REF.mcdonald.2018.357">McDonald et al 2018</a>].</div></li><li class="half_rhythm"><div>A second affected individual, who had a pathogenic variant in <i>RAF1</i>, had multisutural craniosynostosis consistent with a clover-leaf skull that also required surgical correction [<a class="bibr" href="#leopard.REF.rodr_guez.2019.1598" rid="leopard.REF.rodr_guez.2019.1598">Rodríguez et al 2019</a>].</div></li></ul></li><li class="half_rhythm"><div class="half_rhythm"><b>Malignancies.</b> Hematologic malignancies and other tumors have occasionally been reported in individuals with NSML. However, a review of overall tumor risk in individuals with NSML by <a class="bibr" href="#leopard.REF.villani.2017.e83" rid="leopard.REF.villani.2017.e83">Villani et al [2017]</a> noted that the risk is low, such that no routine surveillance for individuals with NSML is recommended. <a class="bibr" href="#leopard.REF.villani.2017.e83" rid="leopard.REF.villani.2017.e83">Villani et al [2017]</a> suggested that there be an awareness of a potential risk of malignancy and a low threshold for investigating any signs or symptoms suggestive of malignancy.</div><div class="half_rhythm"><a class="bibr" href="#leopard.REF.smpokou.2015.516" rid="leopard.REF.smpokou.2015.516">Smpokou et al [2015]</a> reported a total of six individuals with NSML and malignancy:</div><ul><li class="half_rhythm"><div>Three individuals had leukemia; all 3 had a germline pathogenic variant in <i>PTPN11</i> involving amino acid residue 279.</div></li><li class="half_rhythm"><div>One individual had neuroblastoma and one had cerebellar meduloblastoma; both had a germline pathogenic c.1402C>T (p.Thr468Met) <i>PTPN11</i> variant.</div></li><li class="half_rhythm"><div>One individual with a clinical diagnosis of NSML had a unilateral corneal choristoma.</div></li></ul></li></ul></div><div id="leopard.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No genotype-phenotype correlations for <i>BRAF</i>, <i>MAP2K1</i>, or <i>RAF1</i> have been identified in individuals with NSML.</p><p><b><i>PTPN11.</i></b> In contrast to what is observed in Noonan syndrome, the NSML-associated pathogenic variants (see <a href="#leopard.Molecular_Genetics">Molecular Genetics</a>) are strongly associated with a predisposition to hypertrophic cardiomyopathy [<a class="bibr" href="#leopard.REF.tartaglia.2010.99" rid="leopard.REF.tartaglia.2010.99">Tartaglia & Gelb 2010</a>, <a class="bibr" href="#leopard.REF.gelb.2015.13" rid="leopard.REF.gelb.2015.13">Gelb et al 2015</a>]. This specific correlation results from a differential impact of NS- and NSML-causing <i>PTPN11</i> variants on intracellular signalling. In particular, different consequences have been documented on both the MAPK and PI3K-AKT-mTOR pathways [<a class="bibr" href="#leopard.REF.edouard.2010.2498" rid="leopard.REF.edouard.2010.2498">Edouard et al 2010</a>, <a class="bibr" href="#leopard.REF.marin.2011.1026" rid="leopard.REF.marin.2011.1026">Marin et al 2011</a>].</p></div><div id="leopard.Nomenclature"><h3>Nomenclature</h3><p>NSML was referred to as cardiomyopathic lentiginosis in the older medical literature. It was also formerly referred to by the acronym LEOPARD syndrome; this designation is no longer considered appropriate.</p></div><div id="leopard.Prevalence"><h3>Prevalence</h3><p>The population prevalence of NSML is not known.</p></div></div><div id="leopard.Genetically_Related_Allelic_Diso"><h2 id="_leopard_Genetically_Related_Allelic_Diso_">Genetically Related (Allelic) Disorders</h2><p>The phenotypic overlap that occurs in individuals with germline pathogenic variants in genes causing Noonan syndrome with multiple lentigines (NSML), Noonan syndrome (NS), and cardiofaciocutaneous syndrome (CFCS) (see <a href="/books/NBK1383/table/leopard.T.allelic_disorders_in_the_diffe/?report=objectonly" target="object" rid-ob="figobleopardTallelicdisordersinthediffe">Table 3</a>) emphasizes that the three disorders (previously defined as distinct clinical entities) constitute a phenotypic continuum and highlights the usefulness of feature-based management.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figleopardTallelicdisordersinthediffe"><a href="/books/NBK1383/table/leopard.T.allelic_disorders_in_the_diffe/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobleopardTallelicdisordersinthediffe"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="leopard.T.allelic_disorders_in_the_diffe"><a href="/books/NBK1383/table/leopard.T.allelic_disorders_in_the_diffe/?report=objectonly" target="object" rid-ob="figobleopardTallelicdisordersinthediffe">Table 3. </a></h4><p class="float-caption no_bottom_margin">Allelic Disorders in the Differential Diagnosis of Noonan Syndrome with Multiple Lentigines </p></div></div><p><b>Other.</b> Germline heterozygous loss-of-function <i>PTPN11</i> variants are associated with autosomal dominant metachondromatosis [<a class="bibr" href="#leopard.REF.mcfarlane.2016.102" rid="leopard.REF.mcfarlane.2016.102">McFarlane et al 2016</a>].</p><p><b>Sporadic tumors</b> (including leukemia and solid tumors) occurring as single tumors in the absence of any other findings of NSML or NS frequently harbor a somatic pathogenic variant in <i>BRAF</i>, <i>MAP2K1</i>, <i>PTPN11</i>, or <i>RAF1</i> that is <b>not</b> present in the germline; thus, predisposition to these tumors is not heritable. For more details see <a href="#leopard.Molecular_Genetics">Molecular Genetics</a>.</p></div><div id="leopard.Differential_Diagnosis"><h2 id="_leopard_Differential_Diagnosis_">Differential Diagnosis</h2><p>Noonan syndrome with multiple lentigines (NSML) should be distinguished from Turner syndrome, Williams syndrome, and monogenic disorders with developmental delay, short stature, congenital heart defects, and distinctive facies (see <a href="/books/NBK1383/table/leopard.T.monogenic_disorders_of_interes/?report=objectonly" target="object" rid-ob="figobleopardTmonogenicdisordersofinteres">Table 4</a>).</p><p><b>Turner syndrome,</b> found only in females, is distinguished from NSML by demonstration of an X-chromosome abnormality on cytogenetic studies. The characteristic facial features are also distinct, and in Turner syndrome renal anomalies are more common, developmental delay is much less frequently found, and left-sided heart defects are the rule.</p><p><a href="/books/n/gene/williams/?report=reader"><b>Williams syndrome</b></a> and NSML are relatively distinct, as they are associated with different facial features, cardiovascular involvement, skin features, and neurodevelopmental profiles. Early in life, however, the facial features may be less distinct, lentigines have not yet emerged for NSML, and both disorders share impaired growth and neurodevelopmental delays. The diagnosis of Williams syndrome requires detection of a recurrent 7q11.23 contiguous gene deletion of the Williams-Beuren syndrome critical region (WBSCR) that encompasses the elastin gene (<i>ELN</i>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figleopardTmonogenicdisordersofinteres"><a href="/books/NBK1383/table/leopard.T.monogenic_disorders_of_interes/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobleopardTmonogenicdisordersofinteres"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="leopard.T.monogenic_disorders_of_interes"><a href="/books/NBK1383/table/leopard.T.monogenic_disorders_of_interes/?report=objectonly" target="object" rid-ob="figobleopardTmonogenicdisordersofinteres">Table 4. </a></h4><p class="float-caption no_bottom_margin">Monogenic Disorders of Interest in the Differential Diagnosis of Noonan Syndrome with Multiple Lentigines </p></div></div></div><div id="leopard.Management"><h2 id="_leopard_Management_">Management</h2><p>No clinical practice guidelines for Noonan syndrome with multiple lentigines (NSML) have been published.</p><div id="leopard.Evaluations_Following_Initial_Di"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with NSML, the evaluations summarized in <a href="/books/NBK1383/table/leopard.T.recommended_evaluations_follow/?report=objectonly" target="object" rid-ob="figobleopardTrecommendedevaluationsfollow">Table 5</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figleopardTrecommendedevaluationsfollow"><a href="/books/NBK1383/table/leopard.T.recommended_evaluations_follow/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobleopardTrecommendedevaluationsfollow"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="leopard.T.recommended_evaluations_follow"><a href="/books/NBK1383/table/leopard.T.recommended_evaluations_follow/?report=objectonly" target="object" rid-ob="figobleopardTrecommendedevaluationsfollow">Table 5. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with Noonan Syndrome with Multiple Lentigines </p></div></div></div><div id="leopard.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figleopardTtreatmentofmanifestationsin"><a href="/books/NBK1383/table/leopard.T.treatment_of_manifestations_in/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobleopardTtreatmentofmanifestationsin"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="leopard.T.treatment_of_manifestations_in"><a href="/books/NBK1383/table/leopard.T.treatment_of_manifestations_in/?report=objectonly" target="object" rid-ob="figobleopardTtreatmentofmanifestationsin">Table 6. </a></h4><p class="float-caption no_bottom_margin">Treatment of Manifestations in Individuals with Noonan Syndrome with Multiple Lentigines </p></div></div><div id="leopard.Developmental_Delay__Intellectua"><h4>Developmental Delay / Intellectual Disability Management Issues</h4><p>The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Not everyone with NSML will have developmental delay. The following recommendations apply to those in whom neurodevelopmental delays have been noted.</p><p><b>Ages 0-3 years.</b> Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.</p><p><b>All ages.</b> Consultation with a developmental pediatrician, where available, is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:</p><ul><li class="half_rhythm"><div>IEP services:</div><ul><li class="half_rhythm"><div>An IEP provides specially designed instruction and related services to children who qualify.</div></li><li class="half_rhythm"><div>IEP services will be reviewed annually to determine whether any changes are needed.</div></li><li class="half_rhythm"><div>Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.</div></li><li class="half_rhythm"><div>Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.</div></li><li class="half_rhythm"><div>PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</div></li><li class="half_rhythm"><div>As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.</div></li></ul></li><li class="half_rhythm"><div>A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.</div></li><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div><div id="leopard.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p><b>Gross motor dysfunction.</b> Physical therapy is recommended to maximize mobility.</p><p><b>Fine motor dysfunction.</b> Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.</p><p><b>Communication issues.</b> Speech therapy may be beneficial for those with speech delay.</p></div></div><div id="leopard.Surveillance"><h3>Surveillance</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figleopardTrecommendedsurveillancefori"><a href="/books/NBK1383/table/leopard.T.recommended_surveillance_for_i/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobleopardTrecommendedsurveillancefori"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="leopard.T.recommended_surveillance_for_i"><a href="/books/NBK1383/table/leopard.T.recommended_surveillance_for_i/?report=objectonly" target="object" rid-ob="figobleopardTrecommendedsurveillancefori">Table 7. </a></h4><p class="float-caption no_bottom_margin">Recommended Surveillance for Individuals with Noonan Syndrome with Multiple Lentigines </p></div></div></div><div id="leopard.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>For individuals with hypertrophic cardiomyopathy:</p><ul><li class="half_rhythm"><div>Treatment with growth hormone must be undertaken with great caution – if at all – to avoid exacerbating a cardiac condition;</div></li><li class="half_rhythm"><div>Certain physical activities may be curtailed in order to reduce the risk of sudden cardiac death.</div></li></ul></div><div id="leopard.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to evaluate relatives at risk in order to identify as early as possible those with hypertrophic cardiomyopathy who would benefit from initiation of treatment and preventive measures.</p><ul><li class="half_rhythm"><div>If the <i>BRAF</i>, <i>MAP2K1</i>, <i>PTPN11</i>, or <i>RAF1</i> pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.</div></li><li class="half_rhythm"><div>If the pathogenic variant in the family is not known, a thorough physical examination with particular attention to the features of NSML may clarify the disease status of at-risk relatives. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended.</div></li></ul><p>See <a href="#leopard.Genetic_Counseling">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="leopard.Pregnancy_Management"><h3>Pregnancy Management</h3><p>For affected women, cardiac status should be monitored during pregnancy. Those with hypertrophic cardiomyopathy or valve dysfunction may be at risk for the development or exacerbation of heart failure during pregnancy, especially during the second and third trimesters.</p><p>Some affected pregnant women may be on medications for their cardiovascular issues. See <a href="https://www.mothertobaby.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MotherToBaby</a> for further information on medication use during pregnancy.</p></div><div id="leopard.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Clinical Trials.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="leopard.Genetic_Counseling"><h2 id="_leopard_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="leopard.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Noonan syndrome with multiple lentigines (NSML) is inherited in an autosomal dominant manner.</p></div><div id="leopard.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>Some individuals diagnosed with NSML have an affected parent. (Note: Because NSML is associated with variable expressivity and the manifestations of the disorder are frequently subtle, many affected adults are diagnosed only after the birth of a more obviously affected infant.)</div></li><li class="half_rhythm"><div>A proband with NSML may have the disorder as the result of a <i>de novo</i>
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<i>BRAF</i>, <i>MAP2K1</i>, <i>PTPN11</i>, or <i>RAF1</i> pathogenic variant.</div></li><li class="half_rhythm"><div>If the proband is the only family member known to be affected with NSML, recommended evaluations of both parents include:</div><ul><li class="half_rhythm"><div>Molecular genetic testing if the NSML-causing pathogenic variant in the proband is known;</div></li><li class="half_rhythm"><div>A thorough physical examination with particular attention to the features of NSML if the NSML-causing pathogenic variant in the proband is not known. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended.</div></li></ul></li><li class="half_rhythm"><div>If the proband has an NSML-related pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The proband has a <i>de novo</i> pathogenic variant.</div></li><li class="half_rhythm"><div>The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells.</div></li></ul></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with NSML may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).</div></li></ul><p><b>Sibs of a proband.</b> The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div class="half_rhythm">If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.</div><div class="half_rhythm">Because there can be significant intrafamilial variability, sibs may not have the same phenotypic findings as other affected family members.</div></li><li class="half_rhythm"><div class="half_rhythm">If the proband has a known NSML-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [<a class="bibr" href="#leopard.REF.rahbari.2016.126" rid="leopard.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div class="half_rhythm">If the parents are clinically unaffected (based on appropriate clinical evaluation) but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the theoretic possibility of parental germline mosaicism.</div></li></ul><p><b>Offspring of a proband.</b> Each child of an individual with NSML has a 50% chance of inheriting the NSML-related pathogenic variant.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or is known to have the familial pathogenic variant, members of the parent's family may be at risk.</p></div><div id="leopard.Related_Genetic_Counseling_Issue"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#leopard.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.</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="leopard.Prenatal_Testing_and_Preimplanta"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the NSML-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="leopard.Resources"><h2 id="_leopard_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>MedlinePlus</b>
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</div><div>
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<a href="http://www.nlm.nih.gov/medlineplus/ency/article/001473.htm" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Noonan syndrome with multiple lentigines</a>
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</div></li><li class="half_rhythm"><div>
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<b>RASopathies Network</b>
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</div><div><b>Email:</b> info@rasopathiesnet.org</div><div>
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<a href="http://rasopathiesnet.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.rasopathiesnet.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>American Society for Deaf Children</b>
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</div><div><b>Phone:</b> 800-942-2732 (ASDC)</div><div><b>Email:</b> info@deafchildren.org</div><div>
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<a href="https://deafchildren.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">deafchildren.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>National Association of the Deaf</b>
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</div><div><b>Phone:</b> 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)</div><div><b>Fax:</b> 301-587-1791</div><div><b>Email:</b> nad.info@nad.org</div><div>
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<a href="https://www.nad.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">nad.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Noonan Syndrome Foundation</b>
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</div><div><b>Email:</b> info@teamnoonan.org</div><div>
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<a href="http://www.teamnoonan.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.teamnoonan.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>The Children's Heart Foundation</b>
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</div><div><b>Phone:</b> 847-634-6474</div><div><b>Email:</b> info@childrensheartfoundation.org</div><div>
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<a href="http://www.childrensheartfoundation.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.childrensheartfoundation.org</a>
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</div></li></ul>
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</div><div id="leopard.Molecular_Genetics"><h2 id="_leopard_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figleopardmolgenTA"><a href="/books/NBK1383/table/leopard.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobleopardmolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="leopard.molgen.TA"><a href="/books/NBK1383/table/leopard.molgen.TA/?report=objectonly" target="object" rid-ob="figobleopardmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Noonan Syndrome with Multiple Lentigines: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figleopardmolgenTB"><a href="/books/NBK1383/table/leopard.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobleopardmolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="leopard.molgen.TB"><a href="/books/NBK1383/table/leopard.molgen.TB/?report=objectonly" target="object" rid-ob="figobleopardmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Noonan Syndrome with Multiple Lentigines (View All in OMIM) </p></div></div><div id="leopard.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>Noonan syndrome with multiple lentigines (NSML) is a RASopathy, a class of disorders for which genetic variation alters proteins belonging to the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. The pathogenic variants in <i>PTPN11</i> that cause NSML are all pathogenic missense variants. These pathogenic variants are distinct from the pathogenic missense variants in <i>PTPN11</i> that cause Noonan syndrome (NS). The NS-associated pathogenic variants are gain of function, with increased activity of the protein tyrosine phosphatase, SHP-2, encoded by <i>PTPN11</i>. For NSML-associated <i>PTPN11</i> pathogenic variants, however, the effects are different. The altered SHP-2 proteins have reduced, but not eliminated, phosphatase activities. Biochemical studies have suggested both dominant-negative effects and gain-of-function effects, the latter through liquid-liquid phase separation. Efforts to definitively understand how <i>PTPN11</i> pathogenic variants cause NSML are ongoing. NS- and NSML-causing <i>PTPN11</i> pathogenic variants have different effects on the MAPK and PI3k-AKT-mTOR signaling pathways. The other NSML-related genes, <i>BRAF</i>, <i>MAP2K1</i>, and <i>RAF1</i>, encode kinases that phosphorylate proteins in the RAS-MAPK pathway, with positive regulatory functions. The precise mechanism(s) through which alterations in those proteins could mediate NSML have not been well studied.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figleopardTnoonansyndromewithmultiple1"><a href="/books/NBK1383/table/leopard.T.noonan_syndrome_with_multiple_1/?report=objectonly" target="object" title="Table 8. " class="img_link icnblk_img" rid-ob="figobleopardTnoonansyndromewithmultiple1"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="leopard.T.noonan_syndrome_with_multiple_1"><a href="/books/NBK1383/table/leopard.T.noonan_syndrome_with_multiple_1/?report=objectonly" target="object" rid-ob="figobleopardTnoonansyndromewithmultiple1">Table 8. </a></h4><p class="float-caption no_bottom_margin">Noonan Syndrome with Multiple Lentigines: Mechanism of Disease Causation </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figleopardTnoonansyndromewithmultiple2"><a href="/books/NBK1383/table/leopard.T.noonan_syndrome_with_multiple_2/?report=objectonly" target="object" title="Table 9. " class="img_link icnblk_img" rid-ob="figobleopardTnoonansyndromewithmultiple2"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="leopard.T.noonan_syndrome_with_multiple_2"><a href="/books/NBK1383/table/leopard.T.noonan_syndrome_with_multiple_2/?report=objectonly" target="object" rid-ob="figobleopardTnoonansyndromewithmultiple2">Table 9. </a></h4><p class="float-caption no_bottom_margin">Noonan Syndrome with Multiple Lentigines: Notable Pathogenic Variants by Gene </p></div></div></div><div id="leopard.Cancer_and_Benign_Tumors"><h3>Cancer and Benign Tumors</h3><p>Sporadic tumors (including leukemia and solid tumors) occurring as single tumors in the absence of any other findings of NSML may harbor somatic nucleotide variants in <i>BRAF</i>, <i>MAP2K1</i>, <i>PTPN11</i>, or <i>RAF1</i> that are not present in the germline; thus, predisposition to these tumors is not heritable. See <a href="https://cancer.sanger.ac.uk/cosmic" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Catalogue of Somatic Mutations in Cancer</a>.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Solid tumors.</b>
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<i>BRAF</i> variants mutated in solid tumors, such as p.Asp594Gly and p.Thr599Ile, alter the functional activation segment [<a class="bibr" href="#leopard.REF.pandit.2007.1007" rid="leopard.REF.pandit.2007.1007">Pandit et al 2007</a>]. However, no occurrence of the common <i>BRAF</i> oncogenic somatic p.Val600Glu amino acid substitution has been documented to occur as a germline event associated with cardiofaciocutaneous syndrome (CFCS), NS, or NSML.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Leukemia.</b> Juvenile myelomonocytic leukemia (JMML) accounts for one third of childhood cases of myelodysplastic syndrome (MDS) and about 2% of leukemia. Somatic pathogenic variants in exons 3 and 13 of <i>PTPN11</i> have been demonstrated in 34% of a cohort with JMML [<a class="bibr" href="#leopard.REF.tartaglia.2003b.148" rid="leopard.REF.tartaglia.2003b.148">Tartaglia et al 2003b</a>]. Pathogenic variants in exon 3 were also found in 19% of children with MDS with an excess of blast cells, which often evolves into acute myeloid leukemia (AML) and is associated with poor prognosis. Nonsyndromic AML, especially the monocyte subtype FAB-M5, has been shown to be caused by <i>PTPN11</i> pathogenic variants. All these pathogenic variants result in a gain of function of the protein tyrosine phosphatase non-receptor type 11 (SHP-2), likely leading to an early initiating lesion in JMML oncogenesis with increased cell proliferation attributable (in part) to prolonged activation of the RAS/MAPK pathway.</div><div class="half_rhythm">The spectrum of leukemogenesis associated with <i>PTPN11</i> pathogenic variants has been extended to include childhood acute lymphoblastic leukemia (ALL). Pathogenic variants were observed in 8% of B-cell precursor ALL cases, but not among children with T-lineage ALL [<a class="bibr" href="#leopard.REF.tartaglia.2004b.307" rid="leopard.REF.tartaglia.2004b.307">Tartaglia et al 2004b</a>]. Additionally, SHP-2-activating <i>PTPN11</i> pathogenic variants have been found rarely in solid tumors, including breast, lung, and gastric neoplasms and neuroblastoma [<a class="bibr" href="#leopard.REF.bentiresalj.2004.8816" rid="leopard.REF.bentiresalj.2004.8816">Bentires-Alj et al 2004</a>].</div></li></ul></div></div><div id="leopard.Chapter_Notes"><h2 id="_leopard_Chapter_Notes_">Chapter Notes</h2><div id="leopard.Author_Notes"><h3>Author Notes</h3><p>
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<b>Bruce D Gelb, MD</b>
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</p><p>Mindich Institute for Child Health and Development and the Departments of Pediatrics and Genetics & Genomics, Icahn School of Medicine at Mount Sinai, New York, NY<br />Email: <a href="mailto:dev@null" data-email="ude.mssm@bleg.ecurb" class="oemail">ude.mssm@bleg.ecurb</a><br />Web page: <a href="https://icahn.mssm.edu/profiles/bruce-d-gelb" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">icahn.mssm.edu/profiles/bruce-d-gelb</a></p><p>Dr Gelb is trained in pediatric cardiology. His research focuses on understanding the causes and pathogenesis of the RASopathies as well as developing treatments for them. He is a member of the <a href="https://rasopathiesnet.org/about/research-advisory-board/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Scientific Advisory Board of RASopathies Network</a> and the <a href="https://www.cfcsyndrome.org/medical-advisory-board" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Medical Advisory Board of CFC International</a>.</p><p>
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<b>Marco Tartaglia, PhD</b>
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</p><p>Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy<br />Email: <a href="mailto:dev@null" data-email="ten.gbpo@ailgatrat.ocram" class="oemail">ten.gbpo@ailgatrat.ocram</a></p><p>Dr Tartaglia is a molecular geneticist. His research focuses on the molecular bases of human disorders affecting development. He is particularly interested in Noonan syndrome and related disorders, working to identify the genes implicated in these diseases, elucidate the mechanisms underlying pathogenesis, and characterize clinically relevant information for more effective patient care.</p></div><div id="leopard.Acknowledgments"><h3>Acknowledgments</h3><p>This work was supported in part by grants from the National Institutes of Health (HL135742) to BDG; Associazione Italiana Ricerca sul Cancro (AIRC, IG21614), European Joint Program on Rare Diseases (NSEuroNet); Lazio Innova (Progetti Gruppi di Ricerca 2020 - Asse I Ricerca e Innovazione); Italian Ministry of Health (Ricerca Corrente); and Italian Ministry of Research (FOE 2019/2020) to MT.</p></div><div id="leopard.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>30 June 2022 (ma) Comprehensive update posted live</div></li><li class="half_rhythm"><div>14 May 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>16 November 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>30 November 2007 (me) Review posted live</div></li><li class="half_rhythm"><div>13 November 2007 (bdg) Original submission</div></li></ul></div></div><div id="leopard.References"><h2 id="_leopard_References_">References</h2><div id="leopard.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.alfieri.2008.335">Alfieri P, Cesarini L, Zampino G, Pantaleoni F, Selicorni A, Salerni A, Vasta I, Cerutti M, Dickmann A, Colitto F, Staccioli S, Leoni C, Ricci D, Brogna C, Tartaglia M, Mercuri E. 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Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. <span><span class="ref-journal">Nat Genet. </span>2007;<span class="ref-vol">39</span>:1007–12.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17603483" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17603483</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.rahbari.2016.126">Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. <span><span class="ref-journal">Nat Genet. </span>2016;<span class="ref-vol">48</span>:126–33.</span> [<a href="/pmc/articles/PMC4731925/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4731925</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26656846" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26656846</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.razzaque.2007.1013">Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, Kamisago M, Momma K, Katayama H, Nakagawa M, Fujiwara Y, Matsushima M, Mizuno K, Tokuyama M, Hirota H, Muneuchi J, Higashinakagawa T, Matsuoka R. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. <span><span class="ref-journal">Nat Genet. </span>2007;<span class="ref-vol">39</span>:1013–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17603482" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17603482</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.rodr_guez.2019.1598">Rodríguez F, Ponce D, Berward FJ, Lopetegui B, Cassorla F, Aracena M. RAF1 variant in a patient with Noonan syndrome with multiple lentigines and craniosynostosis. <span><span class="ref-journal">Am J Med Genet A. </span>2019;<span class="ref-vol">179</span>:1598–602.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31145547" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31145547</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.sarkozy.2009.695">Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, Scioletti AP, Esposito G, Cordeddu V, Lepri F, Petrangeli V, Dentici ML, Mancini GM, Selicorni A, Rossi C, Mazzanti L, Marino B, Ferrero GB, Silengo MC, Memo L, Stanzial F, Faravelli F, Stuppia L, Puxeddu E, Gelb BD, Dallapiccola B, Tartaglia M. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. <span><span class="ref-journal">Hum Mutat. </span>2009;<span class="ref-vol">30</span>:695–702.</span> [<a href="/pmc/articles/PMC4028130/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4028130</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19206169" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19206169</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.sarkozy.2008.13">Sarkozy A, Digilio MC, Dallapiccola B. Leopard syndrome. <span><span class="ref-journal">Orphanet J Rare Dis. </span>2008;<span class="ref-vol">3</span>:13.</span> [<a href="/pmc/articles/PMC2467408/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2467408</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18505544" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18505544</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.smpokou.2015.516">Smpokou P, Zand DJ, Rosenbaum KN, Summar ML. Malignancy in Noonan syndrome and related disorders. <span><span class="ref-journal">Clin Genet. </span>2015;<span class="ref-vol">88</span>:516–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25683281" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25683281</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.tartaglia.2010.99">Tartaglia M, Gelb BD. Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms. <span><span class="ref-journal">Ann N Y Acad Sci. </span>2010;<span class="ref-vol">1214</span>:99–121.</span> [<a href="/pmc/articles/PMC3010252/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3010252</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20958325" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20958325</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.tartaglia.2004b.307">Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone I, Spinelli M, Palmi C, Carta C, Pession A, Arico M, Masera G, Basso G, Sorcini M, Gelb BD, Biondi A. Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. <span><span class="ref-journal">Blood. </span>2004b;<span class="ref-vol">104</span>:307–13.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14982869" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14982869</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.tartaglia.2003b.148">Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. <span><span class="ref-journal">Nat Genet. </span>2003b;<span class="ref-vol">34</span>:148–50.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12717436" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12717436</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.van_den_heurck.2021">Van den Heurck JJ, Boven KB, Claes CC. Optic disc coloboma and contralateral optic disc pit maculopathy treated by vitrectomy in a patient with Noonan syndrome with multiple lentigines. <span><span class="ref-journal">Retin Cases Brief Rep. </span>2021.</span> Epub ahead of print. [<a href="/pmc/articles/PMC9949519/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9949519</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34009903" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34009903</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.villani.2017.e83">Villani A, Greer MC, Kalish JM, Nakagawara A, Nathanson KL, Pajtler KW, Pfister SM, Walsh MF, Wasserman JD, Zelley K, Kratz CP. Recommendations for cancer surveillance in individuals with RASopathies and other rare genetic conditions with increased cancer risk. <span><span class="ref-journal">Clin Cancer Res. </span>2017;<span class="ref-vol">23</span>:e83–e90.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28620009" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28620009</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.voron.1976.447">Voron DA, Hatfield HH, Kalkhoff RK. Multiple lentigines syndrome. Case report and review of the literature. <span><span class="ref-journal">Am J Med. </span>1976;<span class="ref-vol">60</span>:447–56.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1258892" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1258892</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.watanabe.2011.576">Watanabe Y, Yano S, Niihori T, Aoki Y, Matsubara Y, Yoshino M, Matsuishi T. A familial case of LEOPARD syndrome associated with a high-functioning autism spectrum disorder. <span><span class="ref-journal">Brain Dev. </span>2011;<span class="ref-vol">33</span>:576–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21093184" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21093184</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.witt.1986.150">Witt DR, Keena BA, Hall JG, Allanson JE. Growth curves for height in Noonan syndrome. <span><span class="ref-journal">Clin Genet. </span>1986;<span class="ref-vol">30</span>:150–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3780030" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3780030</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="leopard.REF.zhu.2020.490">Zhu G, Xie J, Kong W, Xie J, Li Y, Du L, Zheng Q, Sun L, Guan M, Li H, Zhu T, He H, Liu Z, Xia X, Kan C, Tao Y, Shen HC, Li D, Wang S, Yu Y, Yu ZH, Zhang ZY, Liu C, Zhu J. Phase separation of disease-associated SHP2 mutants underlies MAPK hyperactivation. <span><span class="ref-journal">Cell. </span>2020;<span class="ref-vol">183</span>:490–502.e18.</span> [<a href="/pmc/articles/PMC7572904/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7572904</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33002410" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33002410</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1383_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Bruce D Gelb</span>, MD<div class="affiliation small">Departments of Pediatrics and Genetics and Genomic Sciences
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Mindich Child Health and Development Institute
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Icahn School of Medicine at Mount Sinai
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New York, New York<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.mssm@bleg.ecurb" class="oemail">ude.mssm@bleg.ecurb</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Marco Tartaglia</span>, PhD<div class="affiliation small">Genetics and Rare Disease Research Division
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Bambino Gesú Children’s Hospital IRCSS
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Rome, Italy<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ten.gbpo@ailgatrat.ocram" class="oemail">ten.gbpo@ailgatrat.ocram</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">November 30, 2007</span>; Last Update: <span itemprop="dateModified">June 30, 2022</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Gelb BD, Tartaglia M. Noonan Syndrome with Multiple Lentigines. 2007 Nov 30 [Updated 2022 Jun 30]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/noonan/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/leigh-nucl-ov/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobleopardTmoleculargenetictestingused"><div id="leopard.T.molecular_genetic_testing_used" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Noonan Syndrome with Multiple Lentigines</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1383/table/leopard.T.molecular_genetic_testing_used/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__leopard.T.molecular_genetic_testing_used_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene <sup>1, 2</sup></th><th id="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_2" style="text-align:left;vertical-align:middle;">Proportion of NSML Attributed to Pathogenic Variants in Gene</th><th id="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>3</sup> Detectable by Method</th></tr><tr><th headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_3" id="hd_h_leopard.T.molecular_genetic_testing_used_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>4</sup></th><th headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_3" id="hd_h_leopard.T.molecular_genetic_testing_used_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></th></tr></thead><tbody><tr><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>BRAF</i>
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</td><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2 individuals</td><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_3 hd_h_leopard.T.molecular_genetic_testing_used_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 6.</td><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_3 hd_h_leopard.T.molecular_genetic_testing_used_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown, none reported <sup>7</sup></td></tr><tr><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MAP2K1</i>
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</td><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1 individual</td><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_3 hd_h_leopard.T.molecular_genetic_testing_used_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 8.</td><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_3 hd_h_leopard.T.molecular_genetic_testing_used_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown, none reported <sup>7</sup></td></tr><tr><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>PTPN11</i>
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</td><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>95%</td><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_3 hd_h_leopard.T.molecular_genetic_testing_used_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nearly 100% <sup>9</sup></td><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_3 hd_h_leopard.T.molecular_genetic_testing_used_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown, none reported <sup>7</sup></td></tr><tr><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>RAF1</i>
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</td><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><3%</td><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_3 hd_h_leopard.T.molecular_genetic_testing_used_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nearly 100% <sup>10</sup></td><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_3 hd_h_leopard.T.molecular_genetic_testing_used_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown, none reported <sup>7</sup></td></tr><tr><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown <sup>11</sup></td><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><3%</td><td headers="hd_h_leopard.T.molecular_genetic_testing_used_1_1_1_3 hd_h_leopard.T.molecular_genetic_testing_used_1_1_2_1 hd_h_leopard.T.molecular_genetic_testing_used_1_1_2_2" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;">NA</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">NA = not applicable</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="leopard.TF.1.1"><p class="no_margin">Genes are listed in alphabetic order.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="leopard.TF.1.2"><p class="no_margin">See <a href="/books/NBK1383/?report=reader#leopard.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="leopard.TF.1.3"><p class="no_margin">See <a href="#leopard.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in these genes.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="leopard.TF.1.4"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="leopard.TF.1.5"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="leopard.TF.1.6"><p class="no_margin">Sequence analysis of all coding exons detected pathogenic missense variants in two individuals with clinical features of NSML [<a class="bibr" href="#leopard.REF.koudova.2009.337" rid="leopard.REF.koudova.2009.337">Koudova et al 2009</a>, <a class="bibr" href="#leopard.REF.sarkozy.2009.695" rid="leopard.REF.sarkozy.2009.695">Sarkozy et al 2009</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="leopard.TF.1.7"><p class="no_margin">No exon or whole-gene deletion or duplication involving <i>BRAF</i>, <i>MAP2K1</i>, <i>PTPN11</i>, or <i>RAF1</i> has been reported as causative of NSML. Based on the molecular mechanisms implicated in disease pathogenesis, exon or whole-gene deletions or duplications are not expected to cause NSML.</p></div></dd></dl><dl class="bkr_refwrap"><dt>8. </dt><dd><div id="leopard.TF.1.8"><p class="no_margin">Sequence analysis of all coding exons detected pathogenic missense variants in one individual with clinical features of NSML [<a class="bibr" href="#leopard.REF.nishi.2015.407" rid="leopard.REF.nishi.2015.407">Nishi et al 2015</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>9. </dt><dd><div id="leopard.TF.1.9"><p class="no_margin">Most pathogenic variants causing NSML are identified in exons 7, 12, and 13 [<a class="bibr" href="#leopard.REF.digilio.2002.389" rid="leopard.REF.digilio.2002.389">Digilio et al 2002</a>, <a class="bibr" href="#leopard.REF.legius.2002.571" rid="leopard.REF.legius.2002.571">Legius et al 2002</a>, <a class="bibr" href="#leopard.REF.sarkozy.2009.695" rid="leopard.REF.sarkozy.2009.695">Sarkozy et al 2009</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>10. </dt><dd><div id="leopard.TF.1.10"><p class="no_margin">Sequence analysis of coding exons 6, 13, and 16 detects all reported pathogenic missense variants [<a class="bibr" href="#leopard.REF.pandit.2007.1007" rid="leopard.REF.pandit.2007.1007">Pandit et al 2007</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>11. </dt><dd><div id="leopard.TF.1.11"><p class="no_margin">It is likely that one or more additional, as-yet undefined genes, possibly related to RAS signal transduction, are associated with a small proportion of individuals with NSML in whom no pathogenic variant has been identified in <i>BRAF</i>, <i>MAP2K1</i>, <i>PTPN11</i>, or <i>RAF1</i>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobleopardTnoonansyndromewithmultiple"><div id="leopard.T.noonan_syndrome_with_multiple" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Noonan Syndrome with Multiple Lentigines: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1383/table/leopard.T.noonan_syndrome_with_multiple/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__leopard.T.noonan_syndrome_with_multiple_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2" colspan="3" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Frequency</th><th id="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" style="text-align:left;vertical-align:middle;">Comment</th></tr><tr><th headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2" id="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Nearly all</th><th headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2" id="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Common</th><th headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2" id="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Infrequent</th></tr></thead><tbody><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lentigines</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Often develop after age 4-5 yrs</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dysmorphic facial features</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypertrophic cardiomyopathy</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Up to 70%; may be progressive</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Café au lait macules</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Short stature</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>50%, but height in most persons is <25th centile for age & sex</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cryptorchidism</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~33% of affected males</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intellectual disability</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~33%; typically in mild range</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pulmonary valve stenosis</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~25%</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">EKG abnormalities</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~25%</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sensorineural hearing loss</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~20%</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Craniosynostosis</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurofibromata</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Malignancies</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_2 hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">●</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Given rarity of this finding, no consensus tumor screening protocol for NSML currently exists [<a class="bibr" href="#leopard.REF.villani.2017.e83" rid="leopard.REF.villani.2017.e83">Villani et al 2017</a>].</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">NSML = Noonan syndrome with multiple lentigines</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobleopardTallelicdisordersinthediffe"><div id="leopard.T.allelic_disorders_in_the_diffe" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Allelic Disorders in the Differential Diagnosis of Noonan Syndrome with Multiple Lentigines</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1383/table/leopard.T.allelic_disorders_in_the_diffe/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__leopard.T.allelic_disorders_in_the_diffe_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_leopard.T.allelic_disorders_in_the_diffe_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NSML Gene(s)</th><th id="hd_h_leopard.T.allelic_disorders_in_the_diffe_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Allelic Disorder</th><th id="hd_h_leopard.T.allelic_disorders_in_the_diffe_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_leopard.T.allelic_disorders_in_the_diffe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>BRAF</i>
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<br />
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<i>MAP2K1</i>
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</td><td headers="hd_h_leopard.T.allelic_disorders_in_the_diffe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/cfc/?report=reader">Cardiofaciocutaneous syndrome</a> (CFCS)</td><td headers="hd_h_leopard.T.allelic_disorders_in_the_diffe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>CFCS & NSML have similar cardiac findings; however, in CFCS, ID is usually more severe, w/higher likelihood of structural CNS anomalies & seizures; more skin pathology; & more severe & long-lasting GI problems. In CFCS, facial appearance tends to be coarser; dolichocephaly & absent eyebrows are more common; & blue eyes are less common than in NS.</div></li><li class="half_rhythm"><div>The proportion of CFCS attributed to pathogenic variants in <i>BRAF</i> is 50%-75%; in <i>MAP2K1</i>, ~10%-15%. See <a href="#leopard.Differential_Diagnosis">Differential Diagnosis</a> for other genes assoc w/CFCS.</div></li></ul>
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</td></tr><tr><td headers="hd_h_leopard.T.allelic_disorders_in_the_diffe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>BRAF</i>
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<br />
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<i>MAP2K1</i>
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<br />
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<i>PTPN11</i>
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<br />
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<i>RAF1</i>
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</td><td headers="hd_h_leopard.T.allelic_disorders_in_the_diffe_1_1_1_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/noonan/?report=reader">Noonan syndrome</a> (NS)</td><td headers="hd_h_leopard.T.allelic_disorders_in_the_diffe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>NS is typically assoc w/short stature, congenital heart defect, broad or webbed neck, pectus deformities, variable DD, cryptorchidism, & characteristic facies. NS shows significant overlap w/NSML, but affected persons are unlikely to be deaf or to have profusion of pigmented lesions, lentigines, & café au lait patches.</div></li><li class="half_rhythm"><div>The proportion of NS attributed to pathogenic variants in <i>BRAF</i> is <2%; in <i>MAP2K1</i> <2%; in <i>PTPN11</i> 50%; & in <i>RAF1</i> 5%. See <a href="#leopard.Differential_Diagnosis">Differential Diagnosis</a> for other genes assoc w/NS.</div></li></ul>
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</td></tr><tr><td headers="hd_h_leopard.T.allelic_disorders_in_the_diffe_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>PTPN11</i>
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</td><td headers="hd_h_leopard.T.allelic_disorders_in_the_diffe_1_1_1_3" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">The <i>PTPN11</i>-related NS phenotypic spectrum encompasses a condition referred to as Noonan-like/multiple giant-cell lesion syndrome (NL/MGCLS). NL/MGCLS is characterized by giant-cell granulomas & bone & joint anomalies that can resemble <a href="/books/n/gene/cherubism/?report=reader">cherubism</a>, lesions observed in neurofibromatosis (see <a href="/books/n/gene/nf1/?report=reader">Neurofibromatosis Type 1</a>), or lesions observed in Ramon syndrome w/juvenile rheumatoid arthritis (polyarticular pigmented villonodular synovitis).</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">CNS = central nervous system; DD = developmental delay; GI = gastrointestinal; ID = intellectual disability; NSML = Noonan syndrome with multiple lentigines</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobleopardTmonogenicdisordersofinteres"><div id="leopard.T.monogenic_disorders_of_interes" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Monogenic Disorders of Interest in the Differential Diagnosis of Noonan Syndrome with Multiple Lentigines</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1383/table/leopard.T.monogenic_disorders_of_interes/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__leopard.T.monogenic_disorders_of_interes_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Characteristics / Comment</th></tr></thead><tbody><tr><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>BRAF</i>
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<br />
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<i>KRAS</i>
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<br />
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<i>MAP2K1</i>
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<br />
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<i>MAP2K2</i>
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</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/cfc/?report=reader">Cardiofaciocutaneous syndrome</a> (CFCS)</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#leopard.Genetically_Related_Allelic_Diso">Genetically Related Disorders</a>.</td></tr><tr><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>BRAF</i><br /><i>KRAS</i><br /><i>LZTR1</i><br /><i>MAP2K1</i><br /><i>MRAS</i><br /><i>NRAS</i><br /><i>PTPN11</i><br /><i>RAF1</i><br /><i>RASA2</i><br /><i>RIT1</i><br /><i>RRAS2</i><br /><i>SOS1</i><br /><i>SOS2</i><br /><i>SPRED2</i> <sup>1</sup></td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/noonan/?report=reader">Noonan syndrome</a> (NS)</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD<br />(AR) <sup>2</sup></td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#leopard.Genetically_Related_Allelic_Diso">Genetically Related Disorders</a>.</td></tr><tr><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>CBL</i> <sup>3</sup></td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NS-like disorder ± JMML (OMIM <a href="https://omim.org/entry/613563" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613563</a>)</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variable phenotype characterized by relatively high frequency of neurologic features, predisposition to JMML, & low prevalence of cardiac defects, ↓ growth, & cryptorchidism <sup>4</sup></td></tr><tr><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FGD1</i>
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</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">X-linked Aarskog syndrome (OMIM <a href="https://omim.org/entry/305400" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">305400</a>)</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Characterized by DD, short stature, congenital heart defects, & distinctive facies</td></tr><tr><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>HRAS</i>
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</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/costello/?report=reader">Costello syndrome</a> (CS)</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CS shares features w/NSML, NS, & CFCS. The typical presentation of CS is characterized by diffuse hypotonia & severe feeding difficulties in infancy; short stature; DD/ID; characteristic facial features; curly or sparse, fine hair; loose soft skin w/deep palmar & plantar creases; papillomata of face & perianal region; joint laxity w/ulnar deviation of wrists & fingers; tight Achilles tendons; & cardiac involvement.</td></tr><tr><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MAPK1</i>
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</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>MAPK1</i>-related neurodevelopmental disorder <sup>5</sup></td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinically variable neurodevelopmental disorder w/in RASopathy phenotypic spectrum, reminiscent of NS in some persons. Shared features incl postnatally ↓ growth, craniofacial anomalies, short/webbed neck, low posterior hairline, & skin features. <sup>5</sup></td></tr><tr><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_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_leopard.T.monogenic_disorders_of_interes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Watson syndrome (<a href="/books/n/gene/nf1/?report=reader">neurofibromatosis 1</a> variant)</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variably present in both Watson syndrome & NSML are short stature, pulmonary valve stenosis, variable intellectual development, & skin pigment changes incl café au lait macules. Lentigines are not described in Watson syndrome.</td></tr><tr><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PPP1CB</i><br /><i>SHOC2</i> <sup>3</sup></td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NS w/loose anagen hair (OMIM <a href="https://omim.org/phenotypicSeries/PS607721" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS607721</a>)</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Characteristics of NS + loose anagen hair. Skin often has tanned appearance. Abnormalities of mitral valve are more common than in NS. Growth hormone deficiency is also commonly observed.</td></tr><tr><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_1" scope="row" rowspan="1" 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_leopard.T.monogenic_disorders_of_interes_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/legius/?report=reader">Legius syndrome</a>
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</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_leopard.T.monogenic_disorders_of_interes_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The majority of affected persons have café au lait macules; 30%-50% have skin freckling; 30% have developmental issues; 15% have Noonan-like facial features.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; GI = gastrointestinal; ID = intellectual disability; JMML = juvenile myelomonocytic leukemia; MOI = mode of inheritance; NSML = Noonan syndrome with multiple lentigines; XL = X-linked</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="leopard.TF.4.1"><p class="no_margin">
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<a class="bibr" href="#leopard.REF.motta.2021.2112" rid="leopard.REF.motta.2021.2112">Motta et al [2021]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="leopard.TF.4.2"><p class="no_margin">NS is most often inherited in an autosomal dominant manner. NS caused by pathogenic variants in <i>LZTR1</i> can be inherited in an autosomal dominant or autosomal recessive manner. NS caused by pathogenic variants in <i>SPRED2</i> is inherited in an autosomal recessive manner.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="leopard.TF.4.3"><p class="no_margin">Because of the significant phenotypic overlap with classic NS, most RASopathy diagnostic gene panels include testing for the common <i>SHOC2</i> variant and <i>CBL</i> gene sequencing.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="leopard.TF.4.4"><p class="no_margin"><a class="bibr" href="#leopard.REF.martinelli.2010.250" rid="leopard.REF.martinelli.2010.250">Martinelli et al [2010]</a>, <a class="bibr" href="#leopard.REF.niemeyer.2010.794" rid="leopard.REF.niemeyer.2010.794">Niemeyer et al [2010]</a>, <a class="bibr" href="#leopard.REF.martinelli.2015.787" rid="leopard.REF.martinelli.2015.787">Martinelli et al [2015]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="leopard.TF.4.5"><p class="no_margin">
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<a class="bibr" href="#leopard.REF.motta.2020.499" rid="leopard.REF.motta.2020.499">Motta et al [2020]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobleopardTrecommendedevaluationsfollow"><div id="leopard.T.recommended_evaluations_follow" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Noonan Syndrome with Multiple Lentigines</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1383/table/leopard.T.recommended_evaluations_follow/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__leopard.T.recommended_evaluations_follow_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_leopard.T.recommended_evaluations_follow_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_leopard.T.recommended_evaluations_follow_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Constitutional</b>
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</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of growth parameters</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider plotting of growth parameters on population-specific growth charts & <a href="/books/n/gene/noonan/?report=reader">Noonan syndrome</a> growth charts. <sup>1</sup></td></tr><tr><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cardiovascular</b>
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</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for congenital heart defects & evidence of hypertrophic cardiomyopathy</td></tr><tr><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Electrocardiogram</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for conduction defects & electrical evidence consistent w/cardiac hypertrophy</td></tr><tr><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hearing</b>
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</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiology eval <sup>2</sup></td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for presence & type/degree of hearing loss</td></tr><tr><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Eyes</b>
|
|
</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmology eval</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for presence of colobomata, stereopsis, & abnormal eye movements <sup>3</sup></td></tr><tr><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurologic</b>
|
|
</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurology eval</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl brain MRI for those w/seizure disorders & (possibly) neurodevelopmental delays</td></tr><tr><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Genitourinary</b>
|
|
</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical exam for cryptorchidism in males</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to urologist.</td></tr><tr><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Renal ultrasound</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider urinalysis if urinary tract anomalies are discovered.</td></tr><tr><td headers="hd_h_leopard.T.recommended_evaluations_follow_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_leopard.T.recommended_evaluations_follow_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To incl motor, adaptive, cognitive, & speech/language eval</div></li><li class="half_rhythm"><div>Eval for early intervention / special education</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Musculoskeletal</b>
|
|
</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical assessment of spine & rib cage</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider radiographs & referral to orthopedist if significant scoliosis or rib cage abnormalities are identified.</td></tr><tr><td headers="hd_h_leopard.T.recommended_evaluations_follow_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_leopard.T.recommended_evaluations_follow_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>4</sup></td><td headers="hd_h_leopard.T.recommended_evaluations_follow_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 NSML to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Family support</b>
|
|
<br />
|
|
<b>& resources</b>
|
|
</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for:
|
|
<ul><li class="half_rhythm"><div>Community or <a href="#leopard.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Social work involvement for parental support;</div></li><li class="half_rhythm"><div>Home nursing referral.</div></li></ul>
|
|
</td><td headers="hd_h_leopard.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">MOI = mode of inheritance; NSML = Noonan syndrome with multiple lentigines</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="leopard.TF.5.1"><p class="no_margin"><a class="bibr" href="#leopard.REF.witt.1986.150" rid="leopard.REF.witt.1986.150">Witt et al [1986]</a>; specific growth charts for NSML are not available.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="leopard.TF.5.2"><p class="no_margin">Complete assessment of auditory acuity using age-appropriate tests (e.g., ABR testing, auditory steady-state response [ASSR] testing, pure-tone audiometry).</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="leopard.TF.5.3"><p class="no_margin"><a class="bibr" href="#leopard.REF.alfieri.2008.335" rid="leopard.REF.alfieri.2008.335">Alfieri et al [2008]</a>, <a class="bibr" href="#leopard.REF.van_den_heurck.2021" rid="leopard.REF.van_den_heurck.2021">Van den Heurck et al [2021]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="leopard.TF.5.4"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobleopardTtreatmentofmanifestationsin"><div id="leopard.T.treatment_of_manifestations_in" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Noonan Syndrome with Multiple Lentigines</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1383/table/leopard.T.treatment_of_manifestations_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__leopard.T.treatment_of_manifestations_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_leopard.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_leopard.T.treatment_of_manifestations_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_leopard.T.treatment_of_manifestations_in_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>
|
|
</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Growth hormone therapy may be considered, although no data on use of growth hormone therapy in persons w/NSML exist.</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Growth hormone therapy may be contraindicated in persons w/HCM.</div></li><li class="half_rhythm"><div>Prior to instituting growth hormone therapy, cardiac eval for HCM is recommended; continued surveillance for development of HCM while on growth hormone therapy is reasonable.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>HCM</b>
|
|
</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per cardiologist & cardiovascular surgeon</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Structural heart defects</b>
|
|
</td></tr><tr><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hearing</b>
|
|
</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing aids may be helpful; per otolaryngologist.</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Community hearing services through early intervention or school district</td></tr><tr><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Consider cochlear implantation for persons w/profound deafness.</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="/books/n/gene/deafness-overview/?report=reader">Hereditary Hearing Loss and Deafness Overview</a>.</td></tr><tr><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Colobomata, stereopsis,</b>
|
|
<br />
|
|
<b>& abnormal eye mvmts</b>
|
|
</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per ophthalmologist</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Seizures</b>
|
|
</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per neurologist</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Cryptorchidism /</b>
|
|
<br />
|
|
<b>Genitourinary anomalies</b>
|
|
</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per urologist</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.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_leopard.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#leopard.Developmental_Delay__Intellectua">Developmental Delay / Intellectual Disability Management Issues</a>.</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Family/Community</b>
|
|
</td><td headers="hd_h_leopard.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>Ensure appropriate social work involvement to connect families w/local resources, respite, & support.</div></li><li class="half_rhythm"><div>Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.</div></li></ul>
|
|
</td><td headers="hd_h_leopard.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ongoing assessment of need for palliative care involvement &/or home nursing</div></li><li class="half_rhythm"><div>Consider involvement in adaptive sports or Special Olympics.</div></li></ul>
|
|
</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">HCM = hypertrophic cardiomyopathy; NSML = Noonan syndrome with multiple lentigines</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobleopardTrecommendedsurveillancefori"><div id="leopard.T.recommended_surveillance_for_i" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Noonan Syndrome with Multiple Lentigines</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1383/table/leopard.T.recommended_surveillance_for_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__leopard.T.recommended_surveillance_for_i_lrgtbl__"><table><thead><tr><th id="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_leopard.T.recommended_surveillance_for_i_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_leopard.T.recommended_surveillance_for_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Growth</b>
|
|
</td><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of growth parameters</td><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Cardiovascular</b>
|
|
</td><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiac auscultation to assess for new heart murmur</td></tr><tr><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram</td><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually until age 3 yrs, then at ages 5 yrs & 10 yrs or as clinically indicated</td></tr><tr><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Hearing</b>
|
|
</td><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiology eval</td><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At least annually in infancy & childhood or as clinically indicated</td></tr><tr><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Eyes</b>
|
|
</td><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmology eval</td><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If nystagmus is noted or as clinically indicated</td></tr><tr><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Neurologic</b>
|
|
</td><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for new manifestations such as seizure.</td><td headers="hd_h_leopard.T.recommended_surveillance_for_i_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_leopard.T.recommended_surveillance_for_i_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_leopard.T.recommended_surveillance_for_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental progress & educational needs.</td></tr><tr><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Family/</b>
|
|
<br />
|
|
<b>Community</b>
|
|
</td><td headers="hd_h_leopard.T.recommended_surveillance_for_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) & care coordination.</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobleopardmolgenTA"><div id="leopard.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Noonan Syndrome with Multiple Lentigines: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1383/table/leopard.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__leopard.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_leopard.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_leopard.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_leopard.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_leopard.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_leopard.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_leopard.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_leopard.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="/gene/673" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
|
<i>BRAF</i>
|
|
</a>
|
|
</td><td headers="hd_b_leopard.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=673" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">7q34</a>
|
|
</td><td headers="hd_b_leopard.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/P15056" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Serine/threonine-protein kinase B-raf</a>
|
|
</td><td headers="hd_b_leopard.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://databases.lovd.nl/shared/genes/BRAF" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">BRAF database</a>
|
|
<br />
|
|
<a href="https://nseuronet.com/php/statistic.php?genotype=5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NSEuroNet database - BRAF</a>
|
|
</td><td headers="hd_b_leopard.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=BRAF" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">BRAF</a>
|
|
</td><td headers="hd_b_leopard.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=BRAF[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">BRAF</a>
|
|
</td></tr><tr><td headers="hd_b_leopard.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="/gene/5604" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
|
<i>MAP2K1</i>
|
|
</a>
|
|
</td><td headers="hd_b_leopard.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=5604" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">15q22<wbr style="display:inline-block"></wbr>​.31</a>
|
|
</td><td headers="hd_b_leopard.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/Q02750" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Dual specificity mitogen-activated protein kinase kinase 1</a>
|
|
</td><td headers="hd_b_leopard.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.LOVD.nl/MAP2K1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MAP2K1 @ LOVD</a>
|
|
<br />
|
|
<a href="https://nseuronet.com/php/statistic.php?genotype=9" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NSEuroNet database - MAP2K1</a>
|
|
</td><td headers="hd_b_leopard.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=MAP2K1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MAP2K1</a>
|
|
</td><td headers="hd_b_leopard.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=MAP2K1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MAP2K1</a>
|
|
</td></tr><tr><td headers="hd_b_leopard.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="/gene/5781" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
|
<i>PTPN11</i>
|
|
</a>
|
|
</td><td headers="hd_b_leopard.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=5781" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">12q24<wbr style="display:inline-block"></wbr>​.13</a>
|
|
</td><td headers="hd_b_leopard.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/Q06124" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Tyrosine-protein phosphatase non-receptor type 11</a>
|
|
</td><td headers="hd_b_leopard.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://databases.lovd.nl/shared/genes/PTPN11" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PTPN11 database</a>
|
|
<br />
|
|
<a href="http://structure.bmc.lu.se/idbase/PTPN11base/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PTPN11base: Database for pathogenic mutations in the SHP-2 SH2 domain</a>
|
|
<br />
|
|
<a href="https://nseuronet.com/php/statistic.php?genotype=7" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NSEuroNet database - PTPN11</a>
|
|
</td><td headers="hd_b_leopard.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=PTPN11" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PTPN11</a>
|
|
</td><td headers="hd_b_leopard.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=PTPN11[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PTPN11</a>
|
|
</td></tr><tr><td headers="hd_b_leopard.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="/gene/5894" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
|
<i>RAF1</i>
|
|
</a>
|
|
</td><td headers="hd_b_leopard.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=5894" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">3p25<wbr style="display:inline-block"></wbr>​.2</a>
|
|
</td><td headers="hd_b_leopard.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/P04049" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">RAF proto-oncogene serine/threonine-protein kinase</a>
|
|
</td><td headers="hd_b_leopard.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://nseuronet.com/php/statistic.php?genotype=6" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NSEuroNet database - RAF1</a>
|
|
</td><td headers="hd_b_leopard.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=RAF1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">RAF1</a>
|
|
</td><td headers="hd_b_leopard.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=RAF1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">RAF1</a>
|
|
</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="leopard.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
|
|
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
|
chromosome locus from
|
|
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
|
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
|
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
|
<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobleopardmolgenTB"><div id="leopard.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Noonan Syndrome with Multiple Lentigines (<a href="/omim/151100,164757,164760,176872,176876,611554,613707" 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/NBK1383/table/leopard.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__leopard.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/151100" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">151100</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LEOPARD SYNDROME 1; LPRD1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/164757" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">164757</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">B-RAF PROTOONCOGENE, SERINE/THREONINE KINASE; BRAF</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/164760" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">164760</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">RAF1 PROTOONCOGENE, SERINE/THREONINE KINASE; RAF1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/176872" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">176872</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1; MAP2K1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/176876" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">176876</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 11; PTPN11</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/611554" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">611554</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LEOPARD SYNDROME 2; LPRD2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/613707" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">613707</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LEOPARD SYNDROME 3; LPRD3</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobleopardTnoonansyndromewithmultiple1"><div id="leopard.T.noonan_syndrome_with_multiple_1" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Noonan Syndrome with Multiple Lentigines: Mechanism of Disease Causation</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1383/table/leopard.T.noonan_syndrome_with_multiple_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__leopard.T.noonan_syndrome_with_multiple_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_leopard.T.noonan_syndrome_with_multiple_1_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_leopard.T.noonan_syndrome_with_multiple_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mechanism</th><th id="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment/Reference</th></tr></thead><tbody><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>BRAF</i>
|
|
</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gain of function</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#leopard.REF.sarkozy.2009.695" rid="leopard.REF.sarkozy.2009.695">Sarkozy et al [2009]</a>
|
|
</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MAP2K1</i>
|
|
</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gain of function</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#leopard.REF.nishi.2015.407" rid="leopard.REF.nishi.2015.407">Nishi et al [2015]</a>
|
|
</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>PTPN11</i>
|
|
</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mixed loss-of-function & dominant-negative effects</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a class="bibr" href="#leopard.REF.kontaridis.2006.6785" rid="leopard.REF.kontaridis.2006.6785">Kontaridis et al [2006]</a>, <a class="bibr" href="#leopard.REF.zhu.2020.490" rid="leopard.REF.zhu.2020.490">Zhu et al [2020]</a></td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>RAF1</i>
|
|
</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gain of function</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a class="bibr" href="#leopard.REF.pandit.2007.1007" rid="leopard.REF.pandit.2007.1007">Pandit et al [2007]</a>, <a class="bibr" href="#leopard.REF.razzaque.2007.1013" rid="leopard.REF.razzaque.2007.1013">Razzaque et al [2007]</a></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="leopard.TF.8.1"><p class="no_margin">Genes from <a href="/books/NBK1383/table/leopard.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobleopardTmoleculargenetictestingused">Table 1</a> in alphabetic order</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobleopardTnoonansyndromewithmultiple2"><div id="leopard.T.noonan_syndrome_with_multiple_2" class="table"><h3><span class="label">Table 9. </span></h3><div class="caption"><p>Noonan Syndrome with Multiple Lentigines: Notable Pathogenic Variants by Gene</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1383/table/leopard.T.noonan_syndrome_with_multiple_2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__leopard.T.noonan_syndrome_with_multiple_2_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_leopard.T.noonan_syndrome_with_multiple_2_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_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide<br />Change</th><th id="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted<br />Protein Change</th><th id="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>BRAF</i>
|
|
</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/187608632" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_004333<wbr style="display:inline-block"></wbr>​.6</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/33188459" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_004324<wbr style="display:inline-block"></wbr>​.2</a>
|
|
</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.721A>C</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Thr241Pro</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.735A>T</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu245Phe</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">FDA-recognized variant</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>MAP2K1</i>
|
|
</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_002755.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_002755<wbr style="display:inline-block"></wbr>​.4</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_002746.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_002746<wbr style="display:inline-block"></wbr>​.1</a>
|
|
</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.199G>A</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asp67Asn</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">FDA-recognized variant</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.305A>G</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Glu102Gly</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_1" rowspan="8" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>PTPN11</i>
|
|
</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_2" rowspan="8" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/33356176" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_002834<wbr style="display:inline-block"></wbr>​.5</a>
|
|
<br />
|
|
<a href="https://www.ncbi.nlm.nih.gov/protein/33356177" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_002825<wbr style="display:inline-block"></wbr>​.3</a>
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|
</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.836A>G</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Tyr279Cys</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1381G>A</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ala461Thr</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1391G>C</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly464Met</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1402C>T</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Thr468Met</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assoc w/malignancy in a small case series [<a class="bibr" href="#leopard.REF.smpokou.2015.516" rid="leopard.REF.smpokou.2015.516">Smpokou et al 2015</a>]</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1507G>C</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly503Arg</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1510A>G</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Met504Val</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">FDA-recognized variant</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1517A>C</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gln506Pro</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1529A>C</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gln510Pro</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">FDA-recognized variant</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>RAF1</i>
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</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/52486392" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_002880<wbr style="display:inline-block"></wbr>​.4</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/4506401" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_002871<wbr style="display:inline-block"></wbr>​.1</a>
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</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.770C>T</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ser257Leu</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">FDA-recognized variant</td></tr><tr><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1837C>G</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu613Val</td><td headers="hd_h_leopard.T.noonan_syndrome_with_multiple_2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">FDA-recognized variant</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="leopard.TF.9.1"><p class="no_margin">Genes from <a href="/books/NBK1383/table/leopard.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobleopardTmoleculargenetictestingused">Table 1</a> in alphabetic order</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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