Atypical left-ventricular hypertrophy with apical aneurysm in Leopard Syndrome.

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Jose Antonio Fernandez-Sanchez, Lucia Cobarro-Galvez, Francisco Jose Bermudez-Jimenez, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4638334/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Jul, 2024 Read the published version in The International Journal of Cardiovascular Imaging → Version 1 posted 7 You are reading this latest preprint version Abstract Noonan Syndrome with Multiple Lentigines (NSML-formerly known as LEOPARD syndrome) is a rare autosomal dominant condition that usually exhibits cardiac involvement with hypertrophic cardiomyopathy (HCM). Here we present a case of a NSML patient with an unusual and patchy cardiac hypertrophy distribution. Figures Figure 1 Figure 2 Main Text Noonan Syndrome with Multiple Lentigines (NSML-formerly known as LEOPARD syndrome) is a rare autosomal dominant condition that exhibits cardiac involvement with hypertrophic cardiomyopathy (HCM), multiple cutaneous lentigines and dysmorphic features such as ocular hypertelorism, genital anomalies, growth deficiencies, and hearing impairment [1]. A 40-year-old woman was referred to our Inherited Cardiac Diseases Unit for familiar screening after her daughter had been diagnosed with NSML. She had no previous personal nor familial cardiovascular history and was asymptomatic. At physical examination she presented facial dysmorphic features, including broad forehead, hypertelorism and low-set posteriorly rotated ears; she also presented with pectus excavatum and multiple lentigines (supplemental figure 1A) which were located mainly in the back. The 12-lead ECG showed sinus rhythm, no axis deviation, narrow QRS without electrical criteria of ventricular hypertrophy and negative T waves in inferior and precordial leads. A twenty-four-hour Holter monitoring demonstrated one episode of non-sustained ventricular tachycardia (NSVT). A transthoracic echocardiogram (TTE) showed an atypical distribution of left ventricular (LV) hypertrophy with a moderately increased thickness (maximum of 16 mm) in the confluence of the basal and mid inferior and inferolateral segments with an increased endocardial echogenicity, suggestive of fibrosis (figure 1A). Furthermore, localized apical hypertrophic segments with regional contractility abnormalities and a small distal aneurysm formation were detected (figure 1B and supplemental video). Ultrasound contrast was used, which verified limited expansion in the distal apical area and a myocardial wall that was thinned and displayed an ace-of-spades shape (figure 1C). Cardiac magnetic resonance was performed showing a non-dilated LV without systolic function impairment. The wall thickness was noticeably increased in the distal apex but also in basal inferior and inferolateral segments (video 1 and figure 2). Patchy late gadolinium enhancement was found in the apical segments where the maximum thickness (16mm) was described and both, extracellular volume and native T1-Mapping times, had increased values in these areas. A genetic study was conducted, revealing the presence of a pathogenic variant in the PTPN11 gene (p.Thr468Met). Her parents were then studied with a negative test in both, so she was classified as a “de novo” case. The pedigree is shown in supplemental figure 1B. Cardiac abnormalities are present in 85% of NSML patients and the hypertrophic cardiomyopathy (HCM), which usually appears during infancy, is the most common cardiac abnormality (70-80%) followed by pulmonary valve stenosis (10-20% of affected individuals) [2]. Limongelli et al. examined 26 patients with NSML and found that asymmetric LVH is the most common hypertrophy pattern, while concentric or apical hypertrophy was rare. In this series, only one patient showed LV apical aneurysm [3]. They described different types of LV remodeling, with absolute regression of the hypertrophy being the most common pattern of LV remodeling, followed by no LV remodeling, progression, and relative regression [4]. Patients with RASopathies are known to carry a high risk of death or heart transplantation, though due to the rarity of NSML there is a lack of data with regard to the progression of the disease and risk of cardiac adverse events [3,4] and this scarce knowledge is also applied to the presence of apical aneurisms as they are associated with increased morbidity in patients with sarcomere-related HCM, but its significance in NSML patients has not been described yet. In summary, our case illustrates an unusual presentation of cardiac phenotype in NSML with patchy hypertrophic cardiomyopathy, involvement of basal and middle segments of the LV and distal apical aneurysm. Declarations Competing interest: the authors have no relevant financial or non-financial interests to disclose. Funding: the authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Ethics approval: Our institution does not require ethical approval for reporting individual cases or case series. Consent: The patient gave his consent to appear in the publication, in accordance with the COPE guidelines. Data availability: The data underlying this article are available in the article and in its online supplementary material. Autorship: All authors whose names appear on the submission: 1) made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data; or the creation of new software used in the work; 2) drafted the work or revised it critically for important intellectual content; 3) approved the version to be published; and 4) agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. References Towbin JA, Jefferies JL, Ryan TD (2017) 154 - Pathophysiology of Cardiomyopathies. In: Polin RA, Abman SH, Rowitch DH, Benitz WE, Fox WW (eds) Fetal and Neonatal Physiology (Fifth Edition) [Internet]. Elsevier, p 15631575e4. [cited 2023 Oct 30] Sarkozy A, Digilio MC, Dallapiccola B (2008) Leopard syndrome. Orphanet J Rare Dis 3:13 Published 2008 May 27. 10.1186/1750-1172-3-13 Limongelli G, Pacileo G, Marino B, Digilio MC, Sarkozy A, Elliott P et al (2007) Prevalence and Clinical Significance of Cardiovascular Abnormalities in Patients With the LEOPARD Syndrome. Am J Cardiol 100(4):736–741 Monda E, Prosnitz A, Aiello R, Lioncino M, Norrish G, Caiazza M et al (2023) Natural History of Hypertrophic Cardiomyopathy in Noonan Syndrome With Multiple Lentigines. Circ Genomic Precis Med 16(4):350–358 Video Video 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Video1def.mp4 Video 1. Cine-motion sequences in cardiac magnetic resonance images acquired at 1.5T. 1A-B A2C and A3C views with localized hypertrophy in basal inferior and inferolateral segments. 1C (4C) showing apical hypertrophy and localized hypoquinesia. Supplfigure1.jpeg Supplemental figure 1. Panel A. Multiple lentigines on patient's back. Panel B. Pedigree with pathogenic variant in the PTPN1 gen . VideoS1.mp4 Supplemental video S1. Transthoracic echocardiography video images acquired with Vivid T8. Video 1. Moderately increased thickness in the confluence of the basal and mid inferior and inferolateral segments with an increased endocardial echogenicity in PLAX (1A), modified-PLAX (1B) and SAX (1C) views. Localized apical hypertrophic segments with regional contractility abnormalities and distal aneurysm formation in A2C (1D) and A4C (1E) views. Contrast-enhanced ecocardiography showing an apical aneurism displaying an ace-of-spades shape (1F). Cite Share Download PDF Status: Published Journal Publication published 08 Jul, 2024 Read the published version in The International Journal of Cardiovascular Imaging → Version 1 posted Editorial decision: Accepted 01 Jul, 2024 Reviews received at journal 29 Jun, 2024 Reviewers agreed at journal 29 Jun, 2024 Reviewers invited by journal 29 Jun, 2024 Editor assigned by journal 26 Jun, 2024 Submission checks completed at journal 26 Jun, 2024 First submitted to journal 25 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4638334","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":321159547,"identity":"14546a57-1e0b-49a8-97c8-425a95efde8d","order_by":0,"name":"Jose Antonio Fernandez-Sanchez","email":"","orcid":"","institution":"Hospital Universitario Virgen de las Nieves","correspondingAuthor":false,"prefix":"","firstName":"Jose","middleName":"Antonio","lastName":"Fernandez-Sanchez","suffix":""},{"id":321159549,"identity":"40f4241e-5dfe-4d43-a76a-f9a0ad142889","order_by":1,"name":"Lucia Cobarro-Galvez","email":"","orcid":"","institution":"Hospital 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18:47:47","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4638334/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4638334/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10554-024-03185-w","type":"published","date":"2024-07-08T19:28:34+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60706215,"identity":"db2311bc-4ba9-4ea9-9f78-94dcd3f084c2","added_by":"auto","created_at":"2024-07-19 19:27:54","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":551803,"visible":true,"origin":"","legend":"\u003cp\u003eTransthoracic echocardiography video images acquired with Vivid T8. \u003cu\u003ePanel 1A\u003c/u\u003e Moderately increased thickness in the confluence of the basal and mid inferior and inferolateral segments with an increased endocardial echogenicity in PLAX view. \u003cu\u003ePanel B\u003c/u\u003e Localized apical hypertrophic segments with regional contractility abnormalities and distal aneurysm formation in A4C view. \u003cu\u003ePanel C\u003c/u\u003e Contrast-enhanced ecocardiography showing an apical aneurism displaying an ace-of-spades shape.\u003c/p\u003e","description":"","filename":"figure1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4638334/v1/0aef37aa13fb03cea1db56a6.jpeg"},{"id":60706216,"identity":"d08b27fd-63c1-487b-8a3b-21cb54006eb2","added_by":"auto","created_at":"2024-07-19 19:27:54","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":682549,"visible":true,"origin":"","legend":"\u003cp\u003eCardiac magnetic resonance images acquired at 1.5T. \u003cu\u003ePanels A-B \u003c/u\u003e2-chambers (2C) and 3-chambers (3C) views localized hypertrophy in basal inferior and inferolateral segment (white arrows). \u003cu\u003ePanel C.\u003c/u\u003e4-chambers (4C) showing apical hypertrophy (white arrow). \u003cu\u003ePanels D-G\u003c/u\u003eBasal, midventricular and apical short-axis views showing apical hypertrophy and localized increased wall thickness in basal inferior and inferolateral segments (white arrows).\u003c/p\u003e","description":"","filename":"Figure2def.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4638334/v1/428c7c0d7e49f23898fd2793.jpeg"},{"id":60707750,"identity":"71831e74-02a7-43fe-81fa-5109847be0f0","added_by":"auto","created_at":"2024-07-19 19:35:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1481515,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4638334/v1/7485756b-acc1-43af-ac36-b96f4ed488c9.pdf"},{"id":60706219,"identity":"0521a376-baea-4223-b636-1ed2f329b24e","added_by":"auto","created_at":"2024-07-19 19:27:55","extension":"mp4","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10002050,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cu\u003e\u003cstrong\u003eVideo 1. \u003c/strong\u003e\u003c/u\u003eCine-motion sequences in cardiac magnetic resonance images acquired at 1.5T. \u003cu\u003e1A-B \u003c/u\u003eA2C and A3C views with localized hypertrophy in basal inferior and inferolateral segments. \u003cu\u003e1C\u003c/u\u003e (4C) showing apical hypertrophy and localized hypoquinesia.\u003c/p\u003e","description":"","filename":"Video1def.mp4","url":"https://assets-eu.researchsquare.com/files/rs-4638334/v1/fc4719d4968b5234b377a770.mp4"},{"id":60707749,"identity":"5e0864e0-4267-4da6-8851-f0456f8e27d9","added_by":"auto","created_at":"2024-07-19 19:35:54","extension":"jpeg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":2483638,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplemental figure 1.\u003c/strong\u003e \u003cu\u003ePanel A.\u003c/u\u003e Multiple lentigines on patient's back. \u003cu\u003ePanel B.\u003c/u\u003e Pedigree with pathogenic variant in the \u003cem\u003ePTPN1 \u003c/em\u003egen\u003cem\u003e.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Supplfigure1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4638334/v1/d56123a1522a6d4986d06cee.jpeg"},{"id":60706218,"identity":"5bada3b9-074d-41d9-bbb2-7af91d80e09d","added_by":"auto","created_at":"2024-07-19 19:27:54","extension":"mp4","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":9152301,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplemental video S1.\u003c/strong\u003e Transthoracic echocardiography video images acquired with Vivid T8. \u003cstrong\u003eVideo 1. \u003c/strong\u003eModerately increased thickness in the confluence of the basal and mid inferior and inferolateral segments with an increased endocardial echogenicity in PLAX \u003cstrong\u003e(1A),\u003c/strong\u003e modified-PLAX \u003cstrong\u003e(1B)\u003c/strong\u003e and SAX \u003cstrong\u003e(1C) \u003c/strong\u003eviews. Localized apical hypertrophic segments with regional contractility abnormalities and distal aneurysm formation in A2C \u003cstrong\u003e(1D)\u003c/strong\u003e and A4C \u003cstrong\u003e(1E)\u003c/strong\u003e views. Contrast-enhanced ecocardiography showing an apical aneurism displaying an ace-of-spades shape \u003cstrong\u003e(1F).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"VideoS1.mp4","url":"https://assets-eu.researchsquare.com/files/rs-4638334/v1/249c4ed72e65fbf137b7dca1.mp4"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eAtypical left-ventricular hypertrophy with apical aneurysm in Leopard Syndrome.\u003c/p\u003e","fulltext":[{"header":"Main Text","content":"\u003cp\u003eNoonan Syndrome with Multiple Lentigines (NSML-formerly known as LEOPARD syndrome) is a rare autosomal dominant condition that exhibits cardiac involvement with hypertrophic cardiomyopathy (HCM), multiple cutaneous lentigines and dysmorphic features such as ocular hypertelorism, genital anomalies, growth deficiencies, and hearing impairment [1].\u003c/p\u003e\n\u003cp\u003eA 40-year-old woman was referred to our Inherited Cardiac Diseases Unit for familiar screening after her daughter had been diagnosed with NSML. She had no previous personal nor familial cardiovascular history and was asymptomatic.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt physical examination she presented facial dysmorphic features, including broad forehead, hypertelorism and low-set posteriorly rotated ears; she also presented with pectus excavatum and multiple lentigines (supplemental figure 1A) which were located mainly in the back. The 12-lead ECG showed sinus rhythm, no axis deviation, narrow QRS without electrical criteria of ventricular hypertrophy and negative T waves in inferior and precordial leads. A twenty-four-hour Holter monitoring demonstrated one episode of non-sustained ventricular tachycardia (NSVT).\u003c/p\u003e\n\u003cp\u003eA transthoracic echocardiogram (TTE) showed an atypical distribution of left ventricular (LV) hypertrophy with a moderately increased thickness (maximum of 16 mm) in the confluence of the basal and mid inferior and inferolateral segments with an increased endocardial echogenicity, suggestive of fibrosis (figure 1A). Furthermore, localized apical hypertrophic segments with regional contractility abnormalities and a small distal aneurysm formation were detected (figure 1B and supplemental video). Ultrasound contrast was used, which verified limited expansion in the distal apical area and a myocardial wall that was thinned and displayed an ace-of-spades shape (figure 1C).\u003c/p\u003e\n\u003cp\u003eCardiac magnetic resonance was performed showing a non-dilated LV without systolic function impairment. The wall thickness was noticeably increased in the distal apex but also in basal inferior and inferolateral segments (video 1 and figure 2). Patchy late gadolinium enhancement was found in the apical segments where the maximum thickness (16mm) was described and both, extracellular volume and native T1-Mapping times, had increased values in these areas.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA genetic study was conducted, revealing the presence of a pathogenic variant in the PTPN11 gene (p.Thr468Met). Her parents were then studied with a negative test in both, so she was classified as a \u0026ldquo;de novo\u0026rdquo; case. The pedigree is shown in supplemental figure 1B.\u003c/p\u003e\n\u003cp\u003eCardiac abnormalities are present in 85% of NSML patients and the hypertrophic cardiomyopathy (HCM), which usually appears during infancy, is the most common cardiac abnormality (70-80%) followed by pulmonary valve stenosis (10-20% of affected individuals) [2]. Limongelli et al. examined 26 patients with NSML and found that asymmetric LVH is the most common hypertrophy pattern, while concentric or apical hypertrophy was rare. In this series, only one patient showed LV apical aneurysm [3].\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;They described different types of LV remodeling, with absolute regression of the hypertrophy being the most common pattern of LV remodeling, followed by no LV remodeling, progression, and relative regression [4].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients with RASopathies are known to carry a high risk of death or heart transplantation, though due to the rarity of NSML there is a lack of data with regard to the progression of the disease and risk of cardiac adverse events [3,4] and this scarce knowledge is also applied to the presence of apical aneurisms as they are associated with increased morbidity in patients with sarcomere-related HCM, but its significance in NSML patients has not been described yet.\u003c/p\u003e\n\u003cp\u003eIn summary, our case illustrates an unusual presentation of cardiac phenotype in NSML with patchy hypertrophic cardiomyopathy, involvement of basal and middle segments of the LV and distal apical aneurysm.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting interest:\u003c/strong\u003e the authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e the authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e Our institution does not require ethical approval for reporting individual cases or case series.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent:\u0026nbsp;\u003c/strong\u003eThe patient gave his consent to appear in the publication, in accordance with\u003c/p\u003e\n\u003cp\u003ethe COPE guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e The data underlying this article are available in the article and in its\u003c/p\u003e\n\u003cp\u003eonline supplementary material.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAutorship:\u003c/strong\u003e All authors whose names appear on the submission:\u003c/p\u003e\n\u003cp\u003e1) made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data; or the creation of new software used in the work;\u003c/p\u003e\n\u003cp\u003e2) drafted the work or revised it critically for important intellectual content;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3) approved the version to be published; and\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4) agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTowbin JA, Jefferies JL, Ryan TD (2017) 154 - Pathophysiology of Cardiomyopathies. In: Polin RA, Abman SH, Rowitch DH, Benitz WE, Fox WW (eds) Fetal and Neonatal Physiology (Fifth Edition) [Internet]. Elsevier, p 15631575e4. [cited 2023 Oct 30]\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSarkozy A, Digilio MC, Dallapiccola B (2008) Leopard syndrome. Orphanet J Rare Dis 3:13 Published 2008 May 27. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/1750-1172-3-13\u003c/span\u003e\u003cspan address=\"10.1186/1750-1172-3-13\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLimongelli G, Pacileo G, Marino B, Digilio MC, Sarkozy A, Elliott P et al (2007) Prevalence and Clinical Significance of Cardiovascular Abnormalities in Patients With the LEOPARD Syndrome. Am J Cardiol 100(4):736\u0026ndash;741\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonda E, Prosnitz A, Aiello R, Lioncino M, Norrish G, Caiazza M et al (2023) Natural History of Hypertrophic Cardiomyopathy in Noonan Syndrome With Multiple Lentigines. Circ Genomic Precis Med 16(4):350\u0026ndash;358\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Video ","content":"\u003cp\u003eVideo 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"the-international-journal-of-cardiovascular-imaging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"caim","sideBox":"Learn more about [The International Journal of Cardiovascular Imaging](https://www.springer.com/journal/10554)","snPcode":"10554","submissionUrl":"https://submission.nature.com/new-submission/10554/3","title":"The International Journal of Cardiovascular Imaging","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4638334/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4638334/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eNoonan Syndrome with Multiple Lentigines (NSML-formerly known as LEOPARD syndrome) is a rare autosomal dominant condition that usually exhibits cardiac involvement with hypertrophic cardiomyopathy (HCM). 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