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Case of Noonan Syndrome With an Expanding Coronary Arterial Aneurysm

2019; Lippincott Williams & Wilkins; Volume: 12; Issue: 9 Linguagem: Inglês

10.1161/circimaging.119.009429

1942-0080

Yoshito Ogihara, Naoki Fujimoto, Hiroyuki Ohashi, Naoki Yamamoto, Hisato Ito, Yoshihide Mitani, Yoko Aoki, Kyoko Imanaka-Yosida, Masaaki Ito, Kaoru Dohi,

Peptidase Inhibition and Analysis

HomeCirculation: Cardiovascular ImagingVol. 12, No. 9Case of Noonan Syndrome With an Expanding Coronary Arterial Aneurysm Free AccessCase ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCase ReportPDF/EPUBCase of Noonan Syndrome With an Expanding Coronary Arterial Aneurysm Yoshito Ogihara, MD, PhD, Naoki Fujimoto, MD, PhD, Hiroyuki Ohashi, MD, Naoki Yamamoto, MD, Hisato Ito, MD, PhD, Yoshihide Mitani, MD, PhD, Yoko Aoki, MD, PhD, Kyoko Imanaka-Yosida, MD, PhD, Masaaki Ito, MD, PhD and Kaoru Dohi, MD, PhD Yoshito OgiharaYoshito Ogihara Department of Cardiology and Nephrology (Y.O., N.F., M.I., K.D.), Mie University Graduate School of Medicine, Tsu, Japan. , Naoki FujimotoNaoki Fujimoto Naoki Fujimoto, MD, PhD, Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2–174 Edobashi, Tsu 514–8507. Email E-mail Address: [email protected] Department of Cardiology and Nephrology (Y.O., N.F., M.I., K.D.), Mie University Graduate School of Medicine, Tsu, Japan. , Hiroyuki OhashiHiroyuki Ohashi Department of Pediatrics (H.O., Y.M.), Mie University Graduate School of Medicine, Tsu, Japan. , Naoki YamamotoNaoki Yamamoto Department of Thoracic and Cardiovascular Surgery (N.Y., H.I.), Mie University Graduate School of Medicine, Tsu, Japan. , Hisato ItoHisato Ito Department of Thoracic and Cardiovascular Surgery (N.Y., H.I.), Mie University Graduate School of Medicine, Tsu, Japan. , Yoshihide MitaniYoshihide Mitani Department of Pediatrics (H.O., Y.M.), Mie University Graduate School of Medicine, Tsu, Japan. , Yoko AokiYoko Aoki Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.A.). , Kyoko Imanaka-YosidaKyoko Imanaka-Yosida Department of Pathology and Matrix Biology (K.I.-Y.), Mie University Graduate School of Medicine, Tsu, Japan. , Masaaki ItoMasaaki Ito Department of Cardiology and Nephrology (Y.O., N.F., M.I., K.D.), Mie University Graduate School of Medicine, Tsu, Japan. and Kaoru DohiKaoru Dohi Department of Cardiology and Nephrology (Y.O., N.F., M.I., K.D.), Mie University Graduate School of Medicine, Tsu, Japan. Originally published27 Aug 2019https://doi.org/10.1161/CIRCIMAGING.119.009429Circulation: Cardiovascular Imaging. 2019;12:e009429Noonan syndrome (NS) is caused by mutations of genes associated with the RAS-MAPK (Ras/mitogen-activated protein kinase) pathway.1 Although patients with NS develop cardiovascular diseases, coronary artery aneurysms (CAAs) have been rarely reported.A 44-year-old man was admitted to our hospital for evaluation of an expanding CAA. Three years before this admission, he was diagnosed with an asymptomatic CAA at the age of 41 by computed tomography (CT) when he developed bacterial pneumonia. He had hypertrophied cardiomyopathy, mental retardation, skeletal deformities, and facial dysmorphia. He had neither a history of Kawasaki disease nor coronary risk factors. Laboratory analysis revealed no signs of inflammation. Contrast-enhanced CT and angiography demonstrated an anomalous left anterior descending artery and the CAAs in the proximal portion of the right coronary artery and the left main coronary trunk (Figure [A and B]). That in the left main coronary trunk was a large thrombosed saccular CAA, which was slightly calcified (Figure [C]). As genetic analysis demonstrated the heterozygous point substitution mutation in exon 13 of the PTPN11 gene, c.1517A>C (p.Q506P), he was diagnosed with NS. Warfarin was prescribed to prevent coronary artery embolism, and careful follow-up was performed.Download figureDownload PowerPointFigure. Coronary angiography (CAG; A, right coronary artery and B, left coronary artery), contrast-enhanced computed tomography (CECT; C and D, axial images), and histopathologic staining (E, G, and H, elastica-sirius red staining; F, hematoxylin-eosin staining; and I–L, immunohistochemical staining). The CAG and CECT showed the anomalous left anterior descending artery (LAD) with retrograde flow arising from the distal portion of the left circumflex due to a defect in the proximal portion of the LAD (red line). The coronary arterial aneurysms (CAAs) were in the proximal portion of the right coronary artery (blue arrow) and the left main coronary trunk (LMT; yellow arrow). On CECT, the CAA in the LMT increased in size from 37×27 mm (C) to 52×35 mm (D) after 3 y. CAU indicates caudal; LAO, left anterior oblique; and RAO, right anterior oblique.On this admission, repeated contrast-enhanced CT revealed that the CAA in the left main coronary trunk had increased in size to 52×35 mm (Figure [C and D]). As the CAA had a risk of rupture, he underwent surgical ligation and coronary artery bypass grafting with bilateral internal thoracic arteries.On pathological examination of the aneurysm wall (Figure [E]), active inflammation with lymphoid follicle formation was noted (Figure [F]). The medial elastic lamellae were completely disrupted (Figure [G]), and well-developed vasa vasorum with intimal thickening was observed in the adventitia (Figure [H]). There was infiltration of T lymphocytes (CD3) containing helper T (CD4) and cytotoxic T (CD8) cells and macrophages (CD68; Figure [I through L]).The cause of CAAs in NS remains unclear. The PTPN11 gene encodes SHP2 (Src homology protein-tyrosine phosphatase 2 domain–containing phosphatase 2), which positively regulates RAS-MAPK signaling and regulates cell fate determination.2 We speculate that the PTPN11 mutations cause the excess activity of SHP2, resulting in the vulnerability of arterial walls.3,4 We confirmed marked inflammatory change in the wall of the CAA. Unknown inflammatory triggers may result in expansion of the CAA because of its vulnerability. Patients with CCAs are often asymptomatic. In addition, it is difficult to detect CAAs by transthoracic echocardiography. We recommend patients with NS to undergo repeated noninvasive imaging tests such as contrast-enhanced CT.DisclosuresNone.FootnotesNaoki Fujimoto, MD, PhD, Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2–174 Edobashi, Tsu 514–8507. Email [email protected]medic.mie-u.ac.jpReferences1. Lin AE, Alexander ME, Colan SD, Kerr B, Rauen KA, Noonan J, Baffa J, Hopkins E, Sol-Church K, Limongelli G, Digilio MC, Marino B, Innes AM, Aoki Y, Silberbach M, Delrue MA, White SM, Hamilton RM, O'Connor W, Grossfeld PD, Smoot LB, Padera RF, Gripp KW. Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: a Ras/MAPK pathway syndrome.Am J Med Genet A. 2011; 155A:486–507. doi: 10.1002/ajmg.a.33857CrossrefMedlineGoogle Scholar2. Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders.Best Pract Res Clin Endocrinol Metab. 2011; 25:161–179. doi: 10.1016/j.beem.2010.09.002CrossrefMedlineGoogle Scholar3. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause noonan syndrome.Nat Genet. 2001; 29:465–468. doi: 10.1038/ng772CrossrefMedlineGoogle Scholar4. Mauro DM, Flors L, Hoyer AW, Norton PT, Hagspiel KD. Development of bilateral coronary artery aneurysms in a child with Noonan syndrome.Pediatr Radiol. 2016; 46:422–425. doi: 10.1007/s00247-015-3472-zCrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Lee M, Meidan E, Son M, Dionne A, Newburger J and Friedman K (2021) Coronary artery aneurysms in children is not always Kawasaki disease: a case report on Takayasu arteritis, BMC Rheumatology, 10.1186/s41927-021-00197-0, 5:1, Online publication date: 1-Dec-2021. Ly R, Soulat G, Iserin L and Ladouceur M (2021) Coronary artery disease in adults with Noonan syndrome: Case series and literature review, Archives of Cardiovascular Diseases, 10.1016/j.acvd.2021.06.006, 114:8-9, (598-605), Online publication date: 1-Aug-2021. Mussa A, Carli D, Giorgio E, Villar A, Cardaropoli S, Carbonara C, Campagnoli M, Galletto P, Palumbo M, Olivieri S, Isella C, Andelfinger G, Tartaglia M, Botta G, Brusco A, Medico E and Ferrero G (2021) MEK Inhibition in a Newborn with RAF1-Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease, Genes, 10.3390/genes13010006, 13:1, (6) September 2019Vol 12, Issue 9 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCIMAGING.119.009429PMID: 31451008 Originally publishedAugust 27, 2019 KeywordstomographyNoonan syndromeaneurysmpathologycardiovascular diseasesPDF download Advertisement SubjectsAneurysmCoronary Artery DiseaseGeneticsImaging