Noonan 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.
Figure.
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.
Disclosures
None.
References
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