Natural history of coronary aneurysms associated with Noonan's syndrome

Abstract

Coronary artery aneurysms (CAAs) in Noonan syndrome (NS) are rare, and their true prevalence remains unclear. While previous cases have been reported, the natural history of this association and its management have not been described. We present a 31-year-old male followed for over 16 years, who was found to have an uncomplicated thrombus during his most recent coronary computed tomography angiography (CCTA) follow-up. We aim to illustrate the natural history of CAAs in NS by presenting findings from transthoracic echocardiography (TTE) and CCTA, discussing diagnostic challenges, and showing how current Kawasaki disease (KD) guidelines can be extrapolated for management. In conclusion, CCTA and TTE play a pivotal role in monitoring CAA progression and guiding individualized therapeutic strategies, with KD guidelines serving as a reference for management.

Learning objective

The association between Noonan syndrome (NS) and giant coronary artery aneurysms (GCAAs) is rare, posing challenges for long-term management. Multimodality imaging, particularly coronary computed tomography angiography, is essential for monitoring GCAA progression, evaluating complications, and guiding thromboprophylaxis and surgery. The potential application of Kawasaki disease guidelines may provide valuable insights into thromboprophylaxis and long-term care in NS patients with GCAAs, helping to address the current lack of condition-specific management strategies.

Introduction

Noonan syndrome (NS) is a genetic disorder characterized by short stature, distinctive facial features, and congenital heart defects. It results from mutations in genes involved in the RAS/MAPK signaling pathway, with PTPN11 being the most implicated. Pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM) are the most common cardiac anomalies, while coronary anomalies were reported in 1 % of cases [1].

The occurrence of giant coronary artery aneurysms (GCAAs) in NS is rare, and their natural history remains undocumented [2]. GCAA are defined as coronaries with Z-score ≥10 or luminal diameter ≥8 mm, carrying risk of thrombosis, rupture, and myocardial infarction. While CAAs are typically associated with atherosclerosis, Kawasaki disease (KD), and connective tissue disorders, their presence in NS raises intriguing questions about a possible predisposition to vascular abnormalities [2].

We present the case of a 31-year-old male followed for over 16 years with multimodality imaging and managed according to KD guidelines. In the absence of condition-specific recommendations, we extrapolated KD guidelines to address the management challenges of CAAs in NS [3].

Case report

A 31-year-old male with NS presented for routine follow-up of GCAAs with coronary computed tomography angiography (CCTA). He was diagnosed with NS in childhood following identification of a pathogenic PTPN11 mutation. His history included facial anomalies, scoliosis, intellectual disability and sensorineural hearing loss. Cardiovascular history was notable for Wolff-Parkinson-White syndrome, HCM—treated with atenolol—, symptomatic right ventricular outflow obstruction—requiring two right ventricular myomectomies at age 13 years—, and GCAAs.

At age 15 years, CAAs were suspected during screening for HCM with echocardiography. CCTA confirmed the diagnosis, size, and extent of involvement of the coronary tree. There was no history of vasculitis (e.g. KD) or atherosclerotic cardiovascular disease (ASCVD), making alternative etiologies for CAAs unlikely. Since diagnosis, surveillance has relied primarily on CCTA (Fig. 1) and TTE (Fig. 2, Video 1), monitoring aneurysm size and morphology.

Fig. 1.

Coronary computed tomography angiography (CCTA) follow-up since diagnosis (axial view). Series of CCTA images display axial views of the heart, illustrating the progressive dilation of the right coronary artery (RCA) and left main (LM) coronary artery over time. (A) CCTA at age 15 years, the LM measures 15 mm (plus sign) and the RCA is 18 mm (asterisk). (B) CCTA at age 23 years, the images depict the LM expanded to 31 mm (plus sign) and the RCA expanded to 35 mm (asterisk). (C) CCTA at age 31 years, the LM reached a diameter of 44 mm (plus sign) and the RCA has expanded to a diameter of 54 mm (asterisk). Additionally, a large burden of thrombus is seen in the mid RCA (arrow). Note: Streak artifacts are present in all CCTA images due to an implantable cardioverter-defibrillator and spine fusion material implanted before the first CCTA was taken at age 15 years.

Ao, aorta; DA, descending aorta; LPA, left pulmonary artery.

Fig. 2.

Transthoracic echocardiography (TTE) follow-up - modified 4-chamber views depicting disease progression of the left circumflex artery (LCX). (A) TTE at age 17 years, images depict dilation of the LCX (asterisk). (B) TTE at age 24 years, showing progressive dilation of the LCX (asterisk) and a dilated right coronary artery (RCA) (arrow). (C) TTE at age 29 years, images show dilated LCX (asterisk). (D) TTE at age 31 years, images depict dilated LCX (asterisk).

Due to the absence of NS-specific guidelines for CAA, thromboprophylaxis strategies were extrapolated from existing KD recommendations [3]. From ages 15 to 23 years, the patient was treated with dual antiplatelet therapy (DAPT)—acetylsalicylic acid and clopidogrel— and warfarin. At his 23-year follow-up, anticoagulation was discontinued after a spontaneous right knee hemarthrosis. At that time, the international normalized ratio (INR) was 2.8, within the recommended range [3]. An extensive hematology work up for bleeding disorders, which are common in NS [4], resulted negative.

Stress tests were performed at ages 21 years and 25 years to assess whether the aneurysms were causing ischemia. Both tests demonstrated reduced exercise capacity and frequent supraventricular premature beats (SVPBs); however, no chest pain was present. The absence of angina, a preserved left ventricular ejection fraction (LVEF), together with the patient's tortuous coronary vasculature, precluded surgical intervention. Current guidelines establish ischemic symptoms as primary indication for coronary artery bypass grafting (CABG) or catheterization.

From ages 23 years to 31 years, the patient was treated only with DAPT due to repeated bleeding episodes and the family's reluctance to resume anticoagulation. At age 24 years, he experienced gastrointestinal bleeding that prompted a brief discontinuation of DAPT, and at age 25 years he had an episode of epistaxis, which required hospitalization. This predisposition to bleeding and the family's reluctance to engage in discussions about anticoagulation, made resuming therapy unfeasible.

On his most recent CCTA, performed at age 31 years, the right coronary artery (RCA) was 54 mm in diameter, left main (LM) 44 mm, left circumflex (LCX) 33 mm, and left anterior descending artery (LAD) 23 mm. Additionally, the RCA was complicated by a non-occlusive thrombus in the proximal and mid segments (Fig. 3). Remarkably, the patient remained asymptomatic. Anticoagulation was again recommended, considering all oral anticoagulants, including direct oral anticoagulants (DOACs); however, after an extensive discussion, the family declined.

Fig. 3.

Coronary computed tomography angiography follow-up at age 31 years. (A) Coronal view demonstrating the course of the right coronary artery (RCA) (arrows) with luminal thrombus (asterisks). (B) Multiplanar reformat of the left circumflex artery, with a maximum diameter of 44 mm (plus sign). (C) This panel illustrates a curved multiplanar reformat of the RCA's lumen (dots), revealing multiple fusiform coronary artery aneurysms, with a maximum diameter of 54 mm and a large mural thrombus burden in the proximal and mid-RCA (asterisks).

Cardiac surgery was considered for aneurysm resection and CABG, aiming to prevent aneurysm rupture and further thrombus progression. However, in the absence of ischemic symptoms, with preserved LVEF, and given the challenging anatomy complicated by two prior myomectomies and the presence of aneurysms in all coronary arteries, the risks and benefits were carefully weighed, and surgery was deemed high risk. The patient's family participated in the decision-making process and agreed that the potential risks of surgery outweighed the expected benefits.

Management continued with DAPT and regular follow-up including regular assessments with TTE, CCTA, and visits to the Adult Congenital Heart Disease clinic. Statin therapy was considered for its potential vascular benefit but was not initiated due to a lack of supporting evidence in this context.

Discussion

The association between NS and CAAs is rare, and the precise prevalence unclear. The CArdiac RASopathy NETwork (CARNET) study reported a 1 % incidence of CAAs among 371 patients with RASopathies [5] compared with 9 % in the cohort analyzed by Ly et al. [2]. The discrepancies may stem from several factors such as absence of associated symptoms and the widespread reliance on TTE alone for screening and follow-up. Echocardiography has limited sensitivity—particularly in older patients—and lacks standardized protocols for evaluating and reporting coronary size or anatomy beyond the coronary origin.

The pathophysiology of CAA in NS has been linked to gain-of-function mutations in PTPN11. This gene encodes the protein tyrosine phosphatase SHP-2, which plays a crucial role in cell growth, differentiation, migration, and apoptosis. It is speculated that excessive SHP-2 activity, weakens the arterial wall and leads to dilation over time [2]. In this patient, a pathophysiology inherent to NS is supported by the progression of CAAs over time in the absence of ASCVD or KD history.

Despite different pathophysiological mechanisms, KD guidelines were used for management. In KD, CAAs result from an acute necrotizing arteritis that degrades the arterial wall within the first two weeks, followed by subacute or chronic vasculitis and luminal myofibroblastic proliferation. These changes persist for months to years, contributing to vascular remodeling that may result in arterial dilation, stenosis or persistent wall abnormalities [3]. In comparison, the arterial fragility in NS seems to be inherent and persistent, accounting for the progressive dilation and its striking size.

As per KD guidelines, thromboprophylaxis with triple therapy –DAPT and anticoagulation– was recommended. The indication for triple therapy is the presence of extensive GCAAs and compromise of the distal portion. Warfarin or low molecular weight heparin should target an INR of 2.0–3.0 and anti-factor Xa levels of 0.5–1.0 U/mL, respectively. DOACs are an alternative given their low rate of bleeding, thrombosis, lack of need for monitoring and fewer interactions. However, further evidence is needed in KD and NS [6].

Beta-blockers and statins may be considered for GCAAs, although definitive evidence remains limited [3]. Beta-blockers may benefit patients at risk of ischemia. Statins may provide anti-inflammatory and endothelial-stabilizing effects, however their role in NS-associated CAAs is not well established.

As previously mentioned, one of the main differences between GCAAs in NS and KD is their size. This marked dilation carries a higher risk of rupture and sudden cardiac death, thereby warranting consideration of surgical intervention. According to KD guidelines, interventional or surgical approaches—including coronary artery bypass grafting or aneurysm ligation— should be considered in patients with stable angina and high-risk coronary anatomy, such as left main coronary artery disease, multivessel coronary disease with reduced LV function, multivessel disease with diabetes mellitus, or high-risk findings on noninvasive ischemia testing [3]. To date, no studies or guidelines recommend intervention of asymptomatic aneurysms based solely on size; decisions are based on case reports, case series, and expert opinion [7]. Moreover, rupture is considered a rare complication [8].

In our patient, despite absence of angina or LV dysfunction, surgery evaluation was considered due to progressive dilation. Consensus was reached that aneurysm resection with CABG would be appropriate but prior right ventricular myomectomies and diffuse coronary tortuosity rendered surgery high risk with poor expected outcomes. The family participated in the decision-making process and declined surgery.

CAA progression or regression guided adjustments in thromboprophylaxis and follow-up strategies, surveillance was done following KD guidelines. Clinical assessment, echocardiography, and electrocardiography were performed every three to six months, with additional CCTA, cardiac magnetic resonance (CMR), or invasive angiography considered every one to five years for further diagnostic and prognostic evaluation [3]. For long-term monitoring of GCAAs, noninvasive imaging—CCTA, CMR, and echocardiography—is preferred [3], although each modality has specific advantages and limitations [9]. Echocardiography is accessible and avoids ionizing radiation but has limited assessment of mid-distal coronary segments and tortuous vessels. CCTA offers superior spatial resolution and a comprehensive view of aneurysm size and thrombus, with radiation exposure mitigated by modern low-dose protocols; in young, non-obese patients, imaging at 70–100 kV further reduces risk [10]. CMR provides information on ventricular function, myocardial perfusion, scarring, and can detect ischemia via stress CMR. However, for myocardial perfusion, CMR has lower resolution in distal coronary segments, cannot detect calcifications, requires longer acquisition times, and its availability varies across institutions [9].

In conclusion, NS-associated CAAs are rare but potentially serious. Management requires combining aggressive thromboprophylaxis, imaging surveillance, and consideration of surgical or percutaneous therapy for extremely large or complicated aneurysms. This case underscores the value of long-term multimodality imaging and the potential benefit of adapting KD guidelines for thromboprophylaxis in the absence of NS-specific protocols. Further research and registry data are needed to clarify the natural history and optimal management for this population.

The following is the supplementary data related to this article.

Video 1

Video depicting a parasternal long-axis (PLAX) view and a modified four-chamber view. The PLAX view shows a dilated right coronary artery (RCA). The modified four-chamber view shows a dilated left circumflex artery (LCX), correlating with the images shown in Fig. 2.

CRediT authorship contribution statement

FJC, DL, AF, and LS planned the case report. FJC, DL, and AF drafted the manuscript and designed the figures. DL performed the reconstruction of the CCTA images. FCY, JCCD, SR, SG, NS, JML revised the manuscript and provided valued intellectual contribution.

Consent statement

Informed consent was waived in accordance with institutional IRB protocols.

Declaration of competing interest

Daniel Lorenzati, Annalisa Filtz and Leandro Slipczuk are supported by institutional grants from Amgen and Philips.

Data availability

No datasets were generated or analyzed during the current study.