Cardiac MRI Characteristics of Noonan Syndrome Associated With Hypertrophic Cardiomyopathy and Congenital Heart Disease

Multiple etiologies can lead to left ventricular hypertrophy, and cardiac magnetic resonance (CMR) can enhance diagnostic accuracy by depicting diverse myocardial histological alterations via multiparametric techniques, as summarized by Cha et al. [1] and recently published in the Korean Journal of Radiology. This article describes two patients with myocardial hypertrophy caused by Noonan syndrome (NS) who were evaluated using CMR.

Patient 1 was a 12-year-old boy with a height of 130 cm and a weight of 26 kg. Facial anomalies included wide-spaced eyes, low-set ears, a broad nose, and depressed root (Fig. 1A). Echocardiography and CT angiography revealed a ventricular septal defect (VSD), atrial septal defect (ASD), and thickening of the interventricular septum and posterior left ventricular wall, causing left ventricular outflow tract (LVOT) obstruction (peak gradient of 89 mmHg) (Fig. 1B, C, arrows). CMR revealed ventricular wall thickening and systolic anterior motion of the mitral valve (Fig. 1D; Supplementary Videos 1, 2). The native T1-mapping was 1314 ms (Fig. 1E). The child underwent Morrow surgery and repair of ASD and VSD.

Fig. 1. A 12-year-old boy with myocardial hypertrophy and Noonan syndrome. A: The child exhibited unique facial features, including wide-spaced eyes, low-set ears, and a broad nose with a depressed root. B, C: CT angiography revealed a perimembranous ventricular septal defect, atrial septal defects, and thickening of the interventricular septum (arrows). D: Cardiac magnetic resonance revealed thickening of the left ventricular septal and lateral walls (stars), along with systolic anterior motion of the mitral valve (arrow). E: T1 mapping imaging, elevated native T1-mapping of 1314 ms (arrow). AO = aorta, RV = right ventricle, LA = left atrium, LV = left ventricle, RA = right atrium.

Patient 2 was a 22-year-old woman with a height of 150 cm, weight of 36 kg, facial anomalies, and fever. CMR revealed thickening of the interventricular septum and inferior wall, and first-pass perfusion revealed ASD (Fig. 2A, arrow), thickening of the posterior mitral valve leaflet (Fig. 2B, arrow), with multiple focal late gadolinium enhancement (LGE) in the myocardial interstitium (Fig. 2C, arrows), and elevated native T1-mapping and extracellular volume values of 1362 ms and 32%, respectively (Fig. 2D, E). Echocardiography indicated LVOT obstruction (peak gradient, 131 mmHg) and vegetation in the LVOT (Supplementary Video 3). After treatment for the infection and fever, the patient’s condition improved, and they were discharged after declining the recommended LVOT decompression surgery.

Fig. 2. A 22-year-old woman with myocardial hypertrophy and Noonan syndrome. A: CMR revealed a thickening of the interventricular septum and the inferior wall, and first-pass perfusion revealed atrial septal defect (arrow). B, C: CMR revealed thickening of the mitral valve and multiple focal areas of late gadolinium enhancement in the myocardial interstitium (arrows). D: T1 mapping imaging reveals elevated native T1-mapping (arrow). E: ECV mapping imaging reveals elevated ECV corresponding to the late gadolinium enhancement image (arrow). CMR = cardiac magnetic resonance, LA = left atrium, LV = left ventricle, ECV = extracellular volume.

Genetic testing identified mutations in RAF1 (c.770C>T, p.Ser257Leu) in patient 1 and MRAS (c.203C>T, p.Thr68Ile) in patient 2. No parental genetic abnormalities were observed in either case.

NS, first reported by Noonan in 1968, is an autosomal dominant disease caused by mutations in the RAS/MAPK signaling pathway, with a few recessive mutations and a prevalence of approximately 1:1000–1:2500 [2]. Variations in various genes, such as PTPNII, RAF1, and MRAS, are associated with NS development [3]. In this case, genetic testing of the two patients revealed pathogenic heterozygous mutations in RAF1 (c.770C>T) on chromosome 3 and in MRAS (c.203C>T).

Over 80% of NS patients have congenital heart disease (CHD), typically presenting as pulmonary stenosis (PS) (50%–60%), hypertrophic cardiomyopathy (HCM) (20%), and ASD [2]. In this case, both patients had ASD, with patient 1 also having VSD, but neither patient had PS, possibly because of gene mutation variability. Specific mutations significantly affect heart development; patients with RAF1 mutations show a high correlation with HCM (73%) and a low incidence of PS [4]. The RAF1:p.Ser257Leu mutation is associated with NS accompanied by HCM and pulmonary hypertension [5]. However, patient 1 presented with HCM combined with ASD and VSD but did not exhibit pulmonary hypertension. MRAS is a newly identified gene associated with NS. As of January 2023, only four cases of MRAS (p.Thr68Ile) site mutations have been reported in the literature [6]. Patient 2 was the fifth patient with this specific mutation causing NS. The four patients with this mutation in the literature all had HCM and exhibited interatrial septal aneurysm, mitral valve prolapse, pulmonary valve stenosis, left ventricular apical aneurysms, and ASD [6]. Patient 2 presented with HCM and ASD. Biventricular hypertrophy and outflow tract obstruction are frequent in NS [2]. Both patients exhibited asymmetrical septal hypertrophy and LVOT obstruction in the present case. Patients with NS have been reported to have LGE in the interventricular septum and the anterior and lateral walls [2]. In patient 2, LGE appeared in these areas as small focal enhancements, consistent with the literature, whereas patient 1 did not show typical LGE. However, both patients had elevated native T1-mapping compared to normal myocardium, suggesting possible diffuse interstitial proliferation in the myocardium.

NS can involve multiple organ systems, and there are differences in facial features at different ages, including a tall forehead, wide-spaced eyes, full lips, and a short neck [7,8]. However, in patient 2, distinctive facial features were not obvious, possibly related to less pronounced facial characteristics in adulthood. Approximately 82% of patients with RAF1 mutations exhibit short stature, possibly related to growth hormone deficiency [4,8]. Up to 80% of male patients with NS suffer from cryptorchidism [9]. Patient 1 also had cryptorchidism; therefore, attention should be paid to the child’s gonadal function and fertility during follow-up.

In summary, NS is characterized by typical facial features, short stature, and other systemic disorders and has a higher risk of HCM and CHD. Therefore, early identification of cardiac involvement using imaging techniques is crucial. CMR has the advantages of multi-sequence, multi-parameter, and multi-planar imaging. It can non-invasively and comprehensively assess the anatomical structure, motion function, blood flow perfusion, and histological characteristics of the heart without radiation.

Supplement

The Supplement is available with this article at https://doi.org/10.3348/kjr.2024.1316.

Video 1

The patient’s CMR cine imaging.

Video 2

The patient’s CMR cine imaging.

Video 3

The patient’s echocardiography imaging.