Multimodality Imaging in Noonan Syndrome: Case Series of Young Children

Abstract

Noonan syndrome (NS) is an autosomal dominant disorder characterized by distinctive facial anomalies, growth failure, and a wide spectrum of cardiac abnormalities. Here, the clinical presentation, multimodality imaging characteristics, and management in a case series of four patients with NS are presented. Multimodality imaging showed frequently biventricular hypertrophy accompanied by biventricular outflow tract obstruction and pulmonary stenosis, similar late gadolinium enhancement pattern, and elevation of native T1 and extracellular volume, which may serve as multimodality imaging features in NS to aid in patient diagnosis and treatment.

Keywords: Pediatrics, Echocardiography, MR Imaging, Cardiac

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© RSNA, 2023

Summary

Multimodality imaging evaluation in patients with Noonan syndrome showed frequently biventricular hypertrophy with biventricular outflow tract obstruction and pulmonary stenosis, similar late gadolinium enhancement pattern, and elevated extracellular volume.

Key Points

• ■ Noonan syndrome (NS) is an autosomal dominant disorder characterized by distinctive facial anomalies, growth failure, and a wide spectrum of congenital heart defects.

• ■ Multimodality imaging in patients with NS showed a high prevalence of frequently biventricular hypertrophy with biventricular outflow tract obstruction and pulmonary stenosis, similar late gadolinium enhancement pattern, and elevated extracellular volume.

• ■ Accurate clinical and genetic diagnosis with comprehensive management of the disorder through multimodality imaging examination is strongly recommended in NS.

Introduction

Noonan syndrome (NS), first recognized as a distinct entity in 1963, is an autosomal dominant disorder with an incidence of one in 1000 to 2500 live births and no known predilection by race or sex (1,2). NS is a genetically and clinically heterogeneous condition characterized by distinctive facial anomalies, growth failure, and a wide spectrum of congenital heart defects (3,4). Heterogeneous mutations in the RAS mitogen-activated protein kinase signaling pathway have been found to account for developmental disorders in NS (5,6). More than 80% of patients with NS have congenital heart defects, which most often manifest as pulmonary stenosis (PS) (50%–60%), hypertrophic cardiomyopathy (HCM) (approximately 20%), and atrial septal defects (ASDs) (4,7). Less frequently reported defects include some rare cardiac abnormalities, including atrioventricular canal defects, double-chambered right ventricle, coronary aneurysm, ventricular diverticulum, and aortic root dilatation (8–12).

The high prevalence and changing phenotype of cardiac involvement in NS justify complete cardiac evaluations at diagnosis and during follow-up. Transthoracic echocardiography (TTE) is a routine first-line imaging modality to evaluate the structure and function of cardiac involvement. However, multiparametric MRI provides a more comprehensive cardiac examination, with detailed information on cardiac structure, function, and myocardial tissue characteristics, and may be an alternative when TTE is of insufficient quality or provides borderline or ambiguous measurements. Additionally, cardiovascular CT is particularly relevant for imaging the great vessels and coronary arteries in NS. Most case reports have discussed NS-associated cardiovascular diseases mainly as evaluated with TTE (13,14), whereas less is known regarding MRI and CT characteristics in NS. In this case series, we report on multimodality imaging findings in four young children with NS. The demographics, genetic analyses, and multimodality imaging findings are summarized in the Table.

Summary of Demographics, Genetic Analysis, and Multimodality Imaging Findings in Noonan Syndrome

Case Presentations

Case 1

A 4-month-old female patient was found with a heart murmur at birth and presented with cyanosis when crying. She had growth retardation with short stature and intellectual disabilities. The patient’s physical findings were as follows: height, 59 cm; weight, 4.2 kg; and no facial anomalies. Grade III systolic murmurs were heard along the left sternal border in the third-to-fourth intercostal space. Local echocardiographic evaluation showed hypertrophic obstructive cardiomyopathy and biventricular outflow tract obstruction, and the patient was admitted to our hospital for further investigation.

TTE revealed diffuse hypertrophy in the interventricular septum and biventricular myocardia and obstruction in the right and left ventricular outflow tracts (RVOT, LVOT) (Fig 1). Continuous-wave Doppler imaging demonstrated a calculated peak gradient of 55 mm Hg (maximum velocity of 3.7 m/sec) across the LVOT and 35 mm Hg (maximum velocity of 3.0 m/sec) across the RVOT at rest. Systolic anterior motion (SAM) of the mitral valve with moderate regurgitation was also detected.

Figure 1:

Imaging findings in a 4-month-old female patient (patient 1). (A) Transthoracic echocardiography in parasternal long-axis view shows biventricular hypertrophy. (B, C) Continuous-wave Doppler imaging demonstrates a calculated peak gradient of 55 mm Hg (maximum velocity of 3.7 m/sec) across the left ventricular outflow tract and 35 mm Hg (maximum velocity of 3.0 m/sec) across the right ventricular outflow tract (RVOT). (D) Cine MRI, RVOT view shows severe hypertrophy with dynamic subvalvular stenosis. (E) Phase-contrast flow and velocity imaging demonstrates flow acceleration through the narrowed RVOT during systole. (F) Contrast-enhanced inversion-recovery gradient-echo imaging in short-axis view shows subendocardial late gadolinium enhancement (LGE) in anterolateral wall and inferior intraventricular septum (white arrows). (G) Extracellular volume (ECV) map in short-axis view reveals elevated ECV corresponding to the LGE image (white arrows).

Cardiac MRI showed diffuse LV hypertrophy (LVH), particularly in the anterolateral wall, with a maximal LV wall thickness of 16 mm. Diffuse RV hypertrophy (RVH) was also demonstrated, with marked thickness in the middle anterior wall (9–12 mm). Additional views documented severe RVOT hypertrophy with dynamic subvalvular stenosis. Gadolinium-enhanced MRI in short-axis view showed subendocardial late gadolinium enhancement (LGE) in the anterolateral wall and inferior intraventricular septum. An elevated extracellular volume (ECV) was observed on the T1 map corresponding to the LGE image; native T1 value was 1279 msec, and the ECV was 28.1%.

NS was confirmed in this patient by using next-generation sequencing, which was applied as whole-exome sequencing. Genetic analysis showed a pathogenic variation (c.1528C>G) in the protein tyrosine phosphatase nonreceptor type 11 (PTPN11) gene, confirming the diagnosis of NS type 1. After pharmacologic therapy with metoprolol and oxygen inhalation, the patient was discharged with medication.

Case 2

A 4-year-old female patient, who was found with a cardiac murmur at physical examination at 4 months after birth, presented to our institution with hypertrophic obstructive cardiomyopathy. She was born from a nonconsanguineous marriage. No significant family history was present. At examination, height was 98 cm, weight was 13.5 kg, and cardiac murmurs were found. No intellectual disabilities were observed. Her clinical findings were unremarkable with no exercise intolerance, shortness of breath, or palpitations. She had characteristic facial traits of ocular hypertelorism and epicanthal folds.

TTE showed biventricular hypertrophy with a maximal LV wall thickness of 19 mm in the septum, causing severe LVOT obstruction (peak gradient of 71 mm Hg, maximum velocity of 4.2 m/sec). SAM of the mitral valve with moderate regurgitation was also detected. Cardiac MRI yielded evidence of biventricular involvement, similar to TTE results (Fig 2). The LVOT view of cine MRI showed LVOT obstruction, SAM of the mitral valve, LVOT flow acceleration, and moderate mitral regurgitation. An additional view of RVOT cine MRI showed no evidence of hemodynamic obstruction. Gadolinium-enhanced MRI in short-axis view showed subendocardial LGE in the anterolateral wall, with corresponding elevated ECV. The patient had a global myocardial native T1 value of 1110 msec and an ECV of 26.2%.

Figure 2:

Imaging findings in a 4-year-old female patient (patient 2). (A) Cine MRI, short-axis view shows biventricular hypertrophy. (B) Cine MRI, right ventricular outflow tract view demonstrates no evidence of obstruction. (C) Contrast-enhanced inversion-recovery gradient-echo imaging in short-axis view shows subendocardial late gadolinium enhancement (LGE) in anterolateral wall (white arrow). (D) Extracellular volume (ECV) map in short-axis view reveals elevated ECV corresponding to the LGE image (white arrow). (E, F) Preoperative cine images show left ventricular outflow tract (LVOT) obstruction, and phase-contrast flow and velocity image shows corresponding flow acceleration. (G, H) Cine image and phase-contrast flow and velocity image show improvement after operation, with nonobstructive LVOT and no flow acceleration.

The genetic analysis report showed a pathogenic variation (c.1528C>G) in the PTPN11 gene, confirming the diagnosis of NS type 1. The patient underwent modified extended Morrow surgery for HCM. Postoperative cardiac MRI showed nonobstructive LVOT and no flow acceleration, with greatly decreased gradients across LVOT, indicating substantial improvement after treatment.

Case 3

A 6-month-old male patient had a heart murmur after birth and was initially diagnosed with PS by using TTE. He presented with exercise intolerance, dyspnea, and cyanosis when crying. He had facial anomalies including ocular hypertelorism, ptosis, and low-set posteriorly rotated ears. He had no intellectual disabilities but did have growth retardation, with a weight of 7.2 kg and a height of 63 cm. His parents did not have a consanguineous marriage. Grade III rumble-like systolic murmurs at the right second-to-third intercostal space and the left sternum second-to-third intercostal space were notable.

TTE revealed severe PS with limited mobility of valvular leaflets and fibromuscular narrowing of the RVOT with multicolored flow acceleration in color Doppler imaging (Movie 1). A systolic pressure gradient of 82 mm Hg (maximum velocity of 4.5 m/sec) was detected across the RVOT (Fig 3), despite the absence of an LV-aortic pressure gradient. TTE also revealed ASDs in this patient.

Figure 3:

Imaging findings in a 6-month-old male patient (patient 3). (A) Cine MRI, short-axis view shows asymmetric septal hypertrophy with more pronounced hypertrophy in the interventricular septum than in the free wall and hypertrophied septum bulged out toward the right ventricle. (B) Cine MRI, right ventricular outflow tract (RVOT) view shows marked narrowing of the RVOT. (C, D) No late gadolinium enhancement was detected in this patient, but there was substantially elevated extracellular volume. (E) Continuous-wave Doppler imaging demonstrates a systolic pressure gradient of 82 mm Hg (maximum velocity of 4.5 m/sec) across the RVOT. (F, G) CT of the pulmonary artery shows thickening of pulmonary valve leaflets, pulmonary valve stenosis, and subvalvular stenosis, as well as proximal stenosis of right pulmonary artery (white arrow in G). (H) Hematoxylin-eosin stain reveals mild hypertrophy and degeneration of RVOT cardiomyocytes. (Original magnification, ×10.)

Movie 1:

Download video file ^{(2.8MB, mp4)}

Color Doppler imaging demonstrates fibromuscular narrowing of infundibular hypertrophy with multicolored flow acceleration across the right ventricular outflow tract.

Cardiac MRI showed asymmetric septal hypertrophy, far more pronounced hypertrophy in the interventricular septum than in the free wall of both ventricles, and marked narrowing of the RVOT. The hypertrophied septum bulged out toward the RV chamber. RVOT obstruction was caused by PS and subvalvular fibromuscular stenosis, whereas there was no substantial LVOT obstruction. No LGE was detected, but the patient had elevated native T1 and ECV values of 1451 msec and 34.2%, respectively. CT imaging of the pulmonary artery also showed thickening of pulmonary valve leaflets, pulmonary valve stenosis, and subvalvular stenosis, as well as proximal stenosis of the right pulmonary artery.

The genetic analysis report showed a pathogenic variation (c.181G>A) in the PTPN11 gene. The patient underwent multiple surgeries, including pulmonary valvotomy for PS, RVOT resection, and repair of a secundum ASD. Histopathologic examination documented mild hypertrophy and degeneration of RV cardiomyocytes.

Case 4

A 6-year-old female patient was genetically diagnosed with NS during early infancy (PTPN11, c.1517A>C), and TTE showed LVH, LVOT obstruction, and PS. She experienced exercise intolerance but denied syncope after squatting. She was of short stature (height, 89.0 cm; weight, 13.0 kg), had characteristic facial traits of a tall forehead, hypertelorism, low-set posteriorly rotated ears, epicanthal folds, and a broad nose with a depressed root and full tip, and had no intellectual disabilities.

TTE revealed diffuse LVH and SAM of the mitral valve with moderate regurgitation. Limited mobility and thickening of pulmonary valve leaflets, with a diameter of 9.8 mm for valve annulus, and fibromuscular narrowing of infundibular hypertrophy with flow acceleration across the RVOT were also detected (Movies 2, 3). Continuous-wave Doppler imaging demonstrated a calculated peak gradient of 104 mm Hg across the LVOT and 134.6 mm Hg across the RVOT at rest. Mitral valve early/late diastolic mitral inflow velocity ratio (E/A) less than 1 (Fig 4) and early mitral inflow/mitral annular peak early diastolic velocity ratio (E/E’) of 37.5 indicated restrictive diastolic dysfunction.

Figure 4:

Imaging findings in a 6-year-old female patient (patient 4). (A) Cine MRI, four-chamber view shows diffuse left ventricular hypertrophy. (B) Cine MRI, right ventricular outflow tract (RVOT) view shows narrowing of the RVOT with a flow void sign. (C, D) Phase-contrast flow and velocity imaging demonstrates flow acceleration through the narrowed right and left ventricular outflow tracts during systole. (E, F) Contrast-enhanced inversion-recovery gradient-echo imaging in short-axis view shows late gadolinium enhancement (LGE) in the intraventricular septum and subendocardial LGE in the inferolateral wall with elevated extracellular volume (ECV) in ECV map. (G) Continuous-wave Doppler imaging demonstrates mitral valve early/late diastolic mitral inflow velocity ratio (E/A) less than 1, indicating diastolic dysfunction. (H) CT of pulmonary artery shows thickening of pulmonary valve leaflets and pulmonary stenosis. (I) Hematoxylin-eosin stain reveals mild myocyte hypertrophy with vacuolar degeneration and disorganization of the muscle bundle, as well as mild interstitial fibrosis. (Original magnification, ×10.)

Movie 2:

Download video file ^{(2.9MB, mp4)}

Transthoracic echocardiography in right ventricular outflow tract view shows limited mobility and thickening of pulmonary valve leaflets and fibromuscular narrowing of infundibular hypertrophy.

Movie 3:

Download video file ^{(2.1MB, mp4)}

Color Doppler imaging demonstrates fibromuscular narrowing of infundibular hypertrophy with multicolored flow acceleration across the right ventricular outflow tract..

MRI demonstrated diffuse LVH with maximal LV wall thickness of 22 mm in the middle septum (Fig 4). LVOT obstruction was also detected, where flow acceleration and SAM of the mitral valve were present. Subvalvular muscular stenosis led to RVOT obstruction with flow acceleration. Of note, MRI revealed mildly decreased LV ejection fraction (43%). Midwall LGE in the basal inferior intraventricular septum and middle intraventricular septum, as well as subendocardial LGE in the inferolateral wall, were also shown. The patient had elevated native T1 (1283 msec) and mean ECV (37.2%), indicating interstitial fibrosis. CT also demonstrated biventricular involvement, including LVH, LVOT obstruction and PS, and subvalvular stenosis.

The patient underwent surgery, including pulmonary valvotomy, RVOT resection, and modified extended Morrow surgery for HCM. Postoperative biopsy specimens demonstrated mild myocyte hypertrophy with vacuolar degeneration and disorganization of the muscle bundle on the resected ventricular muscle, compatible with findings of HCM. Additionally, histopathologic examination revealed mild interstitial fibrosis.

Discussion

To our knowledge, this is the first report of multimodality imaging in NS, including LGE and MRI T1 mapping, by case series. Patients frequently had biventricular hypertrophy with biventricular outflow tract obstruction, particularly RVOT obstruction. The patients in this series also showed a similar LGE pattern, with subendocardial LGE in the anterior and anterolateral walls. Interstitial fibrosis confirmed with elevated ECV was also detected.

In the 2014 European Society of Cardiology guidelines on the diagnosis and management of HCM, biventricular hypertrophy and biventricular outflow tract obstruction are frequent in NS, suggesting a specific cause of HCM (15). The high prevalence of RVH was initially considered secondary to PS, which then progressed to RVOT obstruction due to septal hypertrophy or dynamic subvalvular stenosis resulting from infundibular hypertrophy. However, the presence of RVH in the absence of PS in case 1 suggests that it may be the primary cardiomyopathy involvement in NS, consistent with a previously reported finding of RVH without substantial PS and LVH (16). RVOT obstruction in patients with NS may be attributed to pulmonary valvular stenosis with dysplastic leaflets (4,17) or infundibular hypertrophy and fibromuscular narrowing of the RVOT secondary to RVH (18). In comparison with cases 3 and 4, case 1 showed narrowing of the infundibulum by a grossly hypertrophied interventricular septum, but no evidence of valvular PS or a dysplastic pulmonary valve. Whether PS was present or not, patients had infundibular hypertrophy or dynamic subvalvular stenosis, and a flow jet through the RVOT was best observed in late systole. Although distinguishing between valvular stenosis and subvalvular dynamic stenosis secondary to infundibular hypertrophy can be challenging, cardiac MRI and CT may provide valuable information about valve morphologic characteristics and the location of stenosis, in addition to echocardiography (19).

Tissue characterization for myocardial fibrosis is a unique capability of cardiac MRI, including LGE for replacement fibrosis and T1 mapping for interstitial fibrosis. Apart from the anterior and inferior septum, subendocardial LGE in the anterior and anterolateral walls were noteworthy in our patients. With respect to MRI examinations in patients with NS, case reports demonstrated LGE patterns, including midwall scar in the basal inferoseptal segment and patchy, signal-intense areas in the anterior, anteroseptal, and lateral walls, but none described T1 mapping findings (13,20). Our case series showed elevation of native T1 and ECV in NS, which correlated with myocyte fiber disarray and interstitial fibrosis confirmed in histopathologic analysis of one patient. Kaltenecker et al (21) demonstrated that myocardial fibrosis assessed with LGE and T1 mapping was present in NS, whereas ECV was relatively lower than that in our study. Of note, patients with NS in our case series were all younger than 7 years, indicating that interstitial fibrosis has already begun at such a young age. ECV has exhibited more robust associations with outcomes and provided superior risk stratification in nonischemic cardiomyopathy (22). Similarly, elevated ECV in NS may also have incremental value in risk stratification and prognosis and should be further investigated.

Similar to previous reports of NS demonstrated with or without MRI (9,12), other types of cardiac abnormalities were observed in our case series, including ASDs and proximal stenosis of the right pulmonary artery. Regarding the genotype of NS, our findings were consistent with previous reports indicating PTPN11 as a leading positional candidate gene (4,23,24). NS and related genetic diseases constitute one of the largest groups of developmental disorders, named RASopathies, characterized by distinctive facial features, cardiopathies, growth abnormalities, developmental delay, and intellectual disabilities. Some phenotypically related disorders from the RASopathies spectrum showed substantial phenotypic overlap with NS. Due to the broad spectrum of symptoms and presentations in NS, accurate clinical and genetic diagnosis, including gene-targeted testing and comprehensive genomic testing, and comprehensive management of the disorder through imaging examination are strongly recommended (25,26).

In conclusion, with an understanding of the molecular genetic causes of NS, it is crucial to identify early cardiac involvement and assess cardiac manifestations with multimodality imaging. We performed comprehensive evaluations of NS-associated cardiac abnormalities, including common findings of biventricular hypertrophy accompanied by biventricular outflow tract obstruction and PS. Patients also showed subendocardial LGE in the anterior and anterolateral walls. The presence of interstitial fibrosis in young patients with NS, confirmed with T1 mapping, should be considered with great importance, and further investigation is required to determine its impact on risk stratification and prognosis.