Large left ventricular apical aneurysm in a child with Noonan syndrome and hypertrophic cardiomyopathy

ABSTRACT

Noonan syndrome (NS) is a multisystem disorder with frequent heart defects, including hypertrophic cardiomyopathy (HCM). Left ventricular (LV) apical aneurysm is an extremely rare presentation in pediatric HCM. A 4-year-old child with NS, PTPN-11 mutation and HCM presented with progressive mid-cavity LV obstruction leading to a large LV apical aneurysm. Magnetic resonance imaging confirmed a large, wide-neck LV apical aneurysm. Surgery combined septal myectomy and patch repair of the aneurysm, resulting in uneventful recovery and significant gradient reduction. While multimodal imaging assists surgical planning, longitudinal surveillance should look for recurrences of aneurysm from the repaired segment, arrhythmia, and myocardial function.

INTRODUCTION

Hypertrophic cardiomyopathy (HCM) is a genetic myocardial disorder characterized by left ventricular (LV) hypertrophy, typically occurring in the absence of ventricular dilatation with preserved or increased systolic function. Pediatric HCM differs significantly from the adult form in its clinical course and prognosis, and they are often associated with nonsarcomeric mutations. Noonan syndrome (NS) is an autosomal dominant multisystem disorder caused by gain-of-function mutations that disrupt the rat sarcoma mitogen-activated protein kinase (RAS-MAPK) pathway, which is responsible for cell signals from membrane to nucleus. HCM occurs in 20% of patients with NS. LV apical aneurysms are recognized complications in adults with HCM and mid-ventricular obstruction; however, they are extremely rare in children. This report details the diagnosis and management of a young child with NS and HCM who developed a large LV apical aneurysm.

CASE REPORT

A 4-year-old boy, first child of third-degree consanguineous parents without any family history of heart disease, was referred at 18 months of age for evaluation of abnormal cardiac findings. He had global developmental delay, failure to thrive with a weight of 8.3 kg (weight Z-score of − 2.8), and dysmorphic features including short stature, broad forehead, down-slanting palpebral fissures, hypertelorism, and protruding sternum with widely spaced nipples or wide-spaced nipples suggestive of NS. Clinical examination revealed cardiomegaly with a grade III systolic ejection murmur. Chest X-ray showed cardiomegaly, and electrocardiogram showed features of LV hypertrophy. Echocardiography demonstrated features consistent with HCM, including asymmetric septal hypertrophy, systolic anterior motion of the anterior mitral leaflet with moderate mitral regurgitation, and mild LV outflow obstruction. Genetic analysis confirmed a protein tyrosine phosphatase nonreceptor type 11 (PTPN11) gene mutation consistent with NS. The child was started on maximal tolerated doses of metoprolol. The N-terminal pro-B-type natriuretic peptide (NTproBNP) was elevated to 2293 pg/ml.

During follow-up at 2½ years of age, the child developed generalized tonic–clonic seizures treated with antiepileptic drugs including levetiracetam and clobazam. There were no structural abnormalities on brain magnetic resonance imaging (MRI), and the electroencephalogram was unremarkable. Whole-exome sequencing additionally identified mutations in the SMARCA (SWI/SNF-related, matrix-associated, actin-dependent regulators of chromatin) gene consistent with Nicolaides–Baraitser syndrome, commonly associated with neurological abnormalities.

Echocardiography at 2½ years of age demonstrated progression of LV outflow obstruction with gradients exceeding 100 mmHg and moderate mitral regurgitation. At 4 years of age, additionally identified new findings included severe mid-cavity obstruction as well as a new large LV apical expansile aneurysm [Figure 1]. Cardiac MRI confirmed a large 30 mm × 22 mm × 16 mm wide-necked apical aneurysm communicating with the LV cavity and appeared to burrow toward the left dome of the diaphragm [Figure 2]. The NTproBNP increased to 5580 pg/ml.

Figure 1.

Transesophageal echocardiography (a) shows left ventricular (LV) outflow obstruction due to systolic anterior motion of the anterior mitral leaflet obstruction leading to mitral regurgitation into the left atrium. Modified transgastric view (b) shows apical LV aneurysm. Red arrow marks the junction between the left ventricle and left ventricular aneurysm. The outflow gradient (c) is close to 190 mmHg, and the spectral Doppler at the mouth of the aneurysm (d) shows to and fro flows. LV: Left ventricular, LA: Left atrium, LVA: Left ventricular aneurysm

Figure 2.

Magnetic resonance long axial images (a and b) show hypertrophied left ventricle (LV) and left ventricular apical aneurysm (LVA), that penetrates through the left dome of the diaphragm. LA: Left atrium, Ao: Aortic root

As an LV apical aneurysm was an unusual presentation in a young child, cardiac catheterization was performed to delineate the aneurysm and decide the surgical approach. In addition, the echocardiogram failed to differentiate between obstruction at mid-LV cavity from the region of the septal–mitral contact. The LV systolic pressure was markedly elevated to 235 mmHg, with a peak-to-peak gradient of 135 mmHg between the LV and aorta and a mean gradient of 82 mmHg. The LV end-diastolic pressure was elevated to 22 mmHg [Figure 3]. A transseptal puncture was done to differentiate mid-cavity and outflow gradient, and it showed a near-equal contribution of both levels. The left atrial mean pressure was elevated to 17 mmHg. The mean pulmonary artery pressure was 20 mmHg, the right ventricular infundibulum showed a gradient of 20 mmHg and the right atrial mean pressure was elevated to 10 mmHg. LV angiogram through the transseptal pigtail catheter showed a large LV apical aneurysm with systolic expansion [Figure 4].

Figure 3.

High left atrial pressure (a) is noted after transseptal puncture, while the ascending aorta showed a spike and dome pattern (b). Simultaneous pressures (c) from the left ventricle and ascending aorta showed high peak to peak (P-p) and mean gradients, as well as high filling pressures (d)

Figure 4.

Transseptal catheter advanced into the left ventricular aneurysm delineates it in right anterior oblique view in diastolic (a) and systolic frames (b). The mid-cavity obstruction is also shown in the left anterior oblique view in diastole (c) and systole (d). LVA: Left ventricular aneurysm

He underwent surgery at 4½ years of age, when the outflow was enlarged through a transaortic myectomy along the nadir of the right coronary cusp. After opening the apical aneurysm, an extended transapical septal myectomy was performed in the mid and apical septum. The longitudinally opened apical aneurysm was closed using a composite patch of polytetrafluoroethylene, buttressed by bovine pericardium. As the aneurysm was thick-walled and muscular, it was wrapped around the apical patch. The postoperative course was uneventful, and there was a left bundle branch block [Figure 5]. Echocardiography and cardiac magnetic resonance imaging (CMR) at 6 months demonstrated an unobstructed LV to aorta pathway and secure apical aneurysm closure [Figure 6]. At 5 years of age, he was asymptomatic, but had profound neurodevelopmental delay with motor development corresponding to 9 months of age and language development corresponding to 18 months. Metoprolol was continued, considering the extensive ventricular incisions and patches as potential substrates for arrhythmogenesis despite the presence of left bundle branch block.

Figure 5.

Electrocardiogram before surgery (a) showed left ventricular hypertrophy; following surgery, there was left bundle branch block (b)

Figure 6.

Postsurgical transesophageal echocardiogram (a) demonstrates relief of outflow obstruction. Magnetic resonance imaging shows a reduction in septal thickness after myectomy (b) and elimination of the apical aneurysm (c). LA: Left atrium, RA: Right atrium, LV: Left ventricle, RV: Right ventricle, IVS: Interventricular septum

He presented after 1-year of surgery with low-grade fever and severe abdominal pain, elevated leukocyte counts, and acute phase reactants for 1 week. There was tenderness over the right iliac fossa and umbilical region, and he remained drowsy. Ultrasound abdominal scan demonstrated to-and-fro color flows in a large superior mesenteric artery aneurysm measuring 5 cm. Echocardiography showed a blowout of the LV apical region with a contained pseudoaneurysm measuring 5 cm. Contrast-enhanced computed tomographic imaging showed a large mycotic aneurysm in the superior mesenteric artery and smaller aneurysms in the right iliac artery. Brain imaging demonstrated a large right frontoparietal hemorrhage with midline shift, explaining the drowsiness [Figure 7]. Blood cultures grew Acinetobacter, explaining all the clinical findings related to possible infection of the LV apical surgical patch, leading to its blowout as well as multiple emboli. He had an acute hemodynamic collapse culminating in death within minutes, presumably from exsanguination from one of the aneurysms.

Figure 7.

Contrast-enhanced computed tomography shows blowout of the apical closure patch resulting in a large pseudoaneurysm (a) from the left ventricle with calcified pledgeted sutures seen within the aneurysm. A large 5-cm superior mesenteric artery aneurysm with thrombus layers is seen in the coronal slice (b) of the abdomen. A large frontoparietal hemorrhage with surrounding edema (c) causes midline shift and obliteration of ventricles and sulci. Positron emission tomography (d) shows uptake of tracer in the mycotic aneurysm in the abdomen. LA: Left atrium, LV: Left ventricle, Ao: Aorta

DISCUSSION

NS is a genetic disorder characterized by facial dysmorphism, short stature, skeletal abnormalities and developmental delay. Cardiac involvement is seen in 80% of patients, often manifests as pulmonary valve stenosis with dysplastic valve leaflets in 50%–60% of patients. HCM is the second most common cardiac manifestation, occurring in 20% of patients. Genetic mutations involving components of the RAS-MAPK signaling pathway are responsible for the cardiac phenotype in NS. Mutations in PTPN11, RAF1 (rapidly accelerated fibrosarcoma 1), and RIT1 are frequently associated with the development of HCM in this syndrome.[1,2] The clinical course of HCM in NS differs from that of sarcomeric HCM. Children with NS and HCM present at a younger age and have low hospitalization-free and intervention-free survival compared to sarcomeric HCM.[3] Trametinib, a novel therapeutic agent, has shown clinical improvement in NS by inhibiting mitogen-activated protein kinase activity.[1]

LV apical aneurysm is an increasingly recognized complication of HCM in adults, reported in 4.8% of patients.[4] These aneurysms present with arrhythmias, thromboembolism, and sudden cardiac death in adults. Progressive mid-cavitary obstruction leads to elevated intracavitary pressures, myocardial ischemia, and progressive thinning of the apical myocardium, leading to aneurysm formation.[5] However, this is extremely uncommon in children.[6] CMR accurately delineates myocardial hypertrophy, apical aneurysms, and replacement fibrosis, shown as late gadolinium enhancement.[7] Management strategies for apical aneurysms in HCM, extrapolated from adult experience, include implantable cardioverter–defibrillator or catheter ablation for ventricular arrhythmias, anticoagulation to prevent thromboembolic events, and surgery in large aneurysms.[8]

In pediatric patients with NS and obstructive HCM, septal reduction may be required when medical therapy with a beta-blocker fails. Surgical septal myectomy remains the most common intervention to reduce the systolic gradients and improve symptoms similar to those of children with nonsyndromic obstructive HCM.[9] Given the significant obstruction and substantially large LV apical aneurysm, surgical septal myectomy and aneurysm exclusion were considered the most appropriate therapeutic strategy in this patient. Alternative nonsurgical therapy, such as alcohol septal ablation, is infrequently performed, but may still be applicable for selected pediatric cases.[10]

Unlike adult HCM, pediatric syndromic HCM needs meticulous follow-up on two aspects. Cardiac imaging examinations should focus on recurrence of obstruction, progression of systolic dysfunction, arrhythmia, recurrence of pseudoaneurysm, and increase of the right ventricular infundibular obstruction. Syndromic associations should warrant a multidisciplinary approach for neurodevelopmental delay, seizure control, bleeding disorders, somatic growth to adult heights, orthotic corrections for bony abnormalities, orodental, gastroenterology, and lymphatic issues, and screening for malignancies.

CONCLUSION

HCM, a well-recognized cardiovascular manifestation of NS, often presents early in life and carries significant morbidity. However, LV apical aneurysm due to chronically elevated intracavitary pressures and regional myocardial stress is exceedingly rare in children with HCM. This case highlights this rare association and its management. Longitudinal imaging surveillance is mandatory in NS-associated HCM to identify progression and secondary complications. Timely multidisciplinary evaluation and surgical intervention play a role in mitigating adverse outcomes in these high-risk patients. Despite surgical and medical interventions, detailed counseling about syndromic association and multisystem implications will facilitate patient compliance with multidisciplinary healthcare decisions.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.