Filamin C Cardiomyopathy With Myocarditis in Childhood

We present a case of a child presenting with recurrent myocarditis 5 years before developing dilated cardiomyopathy with a novel filamin C truncating variant. Complicated myocarditis in children is commonly caused by genetic cardiomyopathy. We recommend genetic testing for its provision of important diagnostic, prognostic, therapeutic, and reproductive risk information.

Case

A previously healthy 14-year-old boy presented to hospital with acute pleuritic chest pain, which improved with nonsteroidal anti-inflammatory drug treatment. He had had a respiratory tract illness 3 months prior, no additional sick contacts, and no recent travel. There was no relevant past medical history. There was a family history of sudden cardiac death in 2 maternal uncles.

Clinical examination showed blood pressure 106/73 mm Hg, heart rate 64 bpm, respiratory rate 16 bpm, and oxygen saturation 99% in room air. S1 and S2 heart sounds were normal. There were no extra heart sounds or murmurs. Filling pressures were normal. There was no peripheral edema. The respiratory examination was unremarkable.

Laboratory testing found hemoglobin 168 g/L, leukocytes 6.7 × 10⁹/L, platelets 10⁹/L, creatinine 70 μmol/L, high-sensitivity troponin-T of 1962 ng/L (normal range: 0-13 ng/L), N-terminal prohormone brain natriuretic peptide 271 ng/L (normal range: 0-300 ng/L), creatine kinase 684 U/L, C-reactive protein 7.8 mg/L, and lactate dehydrogenase 538 U/L. Electrocardiography found normal sinus rhythm with second-degree Mobitz type 1 and Mobitz type 2 heart block. Telemetry detected episodes of nonsustained ventricular tachycardia. Transthoracic echocardiography showed normal biventricular systolic function with normal left ventricular (LV) diastolic function. There was normal valvular function with no significant regurgitation and no pericardial effusion.

Cardiac magnetic resonance imaging (CMR) showed normal LV size, low-normal LV function (LV ejection fraction 55.6%), mild right ventricular (RV) dilation (RV end-diastolic volume/body surface area: 100.6 mL/m²), normal RV function (RV ejection fraction 58.1%), mid-lateral myocardial edema, and a band of mid-wall delayed enhancement in the mid to apical inferolateral walls of the LV in keeping with subacute to acute myocarditis (Fig. 1). He was discharged with a clinical diagnosis of idiopathic perimyocarditis. The patient had a recurrent episode of chest pain and a mildly elevated troponin (44 ng/L) 1 year later that self-resolved.

Figure 1.

Index (acute) presentation and 48-month cardiac magnetic resonance imaging findings demonstrating marked, near circumferential subepicardial late gadolinium enhancement (LGE) of the basal to apical left ventricular segments, typical of acute myocarditis. Findings are shown for both short-axis (SAX) and 4-chamber views. Imaging at 48 months demonstrates a convalescent reduction in LGE volume, typical of migration to a mature fibrotic state.

Follow-up CMR showed stable mid-inferolateral wall delayed enhancement at 6 months. Surveillance echocardiograms were normal over 4 years.

The patient transitioned to adult care and was referred for a surveillance echocardiogram at age 20 years that showed mild LV dilation, severe LV systolic dysfunction (LV ejection fraction 29%), global longitudinal strain −16.9%, grade 3 diastolic dysfunction, mild RV dilation, mild RV dysfunction, and no significant valve disease (Video 1, view video online). We started guideline-directed medical therapy.

After 3 months of therapy, a follow-up CMR showed moderate LV dilation (LV end-diastolic volume index: 124 mL/m²) and dysfunction (LV ejection fraction: 43%), borderline RV dilation and dysfunction, mid-wall striae fibrosis, and no significant valve lesions (Fig. 1).

We performed diagnostic genetic testing that identified a novel heterozygous pathogenic filamin C (FLNC) c.2436del (p.Ala813Glnfs∗65) truncating variant. The sequence change creates a premature translational stop signal in the FLNC gene that is expected to result in an absent or disrupted protein product. Loss of function variants in FLNC are known to be pathogenic. This variant is absent in population databases (ie, absent in gnomAD) and not in the literature. For these reasons, it is classified by the American College of Medical Genetics and Genomics criteria as pathogenic.

Discussion

Genetic variants associated with cardiomyopathy are prevalent in children with acute myocarditis and may precede the onset of dilated, nondilated, or arrhythmogenic cardiomyopathy. The yield of genetic testing for children with complicated myocarditis (defined as presenting with acute heart failure, reduced LV ejection fraction, or life-threatening ventricular arrhythmias) is approximately 45%, and the yield for all-comers (adults and children) with uncomplicated myocarditis is 4.2%.¹ The genetic architecture is complex: sarcomeric genes are implicated in 71% of cases of complicated pediatric myocarditis, whereas desmosomal genes are implicated in 69% of all cases of uncomplicated myocarditis.¹

We identified a novel FLNC truncating variant as the probable cause of recurrent myocarditis and eventual dilated cardiomyopathy. FLNC-associated cardiomyopathy is inherited in an autosomal-dominant pattern and is associated with high penetrance and expressivity. FLNC encodes the structural protein FLNC, an actin cross-linking protein that maintains the structural integrity of the sarcomere. Truncating variants with resultant haploinsufficiency result in dilated or nondilated cardiomyopathy with a high risk of sudden death.² Current society guidelines acknowledge this risk and recommend consideration of a primary prevention implantable cardioverter defibrillator for patients with FLNC-associated cardiomyopathy and LVEF <45% or a ring-like pattern of late gadolinium enhancement.³ Accordingly, identifying an FLNC truncating variant impacts treatment recommendations.³ A genetic diagnosis also enables predictive genetic testing for first-degree relatives: we identified clinically silent FLNC-associated cardiomyopathy in his mother through predictive testing.

We advocate for diagnostic testing for genetic cardiomyopathies in children with complicated myocarditis due to the high prevalence of pathogenic and likely pathogenic variants. Indeed, genetic testing is indicated for patients with dilated cardiomyopathy despite a lower yield (20% for nonfamilial and 30%-40% for familial). Genetic testing is cost-effective even in this context of lower yield.⁴ We also suggest genetic testing in uncomplicated myocarditis with a high index of suspicion for a genetic cause, such as a family history of cardiomyopathy or sudden death, or recurrent unexplained myocarditis. A genetic diagnosis informs prognosis, treatment, and reproductive advice for affected probands and at-risk family members.³ Predictive genetic testing is particularly effective for the ability to dismiss variant-negative family members from the need for lifelong clinical surveillance and the ability to tailor diagnostic testing in variant-positive family members at risk. For example, FLNC-associated cardiomyopathy most often presents with significant myocardial fibrosis, only evident on CMR.⁵ Genetic testing for complicated myocarditis in children is sensible for these reasons despite the absence of this recommendation in current guidelines and scientific statements.^6,7

Conclusion

We describe a case of FLNC-associated cardiomyopathy due to a novel FLNC truncating variant that highlights the evolving role of genetic testing in myocarditis in the pediatric population. A genetic diagnosis provides information on prognosis, treatment, and reproductive advice. We recommend genetic testing for complicated and select cases of uncomplicated myocarditis in children.

Novel Teaching Points.

• •Genetic cardiomyopathy is a frequent cause of complicated myocarditis in children.
• •Genetic testing provides essential diagnostic, prognostic, therapeutic, and reproductive risk information.
• •Filamin C cardiomyopathy may present with myocardial inflammation and fibrosis before the onset of dilated cardiomyopathy.
• •Clinicians should consider genetic testing in cases of complicated cardiomyopathy.

Supplementary Material

Video 1

Transthoracic echocardiography with strain analysis showing mild LV dilation, severe LV systolic dysfunction, mild RV dilation, and mild RV dysfunction at the onset of dilated cardiomyopathy.