RASopathies comprise syndromes with overlapping phenotypes caused by germline mutations in the components of the RAS/MAPK signalling pathway, which regulate cell proliferation. Representative syndromes of RASopathies include Noonan syndrome and Noonan syndrome with multiple lentigines, which are known to be associated with cardiac diseases including hypertrophic obstructive cardiomyopathy. Reference Wolf, Zenker and Burkitt-Wright1 Recently, the anti-arrhythmic drug cibenzoline was found effective in adult patients with hypertrophic obstructive cardiomyopathy. Herein, we report two paediatric cases of hypertrophic obstructive cardiomyopathy with RASopathies that have been well controlled with cibenzoline.
Case reports
Case 1
A 2-year-old Japanese boy was admitted to Hokkaido University Hospital for cardiac catheterisation to evaluate hypertrophic obstructive cardiomyopathy. He was born at 39 weeks of gestation without asphyxia. He was not a child of a consanguineous marriage, but his grandmother had a medical history of hypertrophic cardiomyopathy. Soon after birth, a systolic heart murmur was found, and echocardiography showed hypertrophic cardiomyopathy with asymmetrical septal hypertrophy. At 1 year of age, propranolol (daily administration of 1 mg/kg/day) was started because of progressive left ventricular outflow tract stenosis with an estimated pressure gradient of 68 mmHg by echocardiography. Although propranolol dose was subsequently increased up to 2 mg/kg/day, left ventricular outflow tract stenosis did not improve. On admission, his physical examination was unremarkable except for auscultation of Levine 3/VI systolic murmur at the left lower sternum. Echocardiography at admission showed systolic anterior movement of the mitral valve, and the estimated pressure gradient in the left ventricular outflow tract was 87 mmHg. Simultaneously, multiple lentigines were observed, which led to the suspicion of Noonan syndrome with multiple lentigines. Genetic testing found mutated PTPN11: p.Y279C, commonly identified pathogenic variant of Noonan syndrome with multiple lentigines leading to loss of function of SHP2, involved in the RAS/MAPK signaling pathway, and the diagnosis of Noonan syndrome with multiple lentigines was confirmed.
Cardiac catheterisation demonstrated that the left ventricular and aortic systolic pressures were 170 mmHg and 84 mmHg, respectively. Cibenzoline (1.4 mg/kg) was injected intravenously while simultaneously measuring left ventricular and aortic pressures, and 5 min later, the pressures decreased to 94 mmHg and 71 mmHg, respectively (Fig 1).
Figure 1. The results of cardiac catheterization in case 1.
Effect of cibenzoline administration on the LVP gradient. The maximum LVP gradient attenuated from 86 mmHg to 23 mmHg following intravenous injection of cibenzoline. No QT prolongation was observed in the ECG. ECG, electrocardiogram; AoP, aortic pressure; LVP, left ventricular pressure.
Based on the results, cibenzoline was administered orally after fully explaining to the parents that its use was off-label for obstructive hypertrophic cardiomyopathy in children while monitoring the drug concentration. The estimated pressure gradient of the left ventricular outflow tract was only 12 mmHg after 8 years of cibenzoline administration (Fig 2a).
Figure 2. The clinical course of case 1 (a) and 2 (b).
The arrow indicates the point of cibenzoline initiation. The dotted portion of the line indicating the blood levels of cibenzoline was below the sensitivity of the measurement. LVPG, left ventricular pressure gradient; BNP, brain natriuretic peptide.
Case 2
A 6-year-old Japanese boy was followed up because of hypertrophic obstructive cardiomyopathy detected by echocardiography at birth. Minor malformations, such as shortened limbs and short stature (−3.5 standard deviation), were also observed. Along with the neonatal onset of hypertrophic cardiomyopathy, a RASopathy-related disease was also suspected.
At 5 months of age, he was administered propranolol because of progressive left ventricular outflow tract stenosis with an estimated pressure gradient of 33.6 mmHg measured using echocardiography. At 19 months of age, oral cibenzoline (1.0 mg/kg/day) was included in the prophylaxis to prevent further left ventricular outflow tract stenosis progression after fully explaining to the parents that its use was off-label for obstructive hypertrophic cardiomyopathy in children.
He is now 6 years old and is being treated with cibenzoline (3.1 mg/kg/day) and propranolol (1.9 mg/kg/day); no progressive left ventricular outflow tract stenosis has been observed to date (Fig 2b). His genetic analysis at 6 months of age revealed a RAF1 mutation :p.S257L, commonly identified pathogenic variant of Noonan syndrome leading to paradoxical activation of ERK signalling involved in the RAS/MAPK signalling pathway, confirming the diagnosis of Noonan syndrome. For his short stature, the indication of growth hormone therapy was once considered. However, we have been withholding this therapy owing to possible worsening of left ventricular outflow tract stenosis.
Discussion
The efficacy of disopyramide, a class Ia anti-arrhythmic drug, has been previously reported in adult patients with hypertrophic obstructive cardiomyopathy, Reference Sherrid, Delia and Dwyer2 and that of cibenzoline, belonging to the same class, was compared with that of a lesser anticholinergic agent, in adult patients. Reference Hamada, Shigematsu, Ikeda, Nakamura, Ohshima and Ogimoto3
Cibenzoline alleviates left ventricular outflow tract stenosis through a negative inotropic action. Reference Hamada, Shigematsu and Ikeda4 A decrease in intracellular Na+ concentration and inhibition of depolarisation in cardiomyocytes activate the myocardial Na+/Ca2+ exchanger, resulting in an increase in Na+ concentration and a decrease in Ca2+ concentration. The relief of the left ventricular outflow tract stenosis in the acute phase is possibly related to the decrease in Ca2+ concentration. Elevated Ca2+ concentration in cardiomyocytes in hypertrophic obstructive cardiomyopathic patients is closely associated with left ventricular dysfunction and left ventricular myocardial hypertrophy. Reference Hamada, Shigematsu and Ikeda4,Reference Gwathmey, Warren and Briggs5,Reference Palmiter and Solaro6 The myocardial Na+/Ca2+ exchanger is vital in maintaining Ca2+ homeostasis and preventing Ca2+ overload. These effects of cibenzoline may be useful in the relief of left ventricular outflow tract stenosis. Reference Hamada, Shigematsu, Ikeda, Nakamura, Ohshima and Ogimoto3
Although reports on cibenzoline therapy in children with hypertrophic obstructive cardiomyopathy are limited, continuous improvement can be expected with long-term administration in adult patients. Reference Hamada, Shigematsu, Ikeda, Nakamura, Ohshima and Ogimoto3 Long-term observation is required to understand the relief of left ventricular outflow tract stenosis following oral cibenzoline administration; however, the present case report presents evidence in paediatric cases.
Cibenzoline is known to cause adverse event like arrhythmia, hypoglycaemia, and hepatic dysfunction, but none of these adverse event were observed in the two cases.
Growth hormone therapy is widely used for the short stature associated with RASopathies. Reference Noordam7 However, growth hormones stimulate the RAS/MAPK cascade, and this therapy can induce the progression of myocardial hypertrophy. Reference Seo and Yoo8 While growth hormone therapy does not appear to have any adverse effects on the heart, Reference Noonan and Kappelgaard9 there have been some reports where hypertrophic obstructive cardiomyopathy worsened after the initiation of growth hormone therapy. Reference Jo, Kim and Yoon10 Such reports should be considered when considering growth hormone therapy for to patients with hypertrophic obstructive cardiomyopathy. Although case 2 has not received growth hormone therapy yet, if the left ventricular outflow tract stenosis is well controlled by cibenzoline, he may exhibit adaptation to growth hormone therapy in the future.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing.
Financial support
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflicts of interest
None.
Ethical standards
The authors declare that all procedures used in this work comply with the ethical standards of the relevant national guidelines on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008, and have been approved by the respective institutional committees.
