MULTIFOCAL ATRIAL TACHYCARDIA AND HYPERTROPHIC CARDIOMYOPATHY IN THREE PATIENTS WITH COSTELLO SYNDROME

Abstract

Abstract Introduction Costello syndrome is a rare disease, caused by mutation of the HRAS gene, associated with intellectual disability, growth retardation, facial dimorphisms. Cardiac abnormalities, mainly cardiac hypertrophy and multifocal atrial tachycardia, are present in 1/3 of patients. Clinical Cases From 2019 to 2023, 3 newborns with Costello syndrome came under our observation. M.M. showed respiratory distress, hypotonia and dysmorphic notes; genetic analysis highlighted the pathogenic variant c.64C>A (p.Gln22Lys). On the echocardiogram, septal hypertrophic cardiomyopathy was found with left outflow obstruction and mitral insufficiency. Therapy with propranolol was undertaken. Holter ECG never revealed arrhythmias. At the last check–up, SIV hypertrophy, continent mitral valve, free left ventricular outflow. The second patient, O.L., arrived at 10 days of age following a run of supraventricular tachycardia. He had bilateral clubfoot and facial dimorphisms. The echocardiogram was normal. On Holter ECG atrial tachycardia interrupted by rare sinus beats. Therapy with flecainide was undertaken, without benefit. Subsequently, was undertaken amiodarone, then associated with digitalis. She was discharged with satisfactory control of the average ventricular rate, but later due to the appearance of chaotic atrial arrhythmia, propranolol was added; on the Holter ECG in triple therapy, periods of sinus rhythm alternating with short episodes of atrial tachycardia were observed. Genetic analysis revealed the pathogenic variant c.34G>A, p.(Gly12Ser) of the HRAS gene. The third patient, F.A., presented atrial tachycardia. Flecainide therapy had transient benefit. Subsequently propranolol was added, without benefit. Therapy with amiodarone was initiated. Transesophageal electrophysiological study demonstrated multifocal atrial tachycardia, unresponsive to overdrive pacing. Partial control of the average ventricular rate was achieved in triple therapy. On the echocardiogram, mild concentric hypertrophy and dysplastic pulmonary valve. Genetic testing detected the c.35G>C, p(Gly12Ala) variant of the HRAS gene. Conclusions Costello syndrome requires cardiac monitoring for the possible presence of multifocal atrial tachycardia and hypertrophic cardiomyopathy. Arrhythmia, which can also occur independently of hypertrophy, can be self–limited in the first months of life with aggressive pharmacological treatment but can persist or worsen in ¼ of patients.