Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients

Am J Med Genet A. 2018 Aug;176(8):1711-1722. doi: 10.1002/ajmg.a.38854. Epub 2018 Jul 28.

Abstract

Multifocal atrial tachycardia (MAT) has a well-known association with Costello syndrome, but is rarely described with related RAS/MAPK pathway disorders (RASopathies). We report 11 patients with RASopathies (Costello, Noonan, and Noonan syndrome with multiple lentigines [formerly LEOPARD syndrome]) and nonreentrant atrial tachycardias (MAT and ectopic atrial tachycardia) demonstrating overlap in cardiac arrhythmia phenotype. Similar overlap is seen in RASopathies with respect to skeletal, musculoskeletal and cutaneous abnormalities, dysmorphic facial features, and neurodevelopmental deficits. Nonreentrant atrial tachycardias may cause cardiac compromise if sinus rhythm is not restored expeditiously. Typical first-line supraventricular tachycardia anti-arrhythmics (propranolol and digoxin) were generally not effective in restoring or maintaining sinus rhythm in this cohort, while flecainide or amiodarone alone or in concert with propranolol were effective anti-arrhythmic agents for acute and chronic use. Atrial tachycardia resolved in all patients. However, a 4-month-old boy from the cohort was found asystolic (with concurrent cellulitis) and a second patient underwent cardiac transplant for heart failure complicated by recalcitrant atrial arrhythmia. While propranolol alone frequently failed to convert or maintain sinus rhythm, fleccainide or amiodarone, occasionally in combination with propranolol, was effective for RASopathy patient treatment for nonreentrant atrial arrhythmia. Our analysis shows that RASopathy patients may have nonreentrant atrial tachycardia with and without associated cardiac hypertrophy. While nonreentrant arrhythmia has been traditionally associated with Costello syndrome, this work provides an expanded view of RASopathy cardiac arrhythmia phenotype as we demonstrate mutant proteins throughout this signaling pathway can also give rise to ectopic and/or MAT.

Keywords: Calcium; Costello syndrome; Noonan syndrome; Noonan syndrome with multiple lentigines; RAS/MAPK signaling pathway; ectopic atrial tachycardia; multifocal atrial tachycardia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amiodarone / therapeutic use
  • Arrhythmias, Cardiac / drug therapy
  • Arrhythmias, Cardiac / genetics
  • Arrhythmias, Cardiac / physiopathology
  • Calcium / metabolism
  • Cardiomyopathy, Hypertrophic / drug therapy
  • Cardiomyopathy, Hypertrophic / genetics*
  • Cardiomyopathy, Hypertrophic / physiopathology
  • Costello Syndrome / drug therapy
  • Costello Syndrome / genetics*
  • Costello Syndrome / physiopathology
  • Digoxin / therapeutic use
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • LEOPARD Syndrome / genetics
  • LEOPARD Syndrome / physiopathology
  • Male
  • Noonan Syndrome / drug therapy
  • Noonan Syndrome / genetics*
  • Noonan Syndrome / physiopathology
  • Propranolol / therapeutic use
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Proto-Oncogene Proteins c-raf / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • SOS1 Protein / genetics
  • Tachycardia, Ectopic Atrial / drug therapy
  • Tachycardia, Ectopic Atrial / genetics*
  • Tachycardia, Ectopic Atrial / physiopathology
  • ras Proteins / classification
  • ras Proteins / genetics*

Substances

  • KRAS protein, human
  • SOS1 Protein
  • SOS1 protein, human
  • Digoxin
  • Propranolol
  • Proto-Oncogene Proteins c-raf
  • Raf1 protein, human
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Amiodarone
  • Calcium