Author + information
- Received January 31, 2017
- Revision received August 21, 2017
- Accepted August 22, 2017
- Published online April 16, 2018.
- Keith A. Dufendach, MDa,b,
- Katherine Timothy, BSc,
- Michael J. Ackerman, MD, PhDd,e,f,
- Benjamin Blevins, MDg,
- Andreas Pflaumer, MDh,
- Susan Etheridge, MDc,
- James Perry, MDi,
- Nico A. Blom, MDj,k,
- Joel Temple, MDl,
- Devyani Chowdhury, MDm,
- Jonathan R. Skinner, MBChB, DCH, MRCPn,
- Christopher Johnsrude, MDo,
- Andras Bratincsak, MDp,
- J. Martijn Bos, MD, PhDd,e,f and
- Maully Shah, MBBSb,∗ ()
- aDepartment of Pediatrics, Division of Pediatric Cardiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- bDepartment of Pediatrics, Division of Pediatric Cardiology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
- cDepartment of Pediatrics, Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah
- dDepartment of Cardiovascular Diseases, Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota
- eDepartment of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota
- fDepartment of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
- gDepartment of Pediatrics, Division of Pediatric Cardiology, Naval Medical Center San Diego, San Diego, California
- hDepartment of Pediatrics, Division of Pediatric Cardiology, Royal Children’s Hospital, MCRI, and University of Melbourne, Melbourne, Australia
- iDepartment of Pediatrics, Division of Pediatric Cardiology, Rady Children’s Hospital/UC San Diego, San Diego, California
- jDepartment of Medicine, Division of Pediatric Cardiology, Leiden University Medical Center, Leiden, the Netherlands
- kDepartment of Medicine, Division of Pediatric Cardiology, Academic Medical Center, Amsterdam, the Netherlands
- lNemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware
- mCardiology Care for Children, Lancaster, Pennsylvania
- nDepartment of Pediatrics, Division of Pediatric Cardiology, Starship Children's Hospital, Auckland, New Zealand
- oUniversity of Louisville, Louisville, Kentucky
- pPediatric and Adult Congenital Cardiology, Kapi'olani Medical Specialists, Honolulu, Hawaii
- ↵∗Address for correspondence:
Dr. Maully Shah, Perelman School of Medicine, University of Pennsylvania, The Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, Pennsylvania 19104.
Objectives The objective of this study was to evaluate contemporary clinical outcomes and identify triggers for arrhythmias or sudden death in an international cohort of Timothy Syndrome (TS) patients including those with novel TS-associated CACNA1C mutations.
Background TS is an extremely rare genetic disorder of the L-type cardiac channel Cav1.2 encoded by CACNA1C. The syndrome is characterized by multisystem abnormalities consisting of QT prolongation, congenital heart defects, syndactyly, facial dysmorphism, and neurological symptoms.
Methods Patients diagnosed with TS between January 1, 1994, and April 1, 2016, from 12 international tertiary care pediatric centers were included in this retrospective study. Data were gathered via survey from the patients’ electrophysiologists.
Results Seventeen patients diagnosed with TS were identified. Length of follow-up was 4.9 years (range 3.0 to 19.0 years). Mean QTc was 640 ms (range 500 to 976 ms). All patients were treated with beta-blockers; 13 patients (76%) were also treated with an implantable defibrillator. Eleven patients experienced an episode of aborted cardiac arrest, 6 associated with general anesthesia and 2 with hypoglycemia. Four patients died suddenly due to ventricular fibrillation, 2 of whom had associated hypoglycemia.
Conclusions This study shows that mortality in TS patients is due to multifactorial mechanisms, which include ventricular arrhythmias, pulseless electrical activity, and hypoglycemia. A simple nomenclature for ongoing studies of TS and related syndromes is described. A worldwide prospective registry is needed for continued exploration of this syndrome.
This study was approved by the Pediatric and Congenital Electrophysiology Society (PACES). The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. Dr. Ackerman has received consultant fees from Boston Scientific, Gilead Sciences, Medtronic, and St. Jude Medical; and royalties from Transgenomic. Dr. Shah has received a research grant unrelated to the study presented in this manuscript from Medtronic, Inc. Dr. Temple has served as a consultant for St. Jude Medical. All other authors have reported that they have no relationships relevant to this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Received January 31, 2017.
- Revision received August 21, 2017.
- Accepted August 22, 2017.
- 2018 American College of Cardiology Foundation
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