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A rare association of long QT syndrome, syndactyly and atrial septal defect (timothy syndrome) – Case report and literature review
IHJ Cardiovascular Case Reports (CVCR) 1 (2017) 29–31
Contents lists available at ScienceDirect
IHJ Cardiovascular Case Reports (CVCR) journal homepage: www.elsevier.com/locate/ihjccr
Case study
A rare association of long QT syndrome, syndactyly and atrial septal defect (timothy syndrome) – Case report and literature review Bhupendra K. Sihag, Vikas Agrawal ∗ Department of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
a r t i c l e
i n f o
Keywords: Congenital Arrhythmias Syndrome
a b s t r a c t Timothy syndrome (TS) is a rare genetic disorder characterized by an abnormally prolonged cardiac “repolarization” time (long QT interval). This predisposes individuals to arrhythmias, cardiac arrest and sudden death. Other features associated with this syndrome are webbing of fingers and/or toes (syndactyly); congenital heart defects (ASD, VSD, PDA or TOF); a weakened immune system; developmental delays and autism. About 25 cases of timothy syndrome have been reported in the literature until now. We report a case of timothy syndrome presenting at the age of 30 years with ASD, long QT syndrome, syndactyly and recurrent ventricular arrhythmias. © 2016 Published by Elsevier B.V. on behalf of Cardiological Society of India. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Timothy syndrome is a very rare genetic disorder characterized by abnormally prolonged cardiac repolarization time (long QT interval), syndactyly, congenital structural heart disease (ASD, VSD, PDA, PFO and TOF) and autism. We report a case of syndactyly, LQTS, ostium secundum ASD, with mitral valve prolapse. 2. Case report A 30 year young female presented with a history of shortness of breath and early fatigability from last 4 to 5 years. She had recurrent episodes of palpitations with syncope for last 3 days. On examination her pulse rate was 94/min and blood pressure was 96/60 mm of Hg. The cardiac examination revealed a parasternal heave, ejection systolic murmur at the left parasternal area and a wide and fixed splitting of S2 with loud second heart sound. Lung examination was unremarkable. Syndactyly of fingers of all 4 limbs was present (Fig. 1). Results of diagnostic tests including complete blood count and serum electrolytes were normal. Her ECG showed prolonged QT interval (QTc interval 467 ms), right axis deviation and RBBB (Fig. 2). The transthoracic echocardiogram demonstrated mitral valve prolapse with mild mitral regurgitation, large ostium secundum ASD of size ∼30 mm with predominant left to right shunt„ dilated pulmonary arteries, elevated PA pressure and moderate tricuspid regurgitation (Figs. 3–5). Patient was admitted for further evaluation of the cause of syncope.
∗ Corresponding author. E-mail address: [email protected] (V. Agrawal).
During hospitalization the patient developed recurrent episodes of polymorphic ventricular tachycardia for which DC cardioversion was done. Anti arrhythmic treatment with mexiletine was started. Beta blocker (Metoprolol 50 mg twice daily) was also added later. Patient was not willing for ICD implantation. The patient died after aggressive resuscitative efforts when she developed refractory ventricular fibrillation (Fig. 6). A strong family history of syndactyly and sudden death at a young age in last 3 generations (mother, maternal uncle, grandmother, and grandmothers brother) was obtained. Patient has 2 children with syndactyly who require further work up. She was not evaluated prior to this admission for any of her complaints. According to her parents her developmental milestones were normal and there was no history of consanguinity. She had no learning difficulties or any psychiatric disorder. Molecular genetic analysis could not be done. 3. Discussion Classic timothy syndrome (TS) is a rare genetic disorder with dysfunction in multiple organ systems, clinically characterized by long QT syndrome and syndactyly.1 Timothy syndrome was first described in 1992 as sporadic cases of long QT syndrome, congenital heart disease and syndactyly. Since then rare cases have been reported in the literature.2 Classic TS is caused by a single missense mutation G406R of exon 8A of the Cav1.2 L-type calcium channel gene (CACNA1C) and is inherited in an autosomal dominant fashion, although it usually is the result of a de novo mutation.1 Patients with TS are prone to life threatening ventricular arrhythmias as a consequence of prolonged QT interval. Besides cardiac arrhythmias, manifestations of TS include congenital heart defects like
http://dx.doi.org/10.1016/j.ihjccr.2016.12.002 2468-600X/© 2016 Published by Elsevier B.V. on behalf of Cardiological Society of India. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).
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B.K. Sihag, V. Agrawal / IHJ Cardiovascular Case Reports (CVCR) 1 (2017) 29–31
Fig. 3. Apical 4 chamber by 2D echocardiography showing large secundum ASD.
Fig. 1. Syndactyly of upper and lower limbs.
atrial septal defects, ventricular septal defects, patent ductus arteriosus, hypertrophic cardiomyopathy and Tetralogy of Fallot. Since the affected gene is widely expressed in multiple adult and fetal tissues including gastrointestinal system, brain, lungs, immune system and testis, extracardiac manifestations like facial dysmorphy, myopia, immune deficiency with recurrent infections, intermittent hypoglycemia, and hypothermia are common in patients with TS. Many children with TS present with developmental delay, cognitive abnormalities and autism.2 Some reports described the ‘de novo’ mutations in timothy syndrome representing cases of parental mosaicism, with implications for genetic counseling.3 Splawski et al.4 reported 2 individuals with a severe variant of TS in whom they identified de novo missense mutations in exon 8 of the CACNA1C gene (G406R; G402S). In contrast to previously
reported TS patients with a mutation in exon 8A, these patients did not have syndactyly, had an average QT interval that was 60 ms longer, and had multiple episodes of unprovoked arrhythmia; multiple arrhythmias were rare in the patients with mutations in exon 8A, and most were associated with medications and/or anesthesia. They designated the atypical, more severe form due to exon 8 mutations ‘TS2’ (timothy syndrome type 2). Varied clinical features of timothy syndrome have been reported. Hiippala et al.5 studied a 13-year-old Finnish girl who was resuscitated from ventricular fibrillation after collapsing at home and was found to have a slightly prolonged QTc interval of 480 ms. She had a history of 2 similar events in the previous year while walking with friends, from which she recovered spontaneously. Cardiac evaluation showed normal structure and function. An ICD was inserted, but over a follow-up period of 3.5 years, no shocks occurred, and her QTc intervals were in the high-normal range (440–460 ms). She had no learning difficulties or psychiatric disorders, no craniofacial dysmorphism, and no musculoskeletal abnormalities.
Fig. 2. ECG showing right axis deviation, RBBB with prolonged QT interval (QTc interval 467 ms).
B.K. Sihag, V. Agrawal / IHJ Cardiovascular Case Reports (CVCR) 1 (2017) 29–31
Fig. 4. Apical 4 chamber by 2D echocardiography with color flow imaging showing, large secundum ASD with bidirectional shunt.
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Pharmacologic therapies to shorten ventricular repolarization, restore one-to-one conduction, and reduce the risk of arrhythmias include sodium channel blockers and calcium channel blockers. Although verapamil has been used in one case7 and the partial effectiveness of sodium channel blockers mexiletine and ranolazine has been reported for two patients,8,9 no data are available to support their routine use in timothy syndrome. This emphasizes the highly malignant course of this syndrome. Due to the malignant course of TS, implantable cardioverter defibrillators are most important in preventing sudden cardiac death in individuals with TS. It should be considered in every patient with confirmed diagnosis as soon as body weight allows the procedure for primary prophylaxis of sudden cardiac death even in patients without documented ventricular tachycardia.10 Cascade screening of family members has a definite role and allows the identification, as mutation positive, of individuals who would have been otherwise considered unaffected and therefore would have remained at risk for potentially life-threatening arrhythmias either as spontaneous event or more likely as provoked by a variety of drugs. This leads to prophylactic treatment in mutation positive individuals.11 Also important is the fact that those family members who are found to be negative for the family’s disease-causing mutation will be relieved to learn that they are not at risk and that they should not fear for their offspring. 4. Conclusion Timothy syndrome is a rare congenital arrhythmia disorder with dysfunction in multiple organ systems. These patients are at high risk for sudden death due to life threatening ventricular tachyarrhythmias. Drug therapy has not been validated in this subgroup of patients due to small number of patients reported in the literature. Implantation of an ICD at a very young age may be the best means to prevent sudden death. Conflicts of interest The authors have none to declare.
Fig. 5. Small axis view by 2D echocardiography showing dilated pulmonary artery.
Fig. 6. ECG tracing showing torsades de pointes.
The risk for life-threatening ventricular tachyarrhythmias is the limiting factor of TS. Since ventricular tachyarrhythmia is the leading cause of death in patients with TS, effective anti-arrhythmic medication and an implantable cardioverter defibrillator are the mainstay of therapy. None of the drugs have proven to reliably prevent life-threatening ventricular tachycardia in patients with classic TS over a longer period of time. In our patient, we used mexiletine, a class IB anti-arrhythmic drug known to shorten QTInterval and effectively suppress the development of ventricular tachycardia in patients with long QT syndrome type 3.6 However the patient developed recurrent torsades de pointes tachycardia after few days of starting mexiletine. -Blocker was added but did not prove beneficial as the patient died after aggressive resuscitative efforts when found to have ventricular fibrillation.
References 1. Splawski I, Timothy KW, Sharpe LM, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell. 2004;119:19–31. 2. Splawski I, Timothy KW, Priori SG, Napolitano C, Bloise R. Timothy syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. Gene Reviews. 2009. 3. Etheridge SP, Bowles NE, Arrington CB, et al. Somatic mosaicism contributes to phenotypic variation in Timothy syndrome. Am J Med Genet. 2011;155A:2578–2583. 4. Splawski I, Timothy KW, Decher N, et al. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci U S A. 2005;102:8089–8096. 5. Hiippala A, Tallila J, Myllykangas S, Koskenvuo JW, Alastalo TP. Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development. Am J Med Genet. 2015;167A:629–634. 6. Shimizu W, Aiba T, Antzelevitch C. Specific therapy based on the genotype and cellular mechanism in inherited cardiac arrhythmias. Long QT syndrome and Brugada syndrome. Curr Pharm Des. 2005;11:1561–1572. 7. Jacobs A, Knight BP, McDonald KT, Burke MC. Verapamil decreases ventricular tachyarrhythmias in a patient with Timothy syndrome (LQT8). Heart Rhythm. 2006;3:967–970. 8. Shah DP, Baez-Escudero JL, Weisberg IL, Beshai JF, Burke MC. Ranolazine safely decreases ventricular and atrial fibrillation in Timothy syndrome (LQT8). Pacing Clin Electrophysiol. 2012;35:e62–e64. 9. Gao Y, Xue X, Hu D, et al. Inhibition of late sodium current by mexiletine: a novel pharmotherapeutical approach in timothy syndrome. Circ Arrhythm Electrophysiol. 2013;6:614–622. 10. Marks ML, Whisler SL, Clericuzio C, Keating M. A new form of long QT syndrome associated with syndactyly. J Am Coll Cardiol. 1995;25:59–64. 11. Hofman N, Tan HL, Alders M, van Langen IM, Wilde AA. Active cascade screening in primary inherited arrhythmia syndromes: does it lead to prophylactic treatment? J Am Coll Cardiol. 2010;55:2570–2576.
Contents lists available at ScienceDirect
IHJ Cardiovascular Case Reports (CVCR) journal homepage: www.elsevier.com/locate/ihjccr
Case study
A rare association of long QT syndrome, syndactyly and atrial septal defect (timothy syndrome) – Case report and literature review Bhupendra K. Sihag, Vikas Agrawal ∗ Department of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
a r t i c l e
i n f o
Keywords: Congenital Arrhythmias Syndrome
a b s t r a c t Timothy syndrome (TS) is a rare genetic disorder characterized by an abnormally prolonged cardiac “repolarization” time (long QT interval). This predisposes individuals to arrhythmias, cardiac arrest and sudden death. Other features associated with this syndrome are webbing of fingers and/or toes (syndactyly); congenital heart defects (ASD, VSD, PDA or TOF); a weakened immune system; developmental delays and autism. About 25 cases of timothy syndrome have been reported in the literature until now. We report a case of timothy syndrome presenting at the age of 30 years with ASD, long QT syndrome, syndactyly and recurrent ventricular arrhythmias. © 2016 Published by Elsevier B.V. on behalf of Cardiological Society of India. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Timothy syndrome is a very rare genetic disorder characterized by abnormally prolonged cardiac repolarization time (long QT interval), syndactyly, congenital structural heart disease (ASD, VSD, PDA, PFO and TOF) and autism. We report a case of syndactyly, LQTS, ostium secundum ASD, with mitral valve prolapse. 2. Case report A 30 year young female presented with a history of shortness of breath and early fatigability from last 4 to 5 years. She had recurrent episodes of palpitations with syncope for last 3 days. On examination her pulse rate was 94/min and blood pressure was 96/60 mm of Hg. The cardiac examination revealed a parasternal heave, ejection systolic murmur at the left parasternal area and a wide and fixed splitting of S2 with loud second heart sound. Lung examination was unremarkable. Syndactyly of fingers of all 4 limbs was present (Fig. 1). Results of diagnostic tests including complete blood count and serum electrolytes were normal. Her ECG showed prolonged QT interval (QTc interval 467 ms), right axis deviation and RBBB (Fig. 2). The transthoracic echocardiogram demonstrated mitral valve prolapse with mild mitral regurgitation, large ostium secundum ASD of size ∼30 mm with predominant left to right shunt„ dilated pulmonary arteries, elevated PA pressure and moderate tricuspid regurgitation (Figs. 3–5). Patient was admitted for further evaluation of the cause of syncope.
∗ Corresponding author. E-mail address: [email protected] (V. Agrawal).
During hospitalization the patient developed recurrent episodes of polymorphic ventricular tachycardia for which DC cardioversion was done. Anti arrhythmic treatment with mexiletine was started. Beta blocker (Metoprolol 50 mg twice daily) was also added later. Patient was not willing for ICD implantation. The patient died after aggressive resuscitative efforts when she developed refractory ventricular fibrillation (Fig. 6). A strong family history of syndactyly and sudden death at a young age in last 3 generations (mother, maternal uncle, grandmother, and grandmothers brother) was obtained. Patient has 2 children with syndactyly who require further work up. She was not evaluated prior to this admission for any of her complaints. According to her parents her developmental milestones were normal and there was no history of consanguinity. She had no learning difficulties or any psychiatric disorder. Molecular genetic analysis could not be done. 3. Discussion Classic timothy syndrome (TS) is a rare genetic disorder with dysfunction in multiple organ systems, clinically characterized by long QT syndrome and syndactyly.1 Timothy syndrome was first described in 1992 as sporadic cases of long QT syndrome, congenital heart disease and syndactyly. Since then rare cases have been reported in the literature.2 Classic TS is caused by a single missense mutation G406R of exon 8A of the Cav1.2 L-type calcium channel gene (CACNA1C) and is inherited in an autosomal dominant fashion, although it usually is the result of a de novo mutation.1 Patients with TS are prone to life threatening ventricular arrhythmias as a consequence of prolonged QT interval. Besides cardiac arrhythmias, manifestations of TS include congenital heart defects like
http://dx.doi.org/10.1016/j.ihjccr.2016.12.002 2468-600X/© 2016 Published by Elsevier B.V. on behalf of Cardiological Society of India. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).
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B.K. Sihag, V. Agrawal / IHJ Cardiovascular Case Reports (CVCR) 1 (2017) 29–31
Fig. 3. Apical 4 chamber by 2D echocardiography showing large secundum ASD.
Fig. 1. Syndactyly of upper and lower limbs.
atrial septal defects, ventricular septal defects, patent ductus arteriosus, hypertrophic cardiomyopathy and Tetralogy of Fallot. Since the affected gene is widely expressed in multiple adult and fetal tissues including gastrointestinal system, brain, lungs, immune system and testis, extracardiac manifestations like facial dysmorphy, myopia, immune deficiency with recurrent infections, intermittent hypoglycemia, and hypothermia are common in patients with TS. Many children with TS present with developmental delay, cognitive abnormalities and autism.2 Some reports described the ‘de novo’ mutations in timothy syndrome representing cases of parental mosaicism, with implications for genetic counseling.3 Splawski et al.4 reported 2 individuals with a severe variant of TS in whom they identified de novo missense mutations in exon 8 of the CACNA1C gene (G406R; G402S). In contrast to previously
reported TS patients with a mutation in exon 8A, these patients did not have syndactyly, had an average QT interval that was 60 ms longer, and had multiple episodes of unprovoked arrhythmia; multiple arrhythmias were rare in the patients with mutations in exon 8A, and most were associated with medications and/or anesthesia. They designated the atypical, more severe form due to exon 8 mutations ‘TS2’ (timothy syndrome type 2). Varied clinical features of timothy syndrome have been reported. Hiippala et al.5 studied a 13-year-old Finnish girl who was resuscitated from ventricular fibrillation after collapsing at home and was found to have a slightly prolonged QTc interval of 480 ms. She had a history of 2 similar events in the previous year while walking with friends, from which she recovered spontaneously. Cardiac evaluation showed normal structure and function. An ICD was inserted, but over a follow-up period of 3.5 years, no shocks occurred, and her QTc intervals were in the high-normal range (440–460 ms). She had no learning difficulties or psychiatric disorders, no craniofacial dysmorphism, and no musculoskeletal abnormalities.
Fig. 2. ECG showing right axis deviation, RBBB with prolonged QT interval (QTc interval 467 ms).
B.K. Sihag, V. Agrawal / IHJ Cardiovascular Case Reports (CVCR) 1 (2017) 29–31
Fig. 4. Apical 4 chamber by 2D echocardiography with color flow imaging showing, large secundum ASD with bidirectional shunt.
31
Pharmacologic therapies to shorten ventricular repolarization, restore one-to-one conduction, and reduce the risk of arrhythmias include sodium channel blockers and calcium channel blockers. Although verapamil has been used in one case7 and the partial effectiveness of sodium channel blockers mexiletine and ranolazine has been reported for two patients,8,9 no data are available to support their routine use in timothy syndrome. This emphasizes the highly malignant course of this syndrome. Due to the malignant course of TS, implantable cardioverter defibrillators are most important in preventing sudden cardiac death in individuals with TS. It should be considered in every patient with confirmed diagnosis as soon as body weight allows the procedure for primary prophylaxis of sudden cardiac death even in patients without documented ventricular tachycardia.10 Cascade screening of family members has a definite role and allows the identification, as mutation positive, of individuals who would have been otherwise considered unaffected and therefore would have remained at risk for potentially life-threatening arrhythmias either as spontaneous event or more likely as provoked by a variety of drugs. This leads to prophylactic treatment in mutation positive individuals.11 Also important is the fact that those family members who are found to be negative for the family’s disease-causing mutation will be relieved to learn that they are not at risk and that they should not fear for their offspring. 4. Conclusion Timothy syndrome is a rare congenital arrhythmia disorder with dysfunction in multiple organ systems. These patients are at high risk for sudden death due to life threatening ventricular tachyarrhythmias. Drug therapy has not been validated in this subgroup of patients due to small number of patients reported in the literature. Implantation of an ICD at a very young age may be the best means to prevent sudden death. Conflicts of interest The authors have none to declare.
Fig. 5. Small axis view by 2D echocardiography showing dilated pulmonary artery.
Fig. 6. ECG tracing showing torsades de pointes.
The risk for life-threatening ventricular tachyarrhythmias is the limiting factor of TS. Since ventricular tachyarrhythmia is the leading cause of death in patients with TS, effective anti-arrhythmic medication and an implantable cardioverter defibrillator are the mainstay of therapy. None of the drugs have proven to reliably prevent life-threatening ventricular tachycardia in patients with classic TS over a longer period of time. In our patient, we used mexiletine, a class IB anti-arrhythmic drug known to shorten QTInterval and effectively suppress the development of ventricular tachycardia in patients with long QT syndrome type 3.6 However the patient developed recurrent torsades de pointes tachycardia after few days of starting mexiletine. -Blocker was added but did not prove beneficial as the patient died after aggressive resuscitative efforts when found to have ventricular fibrillation.
References 1. Splawski I, Timothy KW, Sharpe LM, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell. 2004;119:19–31. 2. Splawski I, Timothy KW, Priori SG, Napolitano C, Bloise R. Timothy syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. Gene Reviews. 2009. 3. Etheridge SP, Bowles NE, Arrington CB, et al. Somatic mosaicism contributes to phenotypic variation in Timothy syndrome. Am J Med Genet. 2011;155A:2578–2583. 4. Splawski I, Timothy KW, Decher N, et al. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci U S A. 2005;102:8089–8096. 5. Hiippala A, Tallila J, Myllykangas S, Koskenvuo JW, Alastalo TP. Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development. Am J Med Genet. 2015;167A:629–634. 6. Shimizu W, Aiba T, Antzelevitch C. Specific therapy based on the genotype and cellular mechanism in inherited cardiac arrhythmias. Long QT syndrome and Brugada syndrome. Curr Pharm Des. 2005;11:1561–1572. 7. Jacobs A, Knight BP, McDonald KT, Burke MC. Verapamil decreases ventricular tachyarrhythmias in a patient with Timothy syndrome (LQT8). Heart Rhythm. 2006;3:967–970. 8. Shah DP, Baez-Escudero JL, Weisberg IL, Beshai JF, Burke MC. Ranolazine safely decreases ventricular and atrial fibrillation in Timothy syndrome (LQT8). Pacing Clin Electrophysiol. 2012;35:e62–e64. 9. Gao Y, Xue X, Hu D, et al. Inhibition of late sodium current by mexiletine: a novel pharmotherapeutical approach in timothy syndrome. Circ Arrhythm Electrophysiol. 2013;6:614–622. 10. Marks ML, Whisler SL, Clericuzio C, Keating M. A new form of long QT syndrome associated with syndactyly. J Am Coll Cardiol. 1995;25:59–64. 11. Hofman N, Tan HL, Alders M, van Langen IM, Wilde AA. Active cascade screening in primary inherited arrhythmia syndromes: does it lead to prophylactic treatment? J Am Coll Cardiol. 2010;55:2570–2576.