- Email: [email protected]
Hypertrophic Cardiomyopathy in Childhood: Risk Management Through Family Screening
THE JOURNAL OF PEDIATRICS • www.jpeds.com
EDITORIALS
Hypertrophic Cardiomyopathy in Childhood: Risk Management Through Family Screening (age 12.1 ± 1.7 years) with an identified HCM-related gene he spectrum of hypertrophic cardiomyopathy (HCM) mutations, 5 children were diagnosed with HCM at first evaluranges from silent phenotypes, typically with mild ation, and another child was diagnosed after a mean followhypertrophy in asymptomatic patients, to aggressive up of 6.9 ± 3.8 years. In addition, 2 patients phenotypes with malignant arrhythmias or See related article, p ••• were diagnosed much later, at age 25 and hemodynamic compromise in patients with 30 years. This confirms that the penetrance severe hypertrophy and disabling symptoms. for children carrying a HCM-related gene mutation is low, This is true for adult patients as well as for children with HCM. and that likely <10% develop the disease before age 18 years. Reports depicting worst-case scenarios of severe progressive It also indicates that the development of diagnostic hypertrohypertrophy and clinical deterioration in childhood tend to phy may continue into early adulthood. However, in this study, dominate the literature on childhood HCM, and few popuas in the previous studies, severe cardiac events are reported lation studies have been published. The evidence from severe in a relatively small group of children with diagnostic HCM. cases of childhood HCM, along with knowledge of HCM being Three of the 6 children who were diagnosed in childhood dean inherited cardiomyopathy, have motivated family screenveloped severe hypertrophy, with a maximal wall thickness of ing programs for relatives, including children, with a family 28-36 mm during adolescence. One of these children experihistory of HCM. The resulting identification of children with enced an appropriate implantable cardioverter defibrillator mild HCM phenotypes and phenotype-negative mutation carshock. The other 3 children developed only modest hypertroriers warrants careful counseling of children and parents. In phy of <20 mm. This clearly illustrates that the development this process, accurate data on the risks associated with childof hypertrophy during puberty is highly unpredictable and may hood HCM or a positive genotype are essential to put toput individual children at high risk for cardiac events. gether a strong take-home message for affected families. Exact diagnostics are essential to identify manifest disease The generally accepted notion, backed up by convincing at an early stage and to reassure phenotype-negative mutareports of excessive myocardial growth, has been that myotion carriers of their low risk of cardiac events. In children, cardial growth is accelerated during puberty,1 and cases of the diagnostic criteria for HCM is an age- or body surface areasudden cardiac death (SCD) in childhood have emphasized adjusted maximal wall thickness exceeding the upper 95% limit the potential risks in children with HCM.2 This has possibly for the normal population.7 Several sets of normal values are left a somewhat exaggerated picture of the disease that available, but these are not identical; thus, the available normal contrasts with the clinically observed low penetrance and values should be validated against a local population before benign course of the disease in most children included in implementation. Evaluation by echocardiography or cardiac family screening programs. To date, only a few studies have magnetic resonance imaging is essential to establish the diagattempted to estimate the actual risk of cardiac events in nosis and determine the risk of cardiac events. children included in screening programs.3,4 In recent decades, the increased availability of echocardiography and the Vermeer et al confirm previously reported findings indiimplementation of family screening programs have changed cating a significant risk of cardiac events in phenotypethe adult population with HCM by adding patients with mild positive children, and thus the risk should be evaluated at every phenotypes, and have reduced the observed mortality and clinical visit. Electrocardiogram changes, degree of hypertrothe rates of SCD.5 Undoubtedly, this effort also has changed phy, and nonsustained ventricular tachycardia are known the population of children with HCM. Thus, asymptomatic risk factors for SCD in children with HCM, but the risk stratichildren with HCM and genotype-positive children without fication procedures described for adults have not been valihypertrophy are now being identified, and whether these childated in children. dren are at similarly high risk for cardiac events as symptomVermeer et al followed more than 100 phenotype-negative atic child probands is not clear. The few available outcome children who were carrying HCM-related gene mutations with studies from family screening programs indicate that this may a very low phenoconversion rate and did not identify any not be the case, though severe cases of SCD, implantable cardiac events in children who remained phenotype-negative, cardioverter defibrillator discharge, or the need for septal myeven though many of these children had a family history of ectomy were also present in these study populations.3,4 SCD. This finding supports previous studies and indicates that Vermeer et al present an important study on children from families with HCM-related gene mutations.6 Of 119 children
T
The authors declare no conflicts of interest.
HCM SCD
Hypertrophic cardiomyopathy Sudden cardiac death
0022-3476/$ - see front matter. © 2017 Elsevier Inc. All rights reserved. http://dx.doi.org10.1016/j.jpeds.2017.04.068
1 EDI 5.4.0 DTD ■ YMPD9178_proof ■ May 19, 2017
THE JOURNAL OF PEDIATRICS • www.jpeds.com a positive genetic test result in otherwise unaffected children is not a marker of increased risk for cardiac events. Thus, risk stratification for SCD is not rational in this group.8 Based on current data, it seems reasonable to start family screening at or before age 8 years.2 The evaluations should include echocardiography, clinical examination, and electrocardiography. In children with positive findings, the evaluation can be expanded. Genetic testing of children is optional and is not essential for children from families with HCM; however, a negative genetic test result may be important, signaling no need for further follow-up. Genetic testing of children may pose ethical issues, which is why careful counseling of children and parents is essential. The decision of whether to perform genetic testing should be ultimately up to the parents, but can safely be postponed until the child is sufficiently mature to participate in decision making. In conclusion, the study by Vermeer et al emphasizes the important contribution of family screening for identifying children at risk for severe cardiac events. In the setting of clinical and genetic family screening, counseling is important, and with growing confidence we can reassure parents and children that the potential risks are associated with a positive HCM phenotype. Without hypertrophy, the risk is extremely low and is likely close to the risk of the background population. Few genotype-positive children will develop HCM during childhood and adolescence, but in the few children who do develop the disease in childhood, the risk of disease progression and cardiac events is significant. ■ Kim Munk, MD, PhD Morten Kvistholm Jensen, MD, PhD Department of Cardiology Aarhus University Hospital Aarhus, Denmark
Volume ■■
Reprint requests: Morten Kvistholm Jensen, MD, PhD, Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Aarhus 8200, Denmark. E-mail: [email protected]
References 1. Maron BJ, Spirito P, Wesley Y, Arce J. Development and progression of left ventricular hypertrophy in children with hypertrophic cardiomyopathy. N Engl J Med 1986;315:610-4. 2. Ostman-Smith I, Wettrell G, Keeton B, Holmgren D, Ergander U, Gould S, et al. Age- and gender-specific mortality rates in childhood hypertrophic cardiomyopathy. Eur Heart J 2008;29:1160-7. 3. Jensen MK, Havndrup O, Christiansen M, Andersen PS, Axelsson A, Køber L, et al. Echocardiographic evaluation of pre-diagnostic development in young relatives genetically predisposed to hypertrophic cardiomyopathy. Int J Cardiovasc Imaging 2015;31:1511-8. 4. Pasquale F, Syrris P, Kaski JP, Mogensen J, McKenna WJ, Elliott P. Long-term outcomes in hypertrophic cardiomyopathy caused by mutations in the cardiac troponin T gene. Circ Cardiovasc Genet 2012;5:107. 5. Elliott PM, Gimeno JR, Thaman R, Shah J, Ward D, Dickie S, et al. Historical trends in reported survival rates in patients with hypertrophic cardiomyopathy. Heart 2005;92:785-91. 6. Vermeer AM, Clur SB, Blom NA, Wilde AA, Christiaans I. Penetrance of hypertrophic cardiomyopathy in children who are mutation positive. J Pediatr 2017;doi:10.1016/j.jpeds.2017.03.033. 7. Authors/Task Force Members, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy. The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:273379. 8. Christiaans I, Birnie E, van Langen IM, van Spaendonck-Zwarts KY, van Tintelen JP, van den Berg MP, et al. The yield of risk stratification for sudden cardiac death in hypertrophic cardiomyopathy myosin-binding protein C gene mutation carriers: focus on predictive screening. Eur Heart J 2010;31:842-8.
2 EDI 5.4.0 DTD ■ YMPD9178_proof ■ May 19, 2017
EDITORIALS
Hypertrophic Cardiomyopathy in Childhood: Risk Management Through Family Screening (age 12.1 ± 1.7 years) with an identified HCM-related gene he spectrum of hypertrophic cardiomyopathy (HCM) mutations, 5 children were diagnosed with HCM at first evaluranges from silent phenotypes, typically with mild ation, and another child was diagnosed after a mean followhypertrophy in asymptomatic patients, to aggressive up of 6.9 ± 3.8 years. In addition, 2 patients phenotypes with malignant arrhythmias or See related article, p ••• were diagnosed much later, at age 25 and hemodynamic compromise in patients with 30 years. This confirms that the penetrance severe hypertrophy and disabling symptoms. for children carrying a HCM-related gene mutation is low, This is true for adult patients as well as for children with HCM. and that likely <10% develop the disease before age 18 years. Reports depicting worst-case scenarios of severe progressive It also indicates that the development of diagnostic hypertrohypertrophy and clinical deterioration in childhood tend to phy may continue into early adulthood. However, in this study, dominate the literature on childhood HCM, and few popuas in the previous studies, severe cardiac events are reported lation studies have been published. The evidence from severe in a relatively small group of children with diagnostic HCM. cases of childhood HCM, along with knowledge of HCM being Three of the 6 children who were diagnosed in childhood dean inherited cardiomyopathy, have motivated family screenveloped severe hypertrophy, with a maximal wall thickness of ing programs for relatives, including children, with a family 28-36 mm during adolescence. One of these children experihistory of HCM. The resulting identification of children with enced an appropriate implantable cardioverter defibrillator mild HCM phenotypes and phenotype-negative mutation carshock. The other 3 children developed only modest hypertroriers warrants careful counseling of children and parents. In phy of <20 mm. This clearly illustrates that the development this process, accurate data on the risks associated with childof hypertrophy during puberty is highly unpredictable and may hood HCM or a positive genotype are essential to put toput individual children at high risk for cardiac events. gether a strong take-home message for affected families. Exact diagnostics are essential to identify manifest disease The generally accepted notion, backed up by convincing at an early stage and to reassure phenotype-negative mutareports of excessive myocardial growth, has been that myotion carriers of their low risk of cardiac events. In children, cardial growth is accelerated during puberty,1 and cases of the diagnostic criteria for HCM is an age- or body surface areasudden cardiac death (SCD) in childhood have emphasized adjusted maximal wall thickness exceeding the upper 95% limit the potential risks in children with HCM.2 This has possibly for the normal population.7 Several sets of normal values are left a somewhat exaggerated picture of the disease that available, but these are not identical; thus, the available normal contrasts with the clinically observed low penetrance and values should be validated against a local population before benign course of the disease in most children included in implementation. Evaluation by echocardiography or cardiac family screening programs. To date, only a few studies have magnetic resonance imaging is essential to establish the diagattempted to estimate the actual risk of cardiac events in nosis and determine the risk of cardiac events. children included in screening programs.3,4 In recent decades, the increased availability of echocardiography and the Vermeer et al confirm previously reported findings indiimplementation of family screening programs have changed cating a significant risk of cardiac events in phenotypethe adult population with HCM by adding patients with mild positive children, and thus the risk should be evaluated at every phenotypes, and have reduced the observed mortality and clinical visit. Electrocardiogram changes, degree of hypertrothe rates of SCD.5 Undoubtedly, this effort also has changed phy, and nonsustained ventricular tachycardia are known the population of children with HCM. Thus, asymptomatic risk factors for SCD in children with HCM, but the risk stratichildren with HCM and genotype-positive children without fication procedures described for adults have not been valihypertrophy are now being identified, and whether these childated in children. dren are at similarly high risk for cardiac events as symptomVermeer et al followed more than 100 phenotype-negative atic child probands is not clear. The few available outcome children who were carrying HCM-related gene mutations with studies from family screening programs indicate that this may a very low phenoconversion rate and did not identify any not be the case, though severe cases of SCD, implantable cardiac events in children who remained phenotype-negative, cardioverter defibrillator discharge, or the need for septal myeven though many of these children had a family history of ectomy were also present in these study populations.3,4 SCD. This finding supports previous studies and indicates that Vermeer et al present an important study on children from families with HCM-related gene mutations.6 Of 119 children
T
The authors declare no conflicts of interest.
HCM SCD
Hypertrophic cardiomyopathy Sudden cardiac death
0022-3476/$ - see front matter. © 2017 Elsevier Inc. All rights reserved. http://dx.doi.org10.1016/j.jpeds.2017.04.068
1 EDI 5.4.0 DTD ■ YMPD9178_proof ■ May 19, 2017
THE JOURNAL OF PEDIATRICS • www.jpeds.com a positive genetic test result in otherwise unaffected children is not a marker of increased risk for cardiac events. Thus, risk stratification for SCD is not rational in this group.8 Based on current data, it seems reasonable to start family screening at or before age 8 years.2 The evaluations should include echocardiography, clinical examination, and electrocardiography. In children with positive findings, the evaluation can be expanded. Genetic testing of children is optional and is not essential for children from families with HCM; however, a negative genetic test result may be important, signaling no need for further follow-up. Genetic testing of children may pose ethical issues, which is why careful counseling of children and parents is essential. The decision of whether to perform genetic testing should be ultimately up to the parents, but can safely be postponed until the child is sufficiently mature to participate in decision making. In conclusion, the study by Vermeer et al emphasizes the important contribution of family screening for identifying children at risk for severe cardiac events. In the setting of clinical and genetic family screening, counseling is important, and with growing confidence we can reassure parents and children that the potential risks are associated with a positive HCM phenotype. Without hypertrophy, the risk is extremely low and is likely close to the risk of the background population. Few genotype-positive children will develop HCM during childhood and adolescence, but in the few children who do develop the disease in childhood, the risk of disease progression and cardiac events is significant. ■ Kim Munk, MD, PhD Morten Kvistholm Jensen, MD, PhD Department of Cardiology Aarhus University Hospital Aarhus, Denmark
Volume ■■
Reprint requests: Morten Kvistholm Jensen, MD, PhD, Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, Aarhus 8200, Denmark. E-mail: [email protected]
References 1. Maron BJ, Spirito P, Wesley Y, Arce J. Development and progression of left ventricular hypertrophy in children with hypertrophic cardiomyopathy. N Engl J Med 1986;315:610-4. 2. Ostman-Smith I, Wettrell G, Keeton B, Holmgren D, Ergander U, Gould S, et al. Age- and gender-specific mortality rates in childhood hypertrophic cardiomyopathy. Eur Heart J 2008;29:1160-7. 3. Jensen MK, Havndrup O, Christiansen M, Andersen PS, Axelsson A, Køber L, et al. Echocardiographic evaluation of pre-diagnostic development in young relatives genetically predisposed to hypertrophic cardiomyopathy. Int J Cardiovasc Imaging 2015;31:1511-8. 4. Pasquale F, Syrris P, Kaski JP, Mogensen J, McKenna WJ, Elliott P. Long-term outcomes in hypertrophic cardiomyopathy caused by mutations in the cardiac troponin T gene. Circ Cardiovasc Genet 2012;5:107. 5. Elliott PM, Gimeno JR, Thaman R, Shah J, Ward D, Dickie S, et al. Historical trends in reported survival rates in patients with hypertrophic cardiomyopathy. Heart 2005;92:785-91. 6. Vermeer AM, Clur SB, Blom NA, Wilde AA, Christiaans I. Penetrance of hypertrophic cardiomyopathy in children who are mutation positive. J Pediatr 2017;doi:10.1016/j.jpeds.2017.03.033. 7. Authors/Task Force Members, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy. The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:273379. 8. Christiaans I, Birnie E, van Langen IM, van Spaendonck-Zwarts KY, van Tintelen JP, van den Berg MP, et al. The yield of risk stratification for sudden cardiac death in hypertrophic cardiomyopathy myosin-binding protein C gene mutation carriers: focus on predictive screening. Eur Heart J 2010;31:842-8.
2 EDI 5.4.0 DTD ■ YMPD9178_proof ■ May 19, 2017