Canadian Journal of Cardiology 30 (2014) 1249.e1e1249.e3 www.onlinecjc.ca
Case Report
A Case of an Infant With Compound Heterozygous Mutations for Hypertrophic Cardiomyopathy Producing a Phenotype of Left Ventricular Noncompaction Kim Haberer, BA, MA, MD,a Ilan Buffo-Sequeira, MD,b Albert E. Chudley, MD, FRCPC, FCCMG,c Elizabeth Spriggs, PhD, FCCMG,d and Consolato Sergi, MD, PhD, FRCPCe a b
Department of Pediatrics, University of Manitoba, Winnepeg, Manitoba, Canada
Health Sciences Centre, Variety Children’s Heart Centre, Department of Pediatric Cardiology, University of Manitoba, Manitoba, Canada
c
Program in Genetics and Metabolism, Departments of Biochemistry and Medical Genetics and Pediatrics and Child Health, University of Manitoba, Manitoba, Canada
d
Clinical Biochemistry and Genetics, Diagnostic Services Manitoba, Departments of Biochemistry and Medical Genetics and Paediatrics and Child Health, University of Manitoba, Manitoba, Canada e
Department of Laboratory Medicine and Pathology, University of Alberta, and Stollery Children’s Hospital, Edmonton, Alberta, Canada
ABSTRACT
RESUM E
A male infant was born to a 38-year-old G1P0 mother with hypertrophic cardiomyopathy (HCM). Fetal echocardiography was suspicious for HCM; however, postnatal echocardiography demonstrated features consistent with left ventricular noncompaction (LVNC). The infant was initially stable but presented at 2 months of age in cardiogenic shock. On genetic analysis, both parents were heterozygous for mutations associated with HCM. The proband was a compound heterozygote. This case, in which 2 mutations for HCM produced a phenotype of LVNC, has not been demonstrated in humans and raises the question of whether HCM and LVNC represent a continuum of pathologic processes.
d’une mère de 38 ans Un enfant de sexe masculin est ne G1P0 souffrant d’une cardiomyopathie hypertrophique (CMH). chocardiographie fœtale faisait suspecter une CMH. Cependant, L’e chocardiographie postnatale a montre les caracte ristiques d’une nonl’e but, l’enfant e tait stable, compaction du ventricule gauche (NCVG). Au de sente un choc cardioge nique. L’analyse mais, à 2 mois, il a pre ne tique a re ve le des parents he te rozygotes pour les mutations ge es à la CMH. Le proposant e tait un he te rozygote composite. Ce associe cas dont les 2 mutations responsables de la CMH ont produit un notype de NCVG n’a pas e te de montre chez les humains et pose la phe sentent un continuum de question de savoir si la CMH et la NCVG repre processus pathologiques.
Case Presentation A term male infant was born to a mother with hypertrophic cardiomyopathy (HCM). Fetal echocardiography at 36 weeks demonstrated borderline biventricular hypertrophy with normal systolic function. The pregnancy and delivery were uneventful. At 22 days of life, the patient was seen in the cardiology clinic. His examination was unremarkable aside from a II/VI systolic murmur at the left sternal border. The patient was gaining weight and exhibited no signs of cardiac failure. Echocardiography demonstrated globally decreased left
ventricular (LV) function with an ejection fraction of 50%. The left ventricle was highly trabeculated in more than two thirds of the free wall and colour flow was noted in the trabeculae (Fig. 1). A small apical ventricular septal defect was present. The infant was diagnosed with left ventricular noncompaction (LVNC) and started on low-dose acetylsalicylic acid, captopril, and furosemide. At 1month, carvedilol was added because of some mild increasing tachypnea. At 2 months, the infant presented to the emergency department with lethargy and poor feeding. An electrocardiogram demonstrated normal sinus rhythm. Echocardiography demonstrated severe LV dysfunction with an ejection fraction of < 10%. The patient had an episode of profound desaturation followed by a hypoxic seizure. He was intubated, started on inotropic support, and transferred to a surgical center. A Berlin Heart (Berlin, Germany) was implanted and 1 month later the infant received a heart transplant. On gross
Received for publication August 26, 2013. Accepted May 28, 2014. Corresponding author: Dr Kim Haberer, University of California San Francisco, 505 Parnassus Ave, Moffitt Building Rm 1235, Box 0544, San Francisco, California 94143-0544, USA. E-mail: [email protected] See page 1249.e3 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2014.05.021 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
1249.e2
Figure 1. (A) Apical 4-chamber view demonstrating thickening of the apex and the free wall of the left ventricle. Deep trabeculations are seen in the left ventricular free wall. (B) The same image with colour flow. Blood is seen entering the trabeculations that span almost the entire free wall of the left ventricle.
pathologic examination, the explanted heart exhibited diffuse mural thickening and endocardial fibrosis, with prominent trabeculae in the myocardium. Microscopic pathologic examination demonstrated endothelial-lined invaginations that involved greater than half of the myocardium (Fig. 2). These features are consistent with LVNC. The family history was reviewed and the parents were not consanguineous. The mother is of English descent and the father was of Dutch-German Mennonite heritage. The mother, her father, and paternal grandfather had been previously diagnosed with HCM. The mother had moderate to severe hypertrophy of the interventricular septum and required a septal myectomy. The father had no evidence of HCM clinically and by echocardiography. Initially, mother and child were tested for the MYBPC3 mutation in exon 24, c.2373dupG, which has been historically referred to as 791insG. This specific mutation is common in Mennonites and northern Europeans and was available for testing in our laboratory. Although only the baby was determined to be heterozygous for this mutation, further sequencing of genes in the HCM panel available at Laboratory for Molecular Medicine at the Harvard Medical School confirmed that the mother was heterozygous for a different truncating mutation in exon 31, c.3408C>A (p.Tyr1136X) of the MYBPC3 gene. We then tested the father for the c.2373dupG MYBPC3
Canadian Journal of Cardiology Volume 30 2014
Figure 2. Microphotographs (hematoxylin-eosin stain at 12.5 of original magnification [A] and connective tissue stain [B] at 50 of original magnification) of the lower left ventricle from endocardium to myocardium showing trabeculations and bundles of cardiac muscle that extend deep into the chamber close to the epicardium (upper left corner [A]). As indicated, the sponge-like network of muscle fibers, which is normal during ontogenesis, disappears in early fetal life, allowing a compaction of the trabeculations, leading to a smooth and solid myocardial tissue. Conversely, this case shows classic trabeculations, and the connective tissue stain shows the subendocardial fibrosis as identified along the trabeculations.
mutation found in the child and he was determined to be heterozygous for this mutation. The proband was confirmed to have both maternal and paternal mutations and was therefore a compound heterozygote. HCM is a relatively common disorder, with an estimated prevalence of 1 in 500.1 It is inherited in an autosomal dominant pattern. There are > 900 mutations in 20 genes that have been associated with HCM.1 MYBPC3 was first discovered in 1998 and is now considered to be one of the most common genes responsible for HCM (30%).2 By contrast, LVNC is a fairly uncommon disorder, with a prevalence of 0.05%-0.24%.3 LVNC is diagnosed by the presence of trabeculations in the ventricular wall that fill with blood from the LV cavity; there is a ratio of noncompacted to compacted ventricle of > 2:13. The pathogenesis of LVNC is unknown. The clinical manifestations of this disease include congestive heart failure, ventricular arrhythmias, and thromboembolic events.3 The genetic cause of LVNC remains obscure. Sarcomeric proteins implicated in HCM have also been found in patients with isolated LVNC.4 This suggests a
Haberer et al. The Genetics of an Infant With Noncompaction
relationship between HCM and LVNC that remains to be explained. There are several unique features about this case. First, what presented during fetal life as LV hypertrophy and in the neonate as mild dysfunction rapidly progressed to cardiogenic shock. Although LVNC is rare in children, it can present in a severe form in infants.5 However, this form is often identified prenatally with hydrops fetalis. The rapid progression from mild to severe disease, as was the case in our patient, is rare. We speculate that this may be a result of the second unique feature of this case, namely, the compound heterozygous mutation status of the infant. Finally, the third unique feature of the case is the apparent progression from what appeared to be HCM on fetal echocardiography to LVNC shortly after birth. Previous case reports have demonstrated a relationship between these 2 entities and the potential of evolving from 1 to the other.5 This hypothesis puts into doubt the idea that LVNC is a distinct entity and suggests a more dynamic relationship between the cardiomyopathies than might previously have been suspected.
1249.e3
Disclosures The authors have no conflicts of interest to disclose. References 1. Frey N, Luedde M, Katus HA. Mechanisms of disease: hypertrophic cardiomyopathy. Nat Rev Cardiol 2011;9:91-100. 2. Niimura H, Bachinski LL, Sangwatanaroj S, et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 1998;338:1248-57. 3. Captur G, Nihoyannopoulos. Left ventricular non-compaction: genetic heterogeneity, diagnosis and clinical course. Int J Cardiol 2010;140: 145-53. 4. Xu Q, Dewey S, Nguyen S, Gomes AV. Malignant and benign mutations in familial cardiomyopathies: insights into mutations linked to complex cardiovascular phenotypes. J Mol Cell Cardiol 2010;48:899-909. 5. Betrian Blasco P, Albert Brotóns DC, Menduña QF, Noguer FR, García GG. Severe foetal hypertrophic cardiomyopathy evolving to left ventricular non-compaction. Eur J Echocardiogr 2010;11:E36.
Case Report
A Case of an Infant With Compound Heterozygous Mutations for Hypertrophic Cardiomyopathy Producing a Phenotype of Left Ventricular Noncompaction Kim Haberer, BA, MA, MD,a Ilan Buffo-Sequeira, MD,b Albert E. Chudley, MD, FRCPC, FCCMG,c Elizabeth Spriggs, PhD, FCCMG,d and Consolato Sergi, MD, PhD, FRCPCe a b
Department of Pediatrics, University of Manitoba, Winnepeg, Manitoba, Canada
Health Sciences Centre, Variety Children’s Heart Centre, Department of Pediatric Cardiology, University of Manitoba, Manitoba, Canada
c
Program in Genetics and Metabolism, Departments of Biochemistry and Medical Genetics and Pediatrics and Child Health, University of Manitoba, Manitoba, Canada
d
Clinical Biochemistry and Genetics, Diagnostic Services Manitoba, Departments of Biochemistry and Medical Genetics and Paediatrics and Child Health, University of Manitoba, Manitoba, Canada e
Department of Laboratory Medicine and Pathology, University of Alberta, and Stollery Children’s Hospital, Edmonton, Alberta, Canada
ABSTRACT
RESUM E
A male infant was born to a 38-year-old G1P0 mother with hypertrophic cardiomyopathy (HCM). Fetal echocardiography was suspicious for HCM; however, postnatal echocardiography demonstrated features consistent with left ventricular noncompaction (LVNC). The infant was initially stable but presented at 2 months of age in cardiogenic shock. On genetic analysis, both parents were heterozygous for mutations associated with HCM. The proband was a compound heterozygote. This case, in which 2 mutations for HCM produced a phenotype of LVNC, has not been demonstrated in humans and raises the question of whether HCM and LVNC represent a continuum of pathologic processes.
d’une mère de 38 ans Un enfant de sexe masculin est ne G1P0 souffrant d’une cardiomyopathie hypertrophique (CMH). chocardiographie fœtale faisait suspecter une CMH. Cependant, L’e chocardiographie postnatale a montre les caracte ristiques d’une nonl’e but, l’enfant e tait stable, compaction du ventricule gauche (NCVG). Au de sente un choc cardioge nique. L’analyse mais, à 2 mois, il a pre ne tique a re ve le des parents he te rozygotes pour les mutations ge es à la CMH. Le proposant e tait un he te rozygote composite. Ce associe cas dont les 2 mutations responsables de la CMH ont produit un notype de NCVG n’a pas e te de montre chez les humains et pose la phe sentent un continuum de question de savoir si la CMH et la NCVG repre processus pathologiques.
Case Presentation A term male infant was born to a mother with hypertrophic cardiomyopathy (HCM). Fetal echocardiography at 36 weeks demonstrated borderline biventricular hypertrophy with normal systolic function. The pregnancy and delivery were uneventful. At 22 days of life, the patient was seen in the cardiology clinic. His examination was unremarkable aside from a II/VI systolic murmur at the left sternal border. The patient was gaining weight and exhibited no signs of cardiac failure. Echocardiography demonstrated globally decreased left
ventricular (LV) function with an ejection fraction of 50%. The left ventricle was highly trabeculated in more than two thirds of the free wall and colour flow was noted in the trabeculae (Fig. 1). A small apical ventricular septal defect was present. The infant was diagnosed with left ventricular noncompaction (LVNC) and started on low-dose acetylsalicylic acid, captopril, and furosemide. At 1month, carvedilol was added because of some mild increasing tachypnea. At 2 months, the infant presented to the emergency department with lethargy and poor feeding. An electrocardiogram demonstrated normal sinus rhythm. Echocardiography demonstrated severe LV dysfunction with an ejection fraction of < 10%. The patient had an episode of profound desaturation followed by a hypoxic seizure. He was intubated, started on inotropic support, and transferred to a surgical center. A Berlin Heart (Berlin, Germany) was implanted and 1 month later the infant received a heart transplant. On gross
Received for publication August 26, 2013. Accepted May 28, 2014. Corresponding author: Dr Kim Haberer, University of California San Francisco, 505 Parnassus Ave, Moffitt Building Rm 1235, Box 0544, San Francisco, California 94143-0544, USA. E-mail: [email protected] See page 1249.e3 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2014.05.021 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
1249.e2
Figure 1. (A) Apical 4-chamber view demonstrating thickening of the apex and the free wall of the left ventricle. Deep trabeculations are seen in the left ventricular free wall. (B) The same image with colour flow. Blood is seen entering the trabeculations that span almost the entire free wall of the left ventricle.
pathologic examination, the explanted heart exhibited diffuse mural thickening and endocardial fibrosis, with prominent trabeculae in the myocardium. Microscopic pathologic examination demonstrated endothelial-lined invaginations that involved greater than half of the myocardium (Fig. 2). These features are consistent with LVNC. The family history was reviewed and the parents were not consanguineous. The mother is of English descent and the father was of Dutch-German Mennonite heritage. The mother, her father, and paternal grandfather had been previously diagnosed with HCM. The mother had moderate to severe hypertrophy of the interventricular septum and required a septal myectomy. The father had no evidence of HCM clinically and by echocardiography. Initially, mother and child were tested for the MYBPC3 mutation in exon 24, c.2373dupG, which has been historically referred to as 791insG. This specific mutation is common in Mennonites and northern Europeans and was available for testing in our laboratory. Although only the baby was determined to be heterozygous for this mutation, further sequencing of genes in the HCM panel available at Laboratory for Molecular Medicine at the Harvard Medical School confirmed that the mother was heterozygous for a different truncating mutation in exon 31, c.3408C>A (p.Tyr1136X) of the MYBPC3 gene. We then tested the father for the c.2373dupG MYBPC3
Canadian Journal of Cardiology Volume 30 2014
Figure 2. Microphotographs (hematoxylin-eosin stain at 12.5 of original magnification [A] and connective tissue stain [B] at 50 of original magnification) of the lower left ventricle from endocardium to myocardium showing trabeculations and bundles of cardiac muscle that extend deep into the chamber close to the epicardium (upper left corner [A]). As indicated, the sponge-like network of muscle fibers, which is normal during ontogenesis, disappears in early fetal life, allowing a compaction of the trabeculations, leading to a smooth and solid myocardial tissue. Conversely, this case shows classic trabeculations, and the connective tissue stain shows the subendocardial fibrosis as identified along the trabeculations.
mutation found in the child and he was determined to be heterozygous for this mutation. The proband was confirmed to have both maternal and paternal mutations and was therefore a compound heterozygote. HCM is a relatively common disorder, with an estimated prevalence of 1 in 500.1 It is inherited in an autosomal dominant pattern. There are > 900 mutations in 20 genes that have been associated with HCM.1 MYBPC3 was first discovered in 1998 and is now considered to be one of the most common genes responsible for HCM (30%).2 By contrast, LVNC is a fairly uncommon disorder, with a prevalence of 0.05%-0.24%.3 LVNC is diagnosed by the presence of trabeculations in the ventricular wall that fill with blood from the LV cavity; there is a ratio of noncompacted to compacted ventricle of > 2:13. The pathogenesis of LVNC is unknown. The clinical manifestations of this disease include congestive heart failure, ventricular arrhythmias, and thromboembolic events.3 The genetic cause of LVNC remains obscure. Sarcomeric proteins implicated in HCM have also been found in patients with isolated LVNC.4 This suggests a
Haberer et al. The Genetics of an Infant With Noncompaction
relationship between HCM and LVNC that remains to be explained. There are several unique features about this case. First, what presented during fetal life as LV hypertrophy and in the neonate as mild dysfunction rapidly progressed to cardiogenic shock. Although LVNC is rare in children, it can present in a severe form in infants.5 However, this form is often identified prenatally with hydrops fetalis. The rapid progression from mild to severe disease, as was the case in our patient, is rare. We speculate that this may be a result of the second unique feature of this case, namely, the compound heterozygous mutation status of the infant. Finally, the third unique feature of the case is the apparent progression from what appeared to be HCM on fetal echocardiography to LVNC shortly after birth. Previous case reports have demonstrated a relationship between these 2 entities and the potential of evolving from 1 to the other.5 This hypothesis puts into doubt the idea that LVNC is a distinct entity and suggests a more dynamic relationship between the cardiomyopathies than might previously have been suspected.
1249.e3
Disclosures The authors have no conflicts of interest to disclose. References 1. Frey N, Luedde M, Katus HA. Mechanisms of disease: hypertrophic cardiomyopathy. Nat Rev Cardiol 2011;9:91-100. 2. Niimura H, Bachinski LL, Sangwatanaroj S, et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 1998;338:1248-57. 3. Captur G, Nihoyannopoulos. Left ventricular non-compaction: genetic heterogeneity, diagnosis and clinical course. Int J Cardiol 2010;140: 145-53. 4. Xu Q, Dewey S, Nguyen S, Gomes AV. Malignant and benign mutations in familial cardiomyopathies: insights into mutations linked to complex cardiovascular phenotypes. J Mol Cell Cardiol 2010;48:899-909. 5. Betrian Blasco P, Albert Brotóns DC, Menduña QF, Noguer FR, García GG. Severe foetal hypertrophic cardiomyopathy evolving to left ventricular non-compaction. Eur J Echocardiogr 2010;11:E36.
