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Hypoplastic left heart syndrome with intact atrial septum associated with deletion of the short arm of chromosome 18
Cardiovascular Pathology 12 (2003) 102 – 104
Hypoplastic left heart syndrome with intact atrial septum associated with deletion of the short arm of chromosome 18 Julio C. Vasqueza, Raja Rabahb, Ralph E. Deliusa, Henry L. Waltersa,* a b
Department of Cardiovascular Surgery, Children’s Hospital of Michigan, 3901 Beaubien Street, Detroit, MI 48201, USA Department of Pathology, Children’s Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI, USA Received 4 June 2002; received in revised form 20 September 2002; accepted 1 October 2002
Abstract We report on a female newborn with deletion of the short arm of the chromosome 18 (del 18p) and hypoplastic left heart syndrome (HLHS) with intact atrial septum. Several forms of congenital heart disease (CHD) are found in 10% of patients with this chromosomal abnormality, although HLHS has not been reported yet. Interesting coronary artery anomalies, as well as the presence of pulmonary lymphangiectasia, were found in our patient and were contributors to her fatal outcome. Del 18 p must be considered when evaluating a patient with characteristic phenotypical anomalies and HLHS with intact atrial septum. D 2003 Elsevier Inc. All rights reserved.
1. Text Deletion of the short arm of the chromosome 18 (del 18p) is characterized by abnormal facies, mental and growth retardation, short neck and skeletal malformations. Congenital heart disease (CHD) is estimated to be present in 10% of the patients with del 18p [1]. Here, we report a case of hypoplastic left heart syndrome (HLHS) with intact atrial septum in a newborn with del 18p. A female newborn was delivered at 37 weeks of gestation to a 41-year-old G1P0 mother with hypothyroidism and infertility. An ultrasound performed 1 week earlier revealed HLHS, polyhydramnios and pleural effusion. At birth, she weighed 2590 g. She was cyanotic, with Apgar scores of 4 at 5 min and 6 at 10 min. She was promptly intubated and started on prostaglandin E1 at 0.05 mcg/kg/min. Also, chest tubes were placed to treat bilateral pneumothoraces. Her height and weight were between the 5th and 10th percentile for age. She had microcephaly, small chin and a low nasal bridge. Chromosomal studies showed a karyotype of 46,XX, del (18)(p11.1). An echocardiogram showed hypoplasia of the left ventricle (LV) and the mitral valve, aortic valve atresia, intact atrial septum and a large patent ductus arteriosus. An emergency balloon atrial septostomy * Corresponding author. Tel.: +1-313-745-5538; fax: +1-313-9930531. E-mail address: [email protected] (H.L. Walters). 1054-8807/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1054-8807(02)00163-1
was performed. The initial left atrial mean pressure was 25 mm Hg, and this dropped to 9 mm Hg after the procedure, with a 7-mm Hg gradient across the newly created septal defect. Dopamine and dobutamine were started. Her perfusion improved, but her lungs remained very congested as demonstrated by chest X-ray, and she remained intubated. A first stage Norwood procedure was performed at 9 days of age. Once the heart was exposed, the right ventricle (RV) was noted to have a pale, ischemic appearance. A cryopreserved pulmonary homograft patch was used to augment the aorta. This augmented aorta was anastomosed to the root of the main pulmonary artery that had been previously transected. Because of the intact atrial septum, we expected high pulmonary vascular resistance perioperatively. For this reason, we elected to place a larger (4 mm) systemic-to-pulmonary Goretex shunt than we would normally place in a 2.5-kg baby. Despite of this, the patient was relatively cyanotic postoperatively and there was no evidence of low cardiac output due to excessive pulmonary blood flow. This shunt was sutured to the innominate artery proximally and to the right pulmonary artery distally. A generous atrial septectomy was also performed. The total cardiopulmonary bypass time was 112 min, in addition to a 55-min circulatory arrest time. After the discontinuation of cardiopulmonary bypass, it was noted that the RV retained a pale, ischemic appearance, especially on its inferior and apical surfaces. The diminutive LV also appeared ischemic.
J.C. Vasquez et al. / Cardiovascular Pathology 12 (2003) 102–104
While closing the chest, the patient had a clear deterioration in her hemodynamic parameters. She was rapidly heparinized and cardiopulmonary bypass was reinstituted. There was excellent blood flow into the proximal coronary arteries, but distally these arteries were not perfused, appearing white and contracted. During 1 h of warm reperfusion, the RV function improved, but with only slight improvement in the filling of the distal right coronary artery (RCA). Cardiopulmonary bypass was discontinued and, once more, the patient became hypotensive with increasing base deficit. She was transferred to the pediatric intensive care unit where she expired shortly thereafter. Postmortem examination showed that the left atrium had normal pulmonary venous return. The mitral valve was patent but small. The LV wall was thick and no ventricular septal defect was noted. The aortic valve was atretic. The endocardium in the LV was thickened by endocardial fibrosis. The anastomoses were intact and nonobstructive. The coronary arteries were patent proximally, but the distal left anterior descending (LAD) and the distal RCA near the apex were tortuous and prominent. A tortuous marginal branch connected the RCA with the LAD. A tiny fistulous tract was found at the apex and connected the left ventricular cavity to the LAD. Microscopically, it consisted of capillary like sinus structures. Both ventricles had multiple foci of recent ischemia and old myocardial infarction. Sections of both ventricles, near the apex, showed dysplastic epicardial and intramural coronary arteries (Fig. 1). They had unusually thickened media with narrowed lumina and no significant intimal proliferation or occluding thrombi. The lungs had numerous dilated lymphatics within the interlobular septae and beneath the visceral pleural surface, compressing the pulmonary parenchyma (Fig. 2). The interlobular septae were slightly thickened and some peripheral arteries were small with thick medial walls and stenotic lumina. This was consistent with pulmonary lymphangiectasia. In the abdomen, the only abnormal finding
Fig. 1. Cross-section of the apical portion of the left anterior descending artery. There is marked narrowing of the lumen with thick media and prominent adventitia.
103
Fig. 2. Microscopic view of the lung showing markedly dilated interlobular and subpleural lymphatics.
was a nodule of ectopic pancreatic tissue within the wall of the gastric antrum.
2. Comment Del 18p is one of the most common autosomal deletion syndromes. The variability of phenotypical manifestations makes its diagnosis difficult. The positive findings in our patient included: microcephaly, micrognathia, short neck, clinodactyly and a cardiac defect. CHD is associated with complete or partial deletion of the short arm of chromosome 18 in about 10% of the cases. In a recent review of the literature, Digilio et al. [2] collected 12 cases with CHD and del 18p, which included different entities such as patent ductus arteriosus, ventricular septal defect, aortic stenosis, dextrocardia with situs inversus, among others. None of the described patients had HLHS. Although there might be a pathogenetic relationship between del 18p and the development of HLHS, there are, to our knowledge, no reports that elucidate the exact causative mechanism. Large series of infants with CHD show that HLHS has a prevalence of 9%. Untreated it is universally fatal and accounts for 25% of deaths in the first few weeks of life [3]. Current treatment options are reconstructive surgery or cardiac transplantation. HLHS with intact atrial septum occurs in about 6% of patients with HLHS. It results in marked systemic hypoxemia at birth due to the deleterious physiology of obstruction to left atrial egress. It is associated with nonimmune fetal hydrops and pulmonary lymphangiectasia. The high mortality associated with this condition may be related to the presence of a unique structural abnormality of the pulmonary venous vasculature, which appears to be ‘‘arterialized’’ [4]. Early atrial septectomy/ septostomy has been advocated as an initial emergent measure. Pulmonary lymphangiectasia in these patients is thought to be secondary to obstruction of pulmonary venous flow, and it is associated with intractable respiratory failure. Compression of the pulmonary parenchyma is a prominent
104
J.C. Vasquez et al. / Cardiovascular Pathology 12 (2003) 102–104
feature and might explain the respiratory compromise demonstrated by these patients [5]. Our patient had HLHS with mitral stenosis and aortic atresia. Proximally, her coronary arteries had thin walls and were normal in appearance, but distally they were tortuous and prominent. The coronary arteries in HLHS with atresia of the mitral and aortic valves tend to be normal, as opposed to those with mitral stenosis and aortic atresia, which have generally thicker and more tortuous coronary arteries. These patients also tend to have increased medial thickness of the arterial wall, especially in the proximal and middle LAD and circumflex arteries [6]. In our case, the narrowing caused by medial thickening was severe, and unusually located in the distal portions of the LAD and RCA, near the apex. These findings correlated with the pale areas of myocardium observed in the operating room and with the areas of infarction seen in histological examination of the ventricles. A single fistulous connection between the LV and the LAD, as well as endocardial fibroelastosis of the LV, were also found in our case. Fistulous connections between the LV and coronary arteries are present in up to 30% of cases of HLHS with mitral stenosis and aortic atresia. In contrast, patients with atresia of the mitral and aortic valves have only a 2% incidence of this anomaly. Most of these connections are of a sinusoidal type rather than the direct ventriculocoronary arterial connections seen in patients with pulmonary atresia with intact ventricular septum. They usually coexist with endocardial fibroelastosis of the LV [7]. The existence of familial cases of HLHS, as well as its association with noncardiac malformations and chromosomal abnormalities, suggests a genetic etiology for HLHS. Mutated genes may cause decreased blood flow to the developing LV and result in the syndrome [8]. Multiple genes might be involved and, in order to locate them, it is important to identify those patients with defined chromosomal or genetic abnormalities.
This case shows a unique association between HLHS and del 18p. The presence of chromosomal abnormalities in patients with HLHS is not common, but it should be investigated. If del 18p is found, a careful search for ischemic changes in the electrocardiogram should be sought because this might be a consequence of restricted flow in abnormal coronary arteries. In addition to that, the presence of an intact atrial septum and pulmonary lymphangiectasia might compromise even more this adverse clinical scenario. Heart transplantation is not an option under these circumstances. This information should be communicated to the parents, who should be aware of the high mortality associated with this constellation of findings.
References [1] Pearl W. Heart disease associated with deletion of the short arm of chromosome 18. Pediatr Cardiol 1989;10:174 – 6. [2] Digilio MC, Marino B, Giannotti A, DiDonato R, Dallapiccola B. Heterotaxy with left atrial isomerism in a patient with deletion 18p. Am J Med Genet 2000;94:198 – 200. [3] Norwood WI. Hypoplastic left heart syndrome. Ann Thorac Surg 1991; 52:688 – 95. [4] Rychik J, Rome JJ, Collins MH, DiCampli WM, Spray TL. The hypoplastic left heart syndrome with intact atrial septum: atrial morphology, pulmonary vascular histopathology and outcome. J Am Coll Cardiol 1999;34:554 – 60. [5] Luciani GB, Pessotto R, Mombello A, Mazzucco A. Hypoplastic left heart syndrome with restrictive atrial septal defect and congenital pulmonary lymphangiectasia. Cardiovasc Pathol 1999;8:49 – 51. [6] Sauer U, Gittenberger-de Groot AC, Geishauser M, Babic R, Buhlmeyer K. Coronary arteries in the hypoplastic left heart syndrome. Circulation 1989;80(Suppl. I):I168 – 76. [7] Baffa JM, Chen SL, Guttenberg ME, Norwood WI, Weinberg PM. Coronary artery abnormalities and right ventricular histology in hypoplastic left heart syndrome. J Am Coll Cardiol 1992;20:350 – 8. [8] Grossfeld PD. The genetics of hypoplastic left heart syndrome. Cardiol Young 1999;9:627 – 32.
Hypoplastic left heart syndrome with intact atrial septum associated with deletion of the short arm of chromosome 18 Julio C. Vasqueza, Raja Rabahb, Ralph E. Deliusa, Henry L. Waltersa,* a b
Department of Cardiovascular Surgery, Children’s Hospital of Michigan, 3901 Beaubien Street, Detroit, MI 48201, USA Department of Pathology, Children’s Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI, USA Received 4 June 2002; received in revised form 20 September 2002; accepted 1 October 2002
Abstract We report on a female newborn with deletion of the short arm of the chromosome 18 (del 18p) and hypoplastic left heart syndrome (HLHS) with intact atrial septum. Several forms of congenital heart disease (CHD) are found in 10% of patients with this chromosomal abnormality, although HLHS has not been reported yet. Interesting coronary artery anomalies, as well as the presence of pulmonary lymphangiectasia, were found in our patient and were contributors to her fatal outcome. Del 18 p must be considered when evaluating a patient with characteristic phenotypical anomalies and HLHS with intact atrial septum. D 2003 Elsevier Inc. All rights reserved.
1. Text Deletion of the short arm of the chromosome 18 (del 18p) is characterized by abnormal facies, mental and growth retardation, short neck and skeletal malformations. Congenital heart disease (CHD) is estimated to be present in 10% of the patients with del 18p [1]. Here, we report a case of hypoplastic left heart syndrome (HLHS) with intact atrial septum in a newborn with del 18p. A female newborn was delivered at 37 weeks of gestation to a 41-year-old G1P0 mother with hypothyroidism and infertility. An ultrasound performed 1 week earlier revealed HLHS, polyhydramnios and pleural effusion. At birth, she weighed 2590 g. She was cyanotic, with Apgar scores of 4 at 5 min and 6 at 10 min. She was promptly intubated and started on prostaglandin E1 at 0.05 mcg/kg/min. Also, chest tubes were placed to treat bilateral pneumothoraces. Her height and weight were between the 5th and 10th percentile for age. She had microcephaly, small chin and a low nasal bridge. Chromosomal studies showed a karyotype of 46,XX, del (18)(p11.1). An echocardiogram showed hypoplasia of the left ventricle (LV) and the mitral valve, aortic valve atresia, intact atrial septum and a large patent ductus arteriosus. An emergency balloon atrial septostomy * Corresponding author. Tel.: +1-313-745-5538; fax: +1-313-9930531. E-mail address: [email protected] (H.L. Walters). 1054-8807/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1054-8807(02)00163-1
was performed. The initial left atrial mean pressure was 25 mm Hg, and this dropped to 9 mm Hg after the procedure, with a 7-mm Hg gradient across the newly created septal defect. Dopamine and dobutamine were started. Her perfusion improved, but her lungs remained very congested as demonstrated by chest X-ray, and she remained intubated. A first stage Norwood procedure was performed at 9 days of age. Once the heart was exposed, the right ventricle (RV) was noted to have a pale, ischemic appearance. A cryopreserved pulmonary homograft patch was used to augment the aorta. This augmented aorta was anastomosed to the root of the main pulmonary artery that had been previously transected. Because of the intact atrial septum, we expected high pulmonary vascular resistance perioperatively. For this reason, we elected to place a larger (4 mm) systemic-to-pulmonary Goretex shunt than we would normally place in a 2.5-kg baby. Despite of this, the patient was relatively cyanotic postoperatively and there was no evidence of low cardiac output due to excessive pulmonary blood flow. This shunt was sutured to the innominate artery proximally and to the right pulmonary artery distally. A generous atrial septectomy was also performed. The total cardiopulmonary bypass time was 112 min, in addition to a 55-min circulatory arrest time. After the discontinuation of cardiopulmonary bypass, it was noted that the RV retained a pale, ischemic appearance, especially on its inferior and apical surfaces. The diminutive LV also appeared ischemic.
J.C. Vasquez et al. / Cardiovascular Pathology 12 (2003) 102–104
While closing the chest, the patient had a clear deterioration in her hemodynamic parameters. She was rapidly heparinized and cardiopulmonary bypass was reinstituted. There was excellent blood flow into the proximal coronary arteries, but distally these arteries were not perfused, appearing white and contracted. During 1 h of warm reperfusion, the RV function improved, but with only slight improvement in the filling of the distal right coronary artery (RCA). Cardiopulmonary bypass was discontinued and, once more, the patient became hypotensive with increasing base deficit. She was transferred to the pediatric intensive care unit where she expired shortly thereafter. Postmortem examination showed that the left atrium had normal pulmonary venous return. The mitral valve was patent but small. The LV wall was thick and no ventricular septal defect was noted. The aortic valve was atretic. The endocardium in the LV was thickened by endocardial fibrosis. The anastomoses were intact and nonobstructive. The coronary arteries were patent proximally, but the distal left anterior descending (LAD) and the distal RCA near the apex were tortuous and prominent. A tortuous marginal branch connected the RCA with the LAD. A tiny fistulous tract was found at the apex and connected the left ventricular cavity to the LAD. Microscopically, it consisted of capillary like sinus structures. Both ventricles had multiple foci of recent ischemia and old myocardial infarction. Sections of both ventricles, near the apex, showed dysplastic epicardial and intramural coronary arteries (Fig. 1). They had unusually thickened media with narrowed lumina and no significant intimal proliferation or occluding thrombi. The lungs had numerous dilated lymphatics within the interlobular septae and beneath the visceral pleural surface, compressing the pulmonary parenchyma (Fig. 2). The interlobular septae were slightly thickened and some peripheral arteries were small with thick medial walls and stenotic lumina. This was consistent with pulmonary lymphangiectasia. In the abdomen, the only abnormal finding
Fig. 1. Cross-section of the apical portion of the left anterior descending artery. There is marked narrowing of the lumen with thick media and prominent adventitia.
103
Fig. 2. Microscopic view of the lung showing markedly dilated interlobular and subpleural lymphatics.
was a nodule of ectopic pancreatic tissue within the wall of the gastric antrum.
2. Comment Del 18p is one of the most common autosomal deletion syndromes. The variability of phenotypical manifestations makes its diagnosis difficult. The positive findings in our patient included: microcephaly, micrognathia, short neck, clinodactyly and a cardiac defect. CHD is associated with complete or partial deletion of the short arm of chromosome 18 in about 10% of the cases. In a recent review of the literature, Digilio et al. [2] collected 12 cases with CHD and del 18p, which included different entities such as patent ductus arteriosus, ventricular septal defect, aortic stenosis, dextrocardia with situs inversus, among others. None of the described patients had HLHS. Although there might be a pathogenetic relationship between del 18p and the development of HLHS, there are, to our knowledge, no reports that elucidate the exact causative mechanism. Large series of infants with CHD show that HLHS has a prevalence of 9%. Untreated it is universally fatal and accounts for 25% of deaths in the first few weeks of life [3]. Current treatment options are reconstructive surgery or cardiac transplantation. HLHS with intact atrial septum occurs in about 6% of patients with HLHS. It results in marked systemic hypoxemia at birth due to the deleterious physiology of obstruction to left atrial egress. It is associated with nonimmune fetal hydrops and pulmonary lymphangiectasia. The high mortality associated with this condition may be related to the presence of a unique structural abnormality of the pulmonary venous vasculature, which appears to be ‘‘arterialized’’ [4]. Early atrial septectomy/ septostomy has been advocated as an initial emergent measure. Pulmonary lymphangiectasia in these patients is thought to be secondary to obstruction of pulmonary venous flow, and it is associated with intractable respiratory failure. Compression of the pulmonary parenchyma is a prominent
104
J.C. Vasquez et al. / Cardiovascular Pathology 12 (2003) 102–104
feature and might explain the respiratory compromise demonstrated by these patients [5]. Our patient had HLHS with mitral stenosis and aortic atresia. Proximally, her coronary arteries had thin walls and were normal in appearance, but distally they were tortuous and prominent. The coronary arteries in HLHS with atresia of the mitral and aortic valves tend to be normal, as opposed to those with mitral stenosis and aortic atresia, which have generally thicker and more tortuous coronary arteries. These patients also tend to have increased medial thickness of the arterial wall, especially in the proximal and middle LAD and circumflex arteries [6]. In our case, the narrowing caused by medial thickening was severe, and unusually located in the distal portions of the LAD and RCA, near the apex. These findings correlated with the pale areas of myocardium observed in the operating room and with the areas of infarction seen in histological examination of the ventricles. A single fistulous connection between the LV and the LAD, as well as endocardial fibroelastosis of the LV, were also found in our case. Fistulous connections between the LV and coronary arteries are present in up to 30% of cases of HLHS with mitral stenosis and aortic atresia. In contrast, patients with atresia of the mitral and aortic valves have only a 2% incidence of this anomaly. Most of these connections are of a sinusoidal type rather than the direct ventriculocoronary arterial connections seen in patients with pulmonary atresia with intact ventricular septum. They usually coexist with endocardial fibroelastosis of the LV [7]. The existence of familial cases of HLHS, as well as its association with noncardiac malformations and chromosomal abnormalities, suggests a genetic etiology for HLHS. Mutated genes may cause decreased blood flow to the developing LV and result in the syndrome [8]. Multiple genes might be involved and, in order to locate them, it is important to identify those patients with defined chromosomal or genetic abnormalities.
This case shows a unique association between HLHS and del 18p. The presence of chromosomal abnormalities in patients with HLHS is not common, but it should be investigated. If del 18p is found, a careful search for ischemic changes in the electrocardiogram should be sought because this might be a consequence of restricted flow in abnormal coronary arteries. In addition to that, the presence of an intact atrial septum and pulmonary lymphangiectasia might compromise even more this adverse clinical scenario. Heart transplantation is not an option under these circumstances. This information should be communicated to the parents, who should be aware of the high mortality associated with this constellation of findings.
References [1] Pearl W. Heart disease associated with deletion of the short arm of chromosome 18. Pediatr Cardiol 1989;10:174 – 6. [2] Digilio MC, Marino B, Giannotti A, DiDonato R, Dallapiccola B. Heterotaxy with left atrial isomerism in a patient with deletion 18p. Am J Med Genet 2000;94:198 – 200. [3] Norwood WI. Hypoplastic left heart syndrome. Ann Thorac Surg 1991; 52:688 – 95. [4] Rychik J, Rome JJ, Collins MH, DiCampli WM, Spray TL. The hypoplastic left heart syndrome with intact atrial septum: atrial morphology, pulmonary vascular histopathology and outcome. J Am Coll Cardiol 1999;34:554 – 60. [5] Luciani GB, Pessotto R, Mombello A, Mazzucco A. Hypoplastic left heart syndrome with restrictive atrial septal defect and congenital pulmonary lymphangiectasia. Cardiovasc Pathol 1999;8:49 – 51. [6] Sauer U, Gittenberger-de Groot AC, Geishauser M, Babic R, Buhlmeyer K. Coronary arteries in the hypoplastic left heart syndrome. Circulation 1989;80(Suppl. I):I168 – 76. [7] Baffa JM, Chen SL, Guttenberg ME, Norwood WI, Weinberg PM. Coronary artery abnormalities and right ventricular histology in hypoplastic left heart syndrome. J Am Coll Cardiol 1992;20:350 – 8. [8] Grossfeld PD. The genetics of hypoplastic left heart syndrome. Cardiol Young 1999;9:627 – 32.