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J Thorac Cardiovasc Surg 2007;133:1094-1096
© 2007 The American Association for Thoracic Surgery
Brief Communication |
a Kids Heart Research and Adolph Basser Cardiac Institute, The Children’s Hospital at Westmead, Sydney, Australia
b Department of Clinical Genetics, The Children’s Hospital at Westmead, Sydney, Australia
c Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, The Children’s Hospital at Westmead, Sydney, Australia.
Received for publication December 12, 2006; accepted for publication December 18, 2006. * Address for reprints: Dr David Winlaw, Paediatric Cardiac Surgeon, Head, Kids Heart Research, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead NSW 2145, Australia. (Email: davidw{at}chw.edu.au).
Alagille syndrome (AGS) is a complex disorder with multisystemic involvement, including the liver, heart, kidneys, cerebral vasculature, skeleton, eyes, and face.1
A structural heart defect is one of the diagnostic criteria for AGS. These vary in severity, with peripheral pulmonary arterial stenosis being a common problem. Pulmonary atresia (PA) is a rare presentation in AGS, but we were impressed by the poor outcome of such infants following review of our institutional experience over the last 20 years. The information has particular relevance in this era where prenatal diagnosis of both AGS and PA can be made.
A number of information sources including cardiac, genetic, and gastroenterology departmental databases and hospital medical records were searched and cross-referenced to identify patients with AGS and/or PA between 1985 and 2004. We identified 26 patients with AGS and 505 patients with PA, 5 of whom had both diagnoses. Patients with AGS and only peripheral pulmonary arterial stenoses were excluded. Our institution serves a population of more than 6 million people, performs more than 400 cardiac procedures annually, and has a raw operative mortality of <2%.
Five cases of AGS with PA were identified (see Table 1): 4 with PA and ventricular septal defect (VSD), 1 with PA and intact ventricular septum. Four of 5 patients (80%) have died as a result of cardiac disease, and the remaining individual is receiving palliative management.
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AGS is an autosomal-dominant disorder caused by mutations or deletions in the JAG1 gene, located on chromosome 20p11.2-20p12. The JAG1 gene produces a protein, Jagged1, which is an important ligand in the NOTCH signaling pathway and plays an important role in early cell determination.2 The expression of Jagged1 within the developing embryo of both mice and humans correlates with cardiovascular disease in AGS.3 Expression is primarily seen in structures destined to become part of the right-sided circulatory system, including the sixth pharyngeal arch, which gives rise to the pulmonary artery, as well as in the pulmonary outflow tract. No clear genotype–phenotype correlations have yet been established to account for the high degree of variability of both the number and the extent to which the various organ systems are involved. In a study of monozygotic twins with an identical splice site mutation in JAG1, 1 twin had PA and the other had only mild cardiac disease but more severe hepatic involvement.4 Although it is recognized that mutations or deletions in JAG1 cause AGS, other factors including environmental triggers, modifying genetic loci, and epigenetic factors may contribute to the phenotype of an individual, as is the case in many other forms of structural heart disease.
Cardiac disease significantly impacts on the life expectancy of patients with AGS and accounts for 34% of mortality.1 PA alone, with or without a VSD, is a serious condition; however, with contemporary surgical techniques, most patients survive infancy, with an increasing number expected to achieve biventricular repair.5 It is not clear why the patients with AGS who received systemic-to-pulmonary shunts did not show evidence of pulmonary arterial growth. In the 3 who had generous collateral flow, initial palliation was deferred, but in the current era we would aim to augment pulmonary blood flow as soon as possible to achieve what pulmonary arterial growth is possible. Unfortunately, even when this approach was aggressively employed (case 1), satisfactory pulmonary vascular development has not been achieved.
Our study expands on a theme identified by McElhinney and colleagues,2 who noted that patients with a JAG1 mutation and PA/VSD had a poor outcome, with 6 of 8 patients (75%) not surviving treatment in infancy. The survival rate in their patient group mirrors that of our cohort and highlights the severity of the condition. These results have implications for clinical decision making and management of PA in the context of AGS and allow us to calibrate expectations for those requiring surgery.
Acknowledgments
We acknowledge the contributions of Prof Tim Cartmill, Dr David Johnson, Dr Graham Nunn, Dr Ian Nicholson, and Dr Stephen Cooper, who were involved in the clinical management of these patients.
References
This article has been cited by other articles:
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  R. Formigari, G. Michielon, M. C. Digilio, G. Piacentini, A. Carotti, A. Giardini, R. M. Di Donato, and B. Marino Genetic syndromes and congenital heart defects: how is surgical management affected? Eur J Cardiothorac Surg, April 1, 2009; 35(4): 606 - 614. [Abstract] [Full Text] [PDF]
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