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Ann Thorac Surg 2003;76:567-571
© 2003 The Society of Thoracic Surgeons

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Original article: cardiovascular

Deletion of chromosome 22q11.2 and outcome in patients with pulmonary atresia and ventricular septal defect

^a Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
^b division of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
^c division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Georgia, USA

Accepted for publication March 5, 2003.

^* Address reprint requests to Dr Mahle, Sibley Heart Center Cardiology, Children’s Healthcare of Atlanta, 52 Executive Park South, Suite 5200, Atlanta, GA 30329 USA
e-mail: wmahle{at}emory.edu

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
BACKGROUND: The 22q11.2 deletion (del22q) is present in many patients with conotruncal abnormalities including pulmonary atresia with ventricular septal defect (PA/VSD). We sought to determine the impact of the del22q on outcome in subjects with PA/VSD.

METHODS: We reviewed the experience for all patients with PA/VSD who were born between January 1993 and April 2002 and presented to our institution. Patients with conotruncal defects were routinely evaluated for genetic disorders including del22q. Fluorescence in situ hybridization was used to test for del22q.

RESULTS: There were 67 subjects with PA/VSD who presented during that time period; testing for del22q was performed in 58 of 67 (87%) and these 58 patients comprised the study population. The 22q11.2 deletion was present in 20 of 58 (34%) patients tested. Major aortopulmonary collaterals were defined by angiography and were present in 27 (47%). These collaterals were significantly more common among subjects with del22q (13 of 20, 65%; p = 0.04). The median cross sectional area of the pulmonary arteries, the Nakata index, was significantly less for patients with del22q (41 versus 142 mm²/m²; p = 0.006). There were 3 subjects, all of whom had del22q, who did not undergo surgery owing to markedly hypoplastic pulmonary arteries. Of the remaining 55 patients, 53 had arteriopulmonary shunt with or without unifocalization as the initial procedure and 35 patients have undergone complete repair. There were 8 operative deaths and 1 nonoperative death. The 5-year survival was 36% for patients with del22q versus 90% for patients without del22q. The 22q11.2 deletion was a significant risk factor for death, even after adjusting for the presence of major aortopulmonary collaterals (p = 0.004). There was no significant difference between the two groups with respect to the incidence of serious viral, bacterial, or fungal infections in the perioperative period.

CONCLUSIONS: Patients with del22q and PA/VSD are at increased risk for death owing to a variety of factors including less favorable pulmonary artery anatomy. A better understanding of del22q, pulmonary artery anatomy, and outcome is required.

	Introduction

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Microdeletion of chromosome 22q11.2 (del22q) is known to occur in a significant number of patients with conotruncal defects including pulmonary atresia with ventricular septal defect (PA/VSD) [1–4]. Along with congenital heart defects patients with del22q may have a variety of other abnormalities such as the immunodeficiency, abnormal airways, and gastrointestinal complications [5]. It is not known however whether these and other factors contribute to increased morbidity and mortality in this population. In a previously reported series of PA/VSD del22q was not found to be a risk factor for mortality [6]. Recently it has been suggested that del22q is associated with an increased incidence of major aortopulmonary collaterals (MAPCAs) and more severe pulmonary artery hypoplasia in patients with PA/VSD [2, 7, 8]. Although this association has not been reported by all investigators [1, 6], it suggests that genetic factors may contribute to the clinical outcome of patients with del22q. In this report we review our experience with management of PA/VSD with particular attention to the impact of del22q on morbidity and mortality.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Patients
From January 1993 through May 2002, 67 patients with PA/VSD presented to our institution. Deletion analysis for del22q was performed in 58 of 67 subjects (87%). These 58 patients comprise the study population for this analysis. The age at presentation ranged from 1 day to 4.5 years (median, 12 days). Of the 58 patients, 31 (53%) were male and 27 (47%) were female. Two patients had undergone a Blalock-Taussig shunt placement elsewhere prior to presentation at our institution.

Analysis of pulmonary arteries
All study subjects underwent cardiac catheterization with angiography at presentation or before attempted surgical repair. Angiographic examination was performed to image the pulmonary arteries and to identify alternate sources of pulmonary blood flow. The pulmonary artery size was reported as the sum of cross-sectional areas of the right and left pulmonary arteries indexed to body surface area, according to the method described by Nakata and associates [9]. In this study MAPCA was defined as an arterial vessel arising from the aorta, connecting to a pulmonary artery (usually in the pulmonary hilum), and providing blood supply to the lungs. Major aortopulmonary collaterals were first investigated by a descending aortogram, followed by selective pressure measurements and angiography. Native pulmonary arteries were visualized by retrograde filling from a MAPCA injection or a pulmonary venous wedge injection. Both MAPCAs and native pulmonary arteries were classified for origin and size.

Surgical technique
For patients with confluent pulmonary arteries and no MAPCAs (n = 31), the ductus arteriosus was ligated and an aortopulmonary shunt was placed in the newborn period. This consisted of either a Gore-Tex (W.L. Gore, Flagstaff, AZ) shunt or a saphenous vein graft. Complete repair was performed at a median age of 11.1 months (range, 5.4 months to 7.0 years). Complete repair involved VSD closure with a Dacron (C.L. Bard, Haverhill, PA) patch and establishment of a right ventricle to pulmonary artery connection. To date, complete repair has been performed in 23 patients with PA/VSD and no MAPCAs. Continuity between the right ventricle and pulmonary artery was established with a valved pulmonary homograft of appropriate size (n = 15), an aortic homograft (n = 1), a prosthetic (polytetrafluoroethylene or Dacron) conduit (n = 4), or a short transannular patch (n = 3).

For the majority of patients with MAPCAs (22 of 24) the initial strategy was to promote the growth of the native pulmonary arteries with an arteriopulmonary shunt (Fig 1). This involved the use of a modified Blalock-Taussig shunt (left-sided in 12 and right-sided in 9) and in 1 patient the initial operation was to create a confluence between the discontinuous diminutive native right and left pulmonary arteries and place a central shunt into the reconstruction. A total of 16 patients underwent unifocalization. Unifocalization was carried out at the time of the initial systemic to pulmonary shunt in 10 patients. Of the 16 patients who underwent unifocalization, 4 (25%) had this performed as a two-stage procedure. In general unifocalization was performed with tissue-to-tissue anastomosis (end-to-side or side-to-side) or an autologous patch of pericardium was employed. After the completion of the unifocalization the definitive repair was delayed for at least 6 months to allow for maximal growth of the native pulmonary arteries.

View larger version (16K): [in this window] [in a new window]   Fig 1. Management of patients with pulmonary atresia and ventricular septal defect (PA/VSD) and major aortopulmonary collaterals (MAPCAs) who underwent surgical intervention (n = 24). (RV-PAc = right ventricle to pulmonary artery connection; unifocal. = unifocalization.)

Deletion analysis
Patients who presented to our institution with a conotruncal anomaly were evaluated for genetic abnormalities. In the early part of this series (1993 to 1995), fluorescence in situ hybridization was performed when clinical examination or laboratory data suggested the presence of velocardiofacial syndrome. In the later part of the series fluorescence in situ hybridization was performed on all subjects with conotruncal defects. Metaphase chromosomes from peripheral blood lymphocytes were cohybridized with the cosmid probe N25 (D22S75) from within the DiGeorge chromosomal region and a control probe as supplied by Oncor (Gaithersburg, MD).

Statistics
Data are expressed as mean ± SD or median and range, where appropriate. Statistical analysis was performed by Fisher’s exact test, ² test, Wilcoxon rank sum test, Kaplan-Meier survival curve estimates, log-rank tests to compare survival curves, and Cox proportional hazards model for assessing multivariate associations between risk factors and freedom from death. Analysis was performed with STATA 6.0 (College Station, TX). Significance was determined at a p value of less than 0.05. All p values are two-sided and confidence intervals are 95%.

	Results

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Of the 58 patients with PA/VSD in this series, 20 (34%) were found to have del22q. Major aortopulmonary collaterals were significantly more common in subjects with del22q (13 of 20; 65%) than in subjects without del22q (14 of 38; 37%; p = 0.04; Table 1). A right aortic arch was also significantly more common in patients with del22q (13 of 20; 65%) compared with patients without del22q (12 of 38; 32%, p = 0.01). Additional genetic syndromes and associations identified among the 38 subjects without del22q included trisomy 21 (n = 1) and VATER (vertebral anomalies, anal atresia, tracheo-esophageal fistula, esophageal atresia, renal anomalies) syndrome (n = 2).

Of the 58 patients in this series, 23 (40%) developed at nososomial infection during at least one operative hospital stay. Respiratory infections were identified in 13 subjects (22%). Bacterial or fungal infections necessitating antimicrobial treatment were identified in 11 subjects (19%). The most common bacterial and fungal pathogens were Pseudomonas species, Staphylococcus species, and Candida species. Of the 20 patients with del22q, 8 (40%) developed a nosocomial infection, which was not significantly different from the patients without del22q (p = 0.97).

There were 12 deaths among the 58 patients for an overall mortality of 21%. The 1-year and 5-year survival for the entire cohort was 87% and 71% respectively. The 5-year survival for patients with del22q was significantly lower than for patients without del22q (36% versus 90%; Fig 2). In univariate analysis del22q and the presence of MAPCAs were also found to be significantly associated with an increased risk of death (Table 2). A higher Nakata index was associated with improved survival. The presence of MAPCAs was not a predictor of survival in multivariate analysis (Table 3).

View larger version (8K): [in this window] [in a new window]   Fig 2. Kaplan-Meier plot of survival for entire cohort (n = 58) stratified by presence (Del22q-) or absence (Del22q+) of the 22q11.2 deletion (p = 0.001).

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
This study analyzes the impact of del22q on outcome for patients with PA/VSD from a single institution. There was an association between del22q and the presence of MAPCAs and the degree of pulmonary artery hypoplasia. Patients with del22q had a significantly higher mortality rate than patients without del22q, due at least in part to more severe pulmonary artery hypoplasia. Invasive infections did not appear to be a risk factor for increased operative mortality among patients with del22q.

Over the last decade investigators have gained great insight into the relationship of del22q to the development of conotruncal heart defects. Several large series have reported that del22q is common and may be present in more than half of patients with certain heart lesions such as interrupted aortic arch type B [1, 10]. Between 10% and 19% of patients with tetralogy of Fallot have been found to have del22q [1, 12, 13]. In a large prospective study Goldmuntz and colleagues [1] reported that there was no significant difference in the deletion frequency (15.9%) between subjects with PA/VSD and subjects with tetralogy of Fallot and pulmonary stenosis. However several other series have found that the prevalence of del22q is significantly higher in patients with PA/VSD. Chesa and coworkers [7] prospectively studied 40 patients and with PA/VSD and 54 patients with tetralogy of Fallot and found that del22q was significantly more common among patients with PA/VSD (40% versus 17%; p 0.02). Anaclerio and colleagues [14] reported a prevalence of 22% for del22q among 128 patients with PA/VSD. The deletion frequency of 34% in the present study would fall within the range reported in previous series.

In general most large series including our own have found that MAPCAs are present in 40% to 50% of subjects with PA/VSD [15, 16]. More recently investigators have also suggested that the spectrum of pulmonary artery anatomy may be different among those subjects with PA/VSD depending on the presence or absence of del22q. Chesa and colleagues [7] reported that MAPCAs were more common in patients with del22q than in patients without del22q (81% versus 13%). Similarly Marino and coworkers [17] reported a significantly higher incidence of MAPCAs in patients with del22q. In a series from a referral center Momma and colleagues [18] reported that 91% of patients with PA/VSD and del22q had MAPCAs compared with 50% in patients without del22q. Other investigators have failed to find an association between the presence of MAPCAs and del22q [1]. In the current series MAPCAs were present in 65% of patients with del22q significantly higher than patients without del22q. Furthermore the patients with del22q tended to have less favorable arborization of pulmonary arteries. Patients with del22q had a significantly lower Nakata index with fewer lung segments supplied by the pulmonary arteries.

Although previous investigators have demonstrated that the presence of del22q is associated with less favorable pulmonary artery anatomy, the impact of this association on outcome is less well understood. In the current study we found that patients with PA/VSD and del22q has significantly poorer survival than patients without del22q. This poorer survival is due in part to the more significant pulmonary hypoplasia in this population. However even after adjusting for the pulmonary artery size with multivariate analysis the presence of del22q was significantly associated with increased mortality. Most previous series that have examined the outcome for patients with PA/VSD have either not evaluated patients for del22q or have not identified the presence of del22q as a risk factor for mortality [6, 19]. Carotti and coworkers [6] reported no significant association between del22q and survival in a cohort of 15 patients with PA/VSD and MAPCAs. Conversely Reddy and colleagues [20] reported that del22q was associated with lower overall survival in a cohort of 85 patients with PA/VSD and MAPCAs. However del22q was identified in only 14% of subjects in that series so the impact of del22q may have been underestimated.

The mechanism by which del22q contributes to mortality appears to be due in part to the severity of pulmonary artery hypoplasia. There were 3 subjects in this series who never underwent surgical intervention because the severity of pulmonary artery hypoplasia was thought to preclude successful unifocalization. Of the remaining 9 deaths among the patients with PA/VSD, 8 were operative. Most of these deaths occurred after establishment of a right ventricle to pulmonary artery connection or VSD closure. Although del22q is often associated with varying degrees of compromised cellular immunity, the development of serious bacterial, fungal, or viral infection accounted for only a single death in this series. This finding would agree with a report by Jawad and coworkers [21] who have found that while patients with del22q had an increased risk of infections, these infections were seldom life threatening. Similarly Kornfeld and colleagues [22] found that patients with del22 had mild cell-mediated immunodeficiency syndrome.

The survival for the entire cohort of patients with PA/VSD was 87% at 1 year and 71% at 5 years. That is comparable with several other large series. Leonard and associates [16] report a 1-year survival of 66% for neonates identified over a 15-year period. In a series of 85 patients with PA/VSD and MAPCAs—many of whom were adults—Reddy and associates [20] report a 3-year survival of 80%. For patients with MAPCAs some centers have adopted a strategy of early complete repair by performing a single-stage unifocalization and repair [19, 20]. The routine practice at our institution has been to carry out the unifocalization as a separate procedure from the VSD closure, allowing growth of the pulmonary vessels before VSD closure. A recent study by Tchervenkov and colleagues [20] suggests the outcomes for the two approaches are comparable.

The major limitation of this study is that in the early part of this series not all subjects underwent routine screening for del22q. Nine patients who presented during the study period did not have testing for del22q; we elected to exclude these 9 patients. In addition a retrospective study has inherent limitations in determining a cause of death. The cause of death is frequently multifactorial and factors such as metabolic abnormalities or undetected infections may have been underdiagnosed.

In summary, del22q is common among patients with PA/VSD and is associated with abnormalities of the pulmonary arteries and an increased prevalence of MAPCAs. Mortality is significantly higher among patients who have del22q owing in large part to unfavorable pulmonary artery anatomy. ([11])

	References

Top Abstract Introduction Material and methods Results Comment References

 

1. Goldmuntz E., Clark B.J., Mitchell L.E., et al. Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol 1998;32:499-501.[Free Full Text]
2. Matsuoka R., Takao A., Kimura M., et al. Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2. Am J Med Genet 1994;53:285-289.[Medline]
3. Marmon L.M., Balsara R.K., Chen R., Dunn J.M. Congenital cardiac anomalies associated with the DiGeorge syndrome: a neonatal experience. Ann Thorac Surg 1984;38:146-150.[Abstract]
4. Webber S.A., Hatchwell E., Barber J.C., et al. Importance of microdeletions of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study. J Pediatr 1996;129:26-32.[Medline]
5. McDonald-McGinn D.M., LaRossa D., Goldmuntz E., et al. The 22q11.2 deletion: screening, diagnostic workup, and outcome of results; report on 181 patients. Genet Test 1997;1:99-108.[Medline]
6. Carotti A., Di Donato R.M., Squitieri C., Guccione P., Catena G. Total repair of pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals: an integrated approach. J Thorac Cardiovasc Surg 1998;116:914-923.[Abstract/Free Full Text]
7. Chessa M., Butera G., Bonhoeffer P., et al. Relation of genotype 22q11 deletion to phenotype of pulmonary vessels in tetralogy of Fallot and pulmonary atresia-ventricular septal defect. Heart 1998;79:186-190.[Abstract/Free Full Text]
8. Hofbeck M., Rauch A., Buheitel G., et al. Monosomy 22q11 in patients with pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries. Eur J Pediatr 1999;158:302-307.[Medline]
9. Nakata S., Imai Y., Takanashi Y., et al. A new method for quantitative standardization of cross sectional areas of the congenital heart diseases with decreased pulmonary blood flow. J Thorac Cardiovasc Surg 1984;88:610-615.[Abstract]
10. Iserin L., de Lonlay P., Viot G., et al. Prevalence of the microdeletion 22q11 in newborn infants with congenital conotruncal cardiac anomalies. Eur J Pediatr 1998;157:881-884.[Medline]
11. Boudjemline Y., Fermont L., Le Bidois J., Lyonnet S., Sidi D., Bonnet D. Prevalence of 22q11 deletion in fetuses with conotruncal cardiac defects: a 6-year prospective study. J Pediatr 2001;138:520-524.[Medline]
12. Digilio M.C., Marino B., Grazioli S., et al. Comparison of occurrence of genetic syndromes in ventricular septal defect with pulmonic stenosis (classic tetralogy of Fallot) versus ventricular septal defect with pulmonic atresia. Am J Cardiol 1996;77:1375-1376.[Medline]
13. Trainer A.H., Morrison N., Dunlop A., Wilson N., Tolmie J. Chromosome 22q11 microdeletions in tetralogy of Fallot. Arch Dis Child 1996;74:62-63.[Abstract/Free Full Text]
14. Anaclerio S., Marino B., Carotti A., et al. Pulmonary atresia with ventricular septal defect: prevalence of deletion 22q11 in the different anatomic patterns. Ital Heart J 2001;2:384-387.[Medline]
15. Dinarevic S., Redington A., Rigby M., Shinebourne E.A. Outcome of pulmonary atresia and ventricular septal defect during infancy. Pediatr Cardiol 1995;16:276-282.[Medline]
16. Leonard H., Derrick G., O’Sullivan J., Wren C. Natural and unnatural history of pulmonary atresia. Heart 2000;84:499-503.[Abstract/Free Full Text]
17. Marino B., Digilio M.C., Grazioli S., et al. Associated cardiac anomalies in isolated and syndromic patients with tetralogy of Fallot. Am J Cardiol 1996;77:505-508.[Medline]
18. Momma K., Kondo C., Matsuoka R. Tetralogy of Fallot with pulmonary atresia associated with chromosome 22q11 deletion. J Am Coll Cardiol 1996;27:198-202.[Abstract]
19. Tchervenkov C.I., Salasidis G., Cecere R., et al. One-stage midline unifocalization and complete repair in infancy versus multiple-stage unifocalization followed by repair for complex heart disease with major aortopulmonary collaterals. J Thorac Cardiovasc Surg 1997;114:727-735.[Abstract/Free Full Text]
20. Reddy V.M., McElhinney D.B., Amin Z., et al. Early and intermediate outcomes after repair of pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries: experience with 85 patients. Circulation 2000;101:1826-1832.[Abstract/Free Full Text]
21. Jawad A.F., McDonald-Mcginn D.M., Zackai E., Sullivan K.E. Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Pediatr 2001;139:715-723.[Medline]
22. Kornfeld S.J., Zeffren B., Christodoulou C.S., et al. DiGeorge anomaly: a comparative study of the clinical and immunologic characteristics of patients positive and negative by fluorescence in situ hybridization. J Allergy Clin Immunol 2000;105:983-987.[Medline]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Robert M. Campbell Vincent K. H. Tam Kirk R. Kanter Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mahle, W. T. Articles by Kanter, K. R. Search for Related Content PubMed PubMed Citation Articles by Mahle, W. T. Articles by Kanter, K. R. Related Collections Congenital - cyanotic