Unifocalization and repair of pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries

Aim: To correlate anatomic and genetic features of paediatric patients with pulmonary atresia, ventricular septal defect (VSD) and multiple aortopulmonary collateral arteries with surgical outcome.
Methods: 44 consecutive patients aged 33±40 mo underwent either primary one-stage unifocalization ( n =32) or palliative right ventricular outflow tract reconstruction ( n =12) followed by secondary unifocalization and repair ( n =10) based on preoperative morphometric and functional evaluation of pulmonary blood sources. Chromosome 22q11.2 microdeletion occurred in 41% of cases. Combined VSD closure during one-stage procedures was guided by an intraoperative pulmonary flow study. Complete repair was accomplished in 35 cases (83%, 95% CI 72–95%). Variables examined included occurrence of confluent intrapericardial pulmonary arteries, central pulmonary arteries, confluent intraparenchymal pulmonary arteries, dominant collateral or pulmonary arteries, and chromosome 22q11.2 microdeletion. The sensitivity and specificity of the pulmonary flow study in predicting postoperative pulmonary haemodynamics were also tested.
Results: Eight-year actuarial survival and freedom from reoperation were 85% and 63%, respectively. Sensitivity and specificity of the pulmonary flow study were 94% and 100%, respectively. None of the anatomical variables examined was significantly related to the outcome of treatment. The only statistically relevant association was detected between survival and occurrence of 22q11.2 microdeletion ( p <0.003). Logistic analysis showed an increased likelihood of positive outcome in relation to first- ( p <0.02) or second-stage ( p <0.04) complete correction.
Conclusion: Morphology of pulmonary blood supply has no major impact on surgical outcome. Pulmonary flow study is a highly specific and sensitive intraoperative test. Chromosome 22q11.2 microdeletion remains the only variable significantly affecting survival.     

Chromosome 22q11.2 microdeletion in children with conotruncal heart defects: frequency,associated cardiovascular anomalies,and outcome following cardiac surgery

The association of conotruncal heart defects with 22q11.2 chromosomal microdeletions is well established. However, it is not clear whether particular types of conotruncal malformations or additional cardiovascular anomalies are associated with microdeletions. In addition, cardiac surgery outcome in children with conotruncal defects and del22q11.2 is not well described. We prospectively enrolled 214 children with conotruncal defects: 126 with tetralogy of Fallot (TOF), 18 with pulmonary atresia-ventricular septal defect (PA-VSD), 15 with truncus arteriosus communis (TAC) type I, one with interrupted aortic arch (IAA) type B, and 54 with the transposition of great arteries, who were consecutively hospitalized at the Pediatric Cardiology Department between 2003 and 2005. 22q11.2 microdeletion was identified by fluorescence in situ hybridization. The postoperative course following cardiac surgery was compared in patients with TOF and its more severe form, PA-VSD, with/without del22q11.2 (groups A and B) and TAC with/without del22q11.2 (groups C and D). In 15 of 214 patients, 22q11.2 microdeletion was diagnosed (in 11 with TOF/PA-VSD, in three with TAC, in one with IAA type B). In patients with TOF/PA-VSD and microdeletion anatomic features that were significantly associated with 22q11.2, deletion included right aortic arch (p = 0.018), aberrant right subclavian artery (p < 0.001), and major aortopulmonary collateral arteries (p = 0.016). A complicated postoperative course was more frequent and mortality was higher in patients with conotruncal defects and with/without microdeletion. We conclude that additional cardiovascular anomalies are significantly more frequent in children with 22q11.2 microdeletion and TOF/PA-VSD. Children with conotruncal heart defects and 22q11.2 microdeletion more frequently experienced complicated postoperative course after cardiac surgery.     

Clinical relevance of monosomy 22q11.2 in children with pulmonary atresia and ventricular septal defect

The purpose of our study was to describe the prevalence and the clinical spectrum of monosomy 22q11.2 in a population of patients with pulmonary atresia and ventricular septal defect. We examined all 44 patients with this conotruncal cardiac malformation who presented to our institution from January 1994 until December 1997. The type of collateral lung perfusion was recorded including anomalies of the pulmonary arteries as well as facial and immunological abnormalities. Molecular-cytogenetic testing for a 22q11.2 microdeletion was performed using the probes D22S75 and cHKAD26. Statistical differences were evaluated with the Fisher's Exact Test. Monosomy 22q11.2 was present in ten children (23%) with major aortopulmonary collateral arteries (group 1). The remaining 13 children (29%) with major aortopulmonary collateral arteries (group 2) and all 21 children (48%) with ductus arteriosus (group 3) were negative for this microdeletion. All children in group 1 had facial anomalies, six had mild immunological abnormalities including decreased CD 4+ or CD 8+ cells. Anomalies of the pulmonary vascular bed were significantly more frequent in children of group 1 (9/10) than in children of group 2 (4/13) or group 3 (0/21). Due to these pulmonary vascular anomalies, corrective surgery had been accomplished in fewer children with monosomy 22q11.2 (none in group 1) as compared to 7/13 children in group 2 and 14/21 children in group 3. Conclusion In children with pulmonary atresia and ventricular septal defect, monosomy 22q11.2 is preferentially associated with major aortopulmonary collateral arteries. Due to the higher incidence of pulmonary arterial abnormalities, successful surgical repair will require a different therapeutic approach in most patients with this microdeletion. Received: 3 June 1998 / Accepted in revised form: 11 September 1998     

单纯性圆锥动脉干畸形22q11.2微缺失发生率及临床表型研究

目的 探讨单纯性圆锥动脉干畸形(CTD)染色体22q11.2微缺失发生率及临床表型分析.方法 应用多重连接探针扩增法(MLPA)对77例0～10岁单纯性CTD患儿进行染色体22q11.2微缺失筛查,并对阳性样本进行荧光原位杂交(FISH)验证.采用Fisher精度检验,P＜0.05有统计学意义.结果 用MLPA对77例单纯性CTD患儿进行了22号染色体微缺失筛查,其中55例法乐四联症(TOF),4例肺动脉闭锁伴室间隔缺损(PA-VSD),8例右室双出口(DORV),10例大动脉转位(TGA).6例(7.8%)患儿存在染色体22q 11.2微缺失,其中4例为TOF,1例为PA-VSD,1例为DORV;10例TGA患儿中均未发现22q11.2缺失.结论 单纯性CTD染色体22q 11.2微缺失发生率约为7.8%.单纯性CTD患儿中,PA-VSD,DORV及TOF比TGA更易发生染色体22q11.2微缺失.应加强对单纯性CTD患儿的遗传筛查及咨询.     

Concomitant One-Stage Unifocalization and Bidirectional Glenn Procedure

A concomitant one-stage unifocalization and bidirectional Glenn procedure was performed in a patient with a functionally single ventricle, pulmonary atresia, and major aortopulmonary collateral arteries (MAPCAs). Reconstruction of the absent central pulmonary artery was achieved using the MAPCAs as well as the autologous pericardium. After 1 year, cineangiography and cardiac catheterization showed an excellent result: well-developed pulmonary arteries as well as low pressure in the superior vena cava. To the best of our knowledge, this is the first report of a successful concomitant one-stage unifocalization and bidirectional Glenn procedure.     

Diagnosis and treatment of pulmonary atresia and ventricular septal defect

Surgical repair of the intracardiac anatomy in patients with pulmonary atresia and ventricular septal defect can be performed today with a low operative mortality. Diagnostic and therapeutic problems in these patients are almost exclusively related to the nature of collateral lung perfusion and associated anomalies of the pulmonary vascular bed. These anomalies are frequently found in patients with major aortopulmonary collateral arteries and include multifocal pulmonary blood supply, hypoplasia, stenosis, or arborization anomalies of the pulmonary arteries. Diagnostic methods must focus on an exact identification of the collateral pulmonary blood supply, the presence and size of central pulmonary arteries, and the connections of the arterial segments. Recent genetic studies have shown that monosomy 22q11.2 is found in 25–32% of children with pulmonary atresia and ventricular septal defect. This microdeletion is significantly more frequent in patients with major aortopulmonary collateral arteries and it seems to be associated with a higher percentage of pulmonary arterial anomalies. During recent years, efforts have concentrated on earlier treatment of patients with pulmonary atresia with ventricular septal defect with combined catheter and surgical interventions. Early establishment of antegrade flow to the central pulmonary arteries stimulates growth of the pulmonary arteries, optimizes the angiographic diagnosis of abnormalities of the pulmonary vascular bed, and allows for the possibility of balloon angioplasty or stenting of the central pulmonary arteries.     

圆锥动脉干畸形与染色体22q11.2微缺失之间的关系

染色体22q11.2微缺失综合征患儿中约80％合并有先天性心血管畸形.研究发现,染色体22q11.2区内基因(TBX1、CRKL、ERK2)参与染色体22q11.2微缺失的发生.合并染色体22q11.2微缺失最常见的心血管畸形是圆锥动脉干畸形,包括法洛四联症、室间隔缺损型肺动脉闭锁、永存动脉干以及主动脉弓中断.主要表型...     

Outcome of pulmonary atresia and ventricular septal defect during infancy

We evaluated 54 patients with pulmonary atresia and ventricular septal defect who were referred during the first year of life between 1972 and 1992. Particular emphasis was given to the nature of the pulmonary blood supply and its influence on outcome. Ductal supply of confluent pulmonary arteries was present in 30 patients (55.6%, group I), whereas 24 patients (44.4%, group II) had a pulmonary blood supply that was entirely (31.4%) or predominantly (13.0%) dependent on systemic collateral arteries. Over the 20 years these was no significant difference in actuarial survival between the two groups. Corrective surgery was performed in 8 of 30 patients in group I (26.7%)-significantly more than in group II (4 of 24, 16.7%). Arborization abnormalities of the pulmonary arteries (stenosis of unbranched and intrapulmonary arteries) were almost exclusively present in patients with systemic collateral arteries (p<0.03), accounting for the lower probability of undergoing corrective surgery in group II patients. During the first decade of this study (1973–1983) corrective surgery was attempted in 9.6% of patients, with 42% mortality; and during the second decade (1983–1993) surgery was performed in 39.1% of patients, with 26% mortality, a significantly lower figure. Improving surgical results, complete preoperative demarcation of the pulmonary blood supply, and a more aggressive approach with early unifocalization of the pulmonary blood supply may invalidate comparison with retrospective data on the advisability of attempting to correct this anomaly. The present paper provides data against which treatment of infants with pulmonary atresia and ventricular septal defect presenting during the next decade can be compared.     

肺动脉闭锁合并室间隔缺损104例诊断分析

目的　分析肺动脉闭锁合并室间隔缺损 (PA/VSD)的解剖类型及血流动力学改变 ,探讨其适宜的手术方式。方法　对 1992年 6月至 2 0 0 2年 5月在广东省心血管病研究所儿科住院的PA/VSD患儿共 10 4例 ,采用超声心动图结合心血管造影术 ,确定闭锁的部位、肺动脉的发育情况及血供来源。结果　右室流出道及瓣膜闭锁、有肺动脉总干 31例 ;肺动脉总干闭锁、左右肺动脉有汇合 5 0例 ;左肺动脉闭锁 10例 ,右肺动脉闭锁 8例 ;左右肺动脉均闭锁 5例。肺动脉的血供来源 :大的主肺动脉侧支血管 5 1例 ,动脉导管未闭 2 7例 ,多支小的侧支血管 2 6例。合并畸形有卵圆孔未闭、房间隔缺损、大动脉转位、完全性房室间隔缺损、右室双出口、镜面右位心、右旋心及左旋心。结论　合并室间隔缺损的肺动脉闭锁可发生在不同部位 ,肺动脉的血供来源多样化     

Laterality of the aortic arch and anomalies of the subclavian artery—reliable indicators for 22q11.2 deletion syndromes?

A variety of cardiac defects, encompassing truncus arteriosus, tetralogy of Fallot, pulmonary atresia with ventricular septal defect and interrupted aortic arch, are generally summarised as conotruncal malformations. Patients with these cardiac defects were frequently found to have a common microdeletion on chromosome 22, the so-called monosomy 22q11.2. The aim of our study was to determine whether the laterality of the aortic arch or the presence of subclavian artery anomalies (SAA) represent markers for monosomy 22q11.2 in these patients. 170 patients with these cardiac anomalies were recruited at presentation in the paediatric cardiology units of two tertiary referral centres from 1994 until 2003. Of the 170 children and young adults, 33 had interrupted aortic arch, 35 tetralogy of Fallot, 31 truncus arteriosus communis and 71 pulmonary atresia with ventricular septal defect. All were screened for monosomy 22q11.2 and the results were correlated with the laterality of the aortic arch and the presence of SAA contralateral to the aortic arch (aberrant origin from the descending aorta, isolation, distal ductal origin from the pulmonary artery and cervical origin of the right subclavian artery). Monosomy 22q11.2 was present in 59/170 patients (35%). A left aortic arch (LAA) was found in 118 (69%), a right aortic arch (RAA) in 52 (31%) patients. Almost 50% of the patients with RAA (46%), but only 30% of the patients with LAA had monosomy 22q11.2 (P=0.054). A total of 47 patients (28%) had an anomaly of the subclavian artery, 81% of whom had monosomy 22q11.2. This deletion was found in decreasing percentage in patients with LAA+SAA (85%) >RAA+SAA (75%) >RAA without SAA (28%) >LAA without SAA (13%). Conclusion:In patients with conotruncal malformations, anomalies of the subclavian arteries are the most important anatomical marker for the presence of monosomy 22q11.2, independent of the laterality of the aortic arch. Therefore, we recommend cytogenetic testing for this microdeletion in all patients with subclavian artery anomalies and conotruncal malformations.     

肺动脉闭锁合并室间隔缺损的临床病理分析

目的 研究肺动脉闭锁合并室间隔缺损的解剖类型和血流动力学改变,并探讨其适宜的手术方式.方法 回顾性分析233例肺动脉闭锁合并室间隔缺损的造影结果,分析肺血来源、肺动脉发育情况和合并畸形及其与手术预后的影响.结果 233例中中央肺动脉存在,肺血单纯由未闭的动脉导管供应者112例(48.1%),其中1例为双侧动脉导管(0.5%);中央肺动脉和大的主一肺动脉侧支血管(MAPCA)均存在者104例(44.6%);无中央肺动脉,仅有MAPCA供应肺血者17例(7.3%).肺动脉闭锁部位以右室流出道和瓣膜闭锁最多见(48.1%).侧支血管的来源包括直接的主动脉一肺侧支动脉,间接的主动脉一肺侧支动脉和支气管动脉.合并畸形包括心脾综合征、房室连接不一致、心室大动脉连接不一致、多发室间隔缺损、右位主动脉弓、房间隔缺损、左上腔静脉残存、内脏异位症、上下心室、肺静脉异位引流和冠状动脉起源异常等.结论 肺动脉闭锁合并室间隔缺损患者肺血来源多样化,肺动脉发育程度不一,并可合并多种心内、心外畸形,影响手术方法的选掸和手术结果.     

Frequency of 22q11.2 microdeletion in children with congenital heart defects in western poland

Background

The 22q11.2 microdeletion syndrome (22q11.2 deletion syndrome -22q11.2DS) refers to congenital abnormalities, including primarily heart defects and facial dysmorphy, thymic hypoplasia, cleft palate and hypocalcaemia. Microdeletion within chromosomal region 22q11.2 constitutes the molecular basis of this syndrome. The 22q11.2 microdeletion syndrome occurs in 1/4000 births. The aim of this study was to determine the frequency of 22q11.2 microdeletion in 87 children suffering from a congenital heart defect (conotruncal or non-conotruncal) coexisting with at least one additional 22q11.2DS feature and to carry out 22q11.2 microdeletion testing of the deleted children's parents. We also attempted to identify the most frequent heart defects in both groups and phenotypic traits of patients with microdeletion to determine selection criteria for at risk patients.

Methods

The analysis of microdeletions was conducted using fluorescence in situ hybridization (FISH) on metaphase chromosomes and interphase nuclei isolated from venous peripheral blood cultures. A molecular probe (Tuple) specific to the HIRA (TUPLE1, DGCR1) region at 22q11 was used for the hybridisation.

Results

Microdeletions of 22q11.2 region were detected in 13 children with a congenital heart defect (14.94% of the examined group). Microdeletion of 22q11.2 occurred in 20% and 11.54% of the conotruncal and non-conotruncal groups respectively. Tetralogy of Fallot was the most frequent heart defect in the first group of children with 22q11.2 microdeletion, while ventricular septal defect and atrial septal defect/ventricular septal defect were most frequent in the second group. The microdeletion was also detected in one of the parents of the deleted child (6.25%) without congenital heart defect, but with slight dysmorphism. In the remaining children, 22q11.2 microdeletion originated de novo.

Conclusions

Patients with 22q11.2DS exhibit wide spectrum of phenotypic characteristics, ranging from discreet to quite strong. The deletion was inherited by one child. Our study suggests that screening for 22q11.2 microdeletion should be performed in children with conotruncal and non-conotruncal heart defects and with at least one typical feature of 22q11.2DS as well as in the deleted children's parents.     

A search for chromosome 22q11.2 deletions in a series of 176 consecutively catheterized patients with congenital heart disease: no evidence for deletions in non-syndromic patients

Microdeletions in chromosome 22q11.2 are associated with DiGeorge syndrome (DGS), velo-cardio-facial syndrome (VCFS), and several other syndromes, collectively referred to as DG/VCF. Non-dysmorphic patients with cardiac defects have also been attributed to deletions in this chromosomal region. In this study 157 consecutively catheterized patients with isolated, non-syndromic cardiac defects, and 25 patients with cardiac defects and additional stigmata (10 of whom were clinically diagnosed as DG/VCF cases prior to chromosome analysis) were analysed by fluorescence in situ hybridization with the DGS-specific probe D0832. Chromosome 22q11.2 deletions were observed only in the ten patients with the clinical diagnosis of DG/VCF. Conclusion In a large unselected cohort of patients with congenital heart disease no association between isolated or non-syndromic heart defects and the 22q11.2 microdeletion was observed. One can conclude that testing for the 22q11.2 microdeletion is clearly indicated in cases when even mild extracardiac abnormalities are present, particularly in very young infants. Received: 24 February 1998 / Accepted in revised form: 04 May 1999     

The Fate of Children with Microdeletion 22q11.2 Syndrome and Congenital Heart Defect: Clinical Course and Cardiac Outcome

Background This study aimed to evaluate the cardiac outcome for children with microdeletion 22q11.2 and congenital heart defect (CHD). Methods A total of 49 consecutive children with 22q11.2 and CHD were retrospectively identified. The CHD consisted of tetralogy of Fallot and variances (n = 22), interrupted aortic arch (n = 10), ventricular septal defect (n = 8), truncus arteriosus (n = 6), and double aortic arch (n = 1). Extracardiac anomalies were present in 46 of 47 children. Results The median follow-up time was 8.5 years (range, 3 months to 23.5 years). Cardiac surgical repair was performed for 35 children, whereas 5 had palliative surgery, and 9 never underwent cardiac surgery. The median age at repair was 7.5 months (range, 2 days to 5 years). The mean hospital stay was 35 days (range, 7–204 days), and the intensive care unit stay was 15 days (range, 3–194 days). Significant postoperative complications occurred for 26 children (74%), and surgery for extracardiac malformations was required for 21 patients (43%). The overall mortality rate was 22% (11/49), with 1-year survival for 86% and 5-year survival for 80% of the patients. A total of 27 cardiac reinterventions were performed for 16 patients (46%) including 15 reoperations and 12 interventional catheterizations. Residual cardiac findings were present in 25 patients (71%) at the end of the follow-up period. Conclusions Children with microdeletion 22q11.2 and CHD are at high risk for mortality and morbidity, as determined by both the severity of the cardiac lesions and the extracardiac anomalies associated with the microdeletion.     

Monozygotic Twins with Chromosome 22q11 Microdeletion and Discordant Phenotypes in Cardiovascular Patterning

Monozygotic twins with chromosome 22q11 microdeletions offer an ideal situation to observe the association of microdeletion and disrupted cardiovascular patterning. We report monozygotic twins concordant for 22q11.2 microdeletion but discordant for cardiovascular patterning. Both twins showed identical intracardiac defects including tetralogy of Fallot with pulmonary atresia. Nevertheless, their great vessel patternings were variable. These twins show that the mispatterning of the great vessels may not correlate with intracardiac morphogenesis. The discordant development of the great vessels, especially in the pulmonary vascular system, has clinical significance for prognosis. The phenotypic variability of cardiovascular anomalies seen in 22q11 microdeletion cannot be explained on the basis of genotypic difference.     

筛查染色体22q11.2缺失综合征在先天性心血管畸形中的意义

染色体22q11.2缺失综合征(22q111DS)又称DiGeorge综合征、腭-心-面综合征,临床表现极具多样性,可累及心血管、免疫系统、面容、内分泌系统,甚至语言发育、精神等多方面.荧光原位杂交能够检测到染色体22q11.2缺失.目前国内对本病认识尚不足,尚未建立规范的临床筛查体系,确诊率亦低.已报道的22q11D...     

筛查染色体22q11.2缺失综合征在先天性心血管畸形中的意义

染色体22q11.2缺失综合征(22q111DS)又称DiGeorge综合征、腭-心-面综合征,临床表现极具多样性,可累及心血管、免疫系统、面容、内分泌系统,甚至语言发育、精神等多方面.荧光原位杂交能够检测到染色体22q11.2缺失.目前国内对本病认识尚不足,尚未建立规范的临床筛查体系,确诊率亦低.已报道的22q11DS病例中,先天性心血管畸形尤其是圆锥干畸形和主动脉弓畸形发生率很高,也最确切.该文拟综述22q11DS,并分析如何在临床工作中从心血管畸形入手早期发现22q11DS,从而早期干预治疗、综合评估、长期随访及遗传咨询,提高患者及后代生活质量.     

Chromosome 22q11.2 microdeletion syndrome

Chromosome 22q11.2 microdeletion syndrome is the most common microdeletion syndrome in humans. It involves the loss of genetic material on the short arm of one of the chromosome 22 alleles. Until advanced testing was available, this syndrome was known by various names including DiGeorge syndrome and velo-cardio-facial syndrome. This syndrome has a varied presentation with significant abnormalities including congenital heart disease, hypocalcemia, immunologic deficiencies, learning disabilities, and behavioral problems. A multidisciplinary approach is required to diagnose and manage the varied manifestations.     

Pulmonary Atresia with Intact Ventricular Septum and Major Aortopulmonary Collaterals: Association with Deletion 22q11.2

We describe the first association of pulmonary atresia, intact ventricular septum, and absent central pulmonary arteries with deletion 22q11.2. The pulmonary blood flow was derived from major aortopulmonary collaterals. The role of the deletion in pulmonary arborization is discussed.     

Three- and Four-Dimensional Ultrasound in the Diagnosis of Fetal Tetralogy of Fallot With Absent Pulmonary Valve and Microdeletion 22q11

Tetralogy of Fallot (TOF) with concomitant absent pulmonary valve syndrome (APVS) constitutes a rare prenatal condition characterized by rudimentary cusps of the pulmonary valve, pulmonary regurgitation, and a variable degree of dilatation of the main and branch pulmonary arteries. Although early prenatal diagnosis of this complex malformation is feasible, the antenatal course of affected fetuses clearly depends on the presence of associated structural (absence of the ductus venosus) and chromosomal anomalies (microdeletion 22q11, DiGeorge syndrome). Postnatally, the outcome is closely related to the degree of airway obstruction and subsequent bronchomalacia. We describe the beneficial contribution of three- and four-dimensional ultrasound in establishing the diagnosis of TOF-APVS in a fetus at age 22 gestational weeks.