Prevalence of the microdeletion 22q11 in newborn infants with congenital conotruncal cardiac anomalies

Conotruncal malformations account for about 50% of congenital heart defects diagnosed in newborns. We studied prospectively 104 patients admitted in our neonatal intensive care unit for conotruncal defects by fluorescence in situ hybridization to estimate the prevalence of the interstitial deletion in this category of congenital heart disease. Cardiac phenotypes were: truncus arteriosus (17), interrupted aortic arch (18), tetralogy of Fallot with or without pulmonary valve atresia (55), tetralogy of Fallot with absent pulmonary valves (5), ventricular septal defect with malalignment of the conal septum (9). We discovered a microdeletion 22q11 at loci D22S39 or D22S398 in 50 newborns (48%). The prevalence of this microdeletion in different groups of conotruncal defects was: truncus arteriosus 7/17, interrupted aortic arch 16/18, tetralogy of Fallot 19/55, absent pulmonary valves 2/5, and ventricular septal defect 6/9 respectively. Only two patients without any clinical or biological feature of the so called CATCH22 syndrome exhibited the deletion. Parental studies confirmed that the deletion occurred de novo in 47/50 cases (three parental microdeletions). On the other hand, recurrence of conotruncal heart defects in families of “undeleted probands” was higher than expected (13%). Conclusion In 50/104 newborns with conotruncal defects, an interstitial deletion 22q11 was found. Fluorescence in Situ Hybridization should be performed in newborn infants with conotruncal defect and at least one additional manifestation of the CATCH22 phenotype. Received: 11 February 1998 / Accepted: 16 March 1998     

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...     

单纯性圆锥动脉干畸形患者染色体22q11.2微缺失的研究

目的：心血管畸形是22q11.2缺失综合征常见的临床表现,随着研究的深入,该综合征发生率逐渐提高。该文就单纯性心脏圆锥动脉干畸形患者染色体22q11.2微缺失发生率进行研究。方法：对24例单纯型圆锥动脉干畸形患者,包括2例永存动脉干,5例肺动脉闭锁/室间隔缺损,13例法洛四联症,4例右室双出口进行22q11.2内位点DNA探针荧光原位杂交（FISH）检测。结果：24例单纯性圆锥动脉干畸形患者中仅1例患者有22q11.2缺失,发生率为4.2%,低于以往报道。结论：尽管22q11.2缺失在伴其他系统异常的心脏圆锥动脉干畸形患者中较常见,单纯性圆锥动脉干畸形患者很少发现该缺失。［中国当代儿科杂志,2009,11（1）：25-28］     

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     

C1-2 vertebral anomalies in 22q11.2 microdeletion syndrome

BACKGROUND: Chromosome 22q11.2 microdeletion syndrome (22q11DS) is characterized by cleft palate, cardiac anomalies, characteristic facies, high prevalence of skeletal anomalies and learning disability. OBJECTIVE: To evaluate the prevalence of craniovertebral junction anomalies in children with 22q11DS and compare these findings to those in nonsyndromic children with velopharyngeal insufficiency (VPI). MATERIALS AND METHODS: Sequential CT scans performed for presurgical carotid assessment in 76 children (45 children positive for chromosome 22q11.2 deletion and 31 negative for the deletion) with VPI were retrospectively evaluated for assessment of C1-2 anomalies. RESULTS: C1-2 vertebral anomalies, specifically midline C1 defects, uptilted or upswept posterior elements of C2 and fusions of C2-3, were nearly universal in our cohort of 22q11DS patients with VPI. They were strikingly absent in the majority of non-22q11DS patients with VPI. CONCLUSION: C1-2 vertebral anomalies, particularly those listed above, are important radiographic markers for 22q11DS.     

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...     

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     

Chromosome 22q11 Deletions in Patients with Conotruncal Heart Defects

We performed this study to determine the frequency of 22q11 deletions and associated phenotypic features and abnormalities in conotruncal heart defects. Sixty-one patients with conotruncal heart defects, including tetralogy of Fallot (TOF; n = 32), pulmonary atresia/ventricular septal defect (PAVSD; n = 12), double-outlet right ventricle (DORV; n = 5), transposition of the great arteries (TGA; n = 4 ), truncus arteriosus (TA; n = 4), subpulmonary ventricular septal defect (SPVSD; n = 3), and interrupted aortic arch (IAA; n = 1), were enrolled in this study and screened for 22q11 deletions by the fluorescence in situ hybridization technique. Phenotypic features and associated abnormalities, including submucosal cleft palate, abnormal facies, square nose, nasal voice, abnormal ears, long and slender fingers, delayed development, mental retardation, delayed growth, short stature, and hypocalcemia, were examined in these patients. Nine of 61 patients (14.8%) had 22q11 deletions, including 100% of IAA, 50% of TA, 33.3% of SPVSD, 33.3% of PAVSD, and 3.1% of TOF. Deletions were not detected in DORV and TGA. In all patients with 22q11 deletions, ≥1 phenotypic features or associated abnormalities were observed. A subgroup of patients with IAA, TA, SPVSD, and PAVSD associated with phenotypic features or abnormalities warrants evaluation for the presence of 22q11 deletions.     

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.     

Chromosome 22 microdeletion by F.I.S.H. in isolated congenital heart disease

Objective To analyze the frequency of del22q11.2 in non-syndromic CHDs using classical cytogenetics and Fluorescence In Situ Hybridization (FISH) technique in Indian population. Methods 105 prospective cases which included 6 families with isolated, non-syndromic cardiac defects were analyzed clinically by a cardiologist and a geneticist. The cases were then subjected to karyotypic (classical cytogenetics) as well as FISH analysis. The efficacy of FISH technique was compared with inference drawn from classical cytogenetics. Results Karyotypic analysis of all the 105 patients revealed a normal chromosomal complement. Microdeletion 22q11.2 was observed in six patients (5.71%) by FISH studies. FISH studies were also performed on the parents of these six patients who revealed a normal chromosome 22. No correlation was found between clinical features (mild or unspecific) with 22q11.2 microdeletion. Conclusion The testing for microdeletion 22q11.2 in isolated non-syndromic patients using FISH technique is mandatory even when mild/unspecific extracardiac abnormalities are seen in the patients.     

Variation in prevalence of chromosome 22q11 deletion in subtypes of conotruncal defect in 254 children

Aim: To determine the frequency of chromosomal aberrations particularly 22q11 deletion in Indian children ≤2 years with different types of conotruncal malformations and their association with abnormal aortic arch. Additionally, extracardiac features were also studied. Methods: Conventional cytogenetic and fluorescence in situ hybridization analyses were performed in 254 patients with conotruncal defects. Multivariable logistic regression analysis was performed to ascertain extracardiac features helpful in identifying high‐risk patients with deletion. Results: Chromosomal abnormalities were identified in 52 (21%) children, of whom 49 (94%) showed 22q11 deletion and 3 (6%) had abnormalities of chromosome 6, 2 and X. None of the 11/254 children with tetralogy of Fallot with absent pulmonary valve showed deletion. The association of 22q11 deletion with right sidedness of the aortic arch varied with the type of conotruncal defect. The eight extracardiac features in combination showed 93.5% agreement with the presence of deletion. Conclusion: The extracardiac features along with specific type of conotruncal defect and associated cardiovascular anomaly should alert the clinician for 22q11 deletion testing. However, if deletion analysis is not possible, specific extracardiac features (six dysmorphic facial features, thin long fingers and hypocalcemia) can help to identify an increased risk of 22q11 deletion in patients with conotruncal defect.     

Clinical characteristics of children with hypoparathyroidism due to 22q11.2 microdeletion

The phenotypes of chromosomal 22q11.2 microdeletion are quite variable among individuals and hypoparathyroidism (HP) constitutes a definite portion of the clinical spectrum. For the correct diagnosis and pertinent follow up of the HP children due to del22q11.2, we tried to delineate the clinical characteristics of such patients. By employing fluorescence in situ hybridization (FISH) to all the patients diagnosed as HP in our clinic, ten possessed the 22q11.2 microdeletion. Among them, the incidence of cardiac defect (5/10), recurrent infection (1/10) and cleft palate (1/10) was modest. Additionally, seven of them had been diagnosed as HP during the infantile period, when their facial abnormality and intellectual problem had not become evident. Notably, two patients were complicated by Graves disease, while the association of idiopathic thrombocytopenic purpura was also observed in two girls. Conclusion HP due to del22q11.2 may be misdiagnosed as idiopathic, especially in an infant who lacks apparent complications like cardiac anomaly. They should be closely followed up for auto-immune complications. Received: 11 February 1997 and in revised form: 20 June 1997 / Accepted: 6 July 1997     

Frequency of a 22q11 deletion in patients with conotruncal cardiac malformations: A prospective study

Recent molecular studies have revealed that a 22q11 deletion is frequently detected in DiGeorge syndrome (DGS), velo-cardio-facial syndrome (VCFS), and conotruncal anomaly face syndrome (CTAFS). As one of the major clinical manifestations in these three syndromes is conotruncal cardiac malformation, we prospectively studied the frequency of a 22q11 deletion in a group of patients with conotruncal cardiac malformation. Fluorescence in situ hybridization (FISH) analyses using N25 (D22S75) DiGeorge Chromosome Region probe were performed on 64 patients with conotruncal cardiac malformation, who visited our clinic from October 1993 to January 1994. Of the 64 patients studied, a 22q11 deletion was detected in 5 patients (7.8%): 3 out of 30 patients with tetralogy of Fallot, one of three with interruption of the aortic arch, and one hemitruncus patient. No deletion was found in 16 patients with complete transposition of the great arteries, 8 with double outlet right ventricle and 2 with aortopulmonary window. In these five patients with 22q11 deletion, patient 1 was clinically diagnosed as having DGS, patients 2 and 3 had CTAFS, and patient 4 had VCFS. Patient 5 could not be dysmorphologically evaluated. It was noteworthy that all patients with a 22q11 deletion, except a non-evaluated patient, had some symptoms of syndromes DGS, CTAFS or VCFS, and that we failed to identify a non-syndromic 22q11 deletion positive patients in the present series of 64 patients.Conclusion This study suggests that it is advisable to bear 22q11 deletion in mind when a patient with conotruncal cardiac anomalies has some other features of DGS, VCFS or CTAFS.     

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.     

FISH investigation of 22q11.2 deletion in patients with immunodeficiency and/or cardiac abnormalities

DiGeorge anomaly/velocardiofacial syndrome (DG/VCFS), called 22q11.2 deletion syndrome in general, is the most common chromosomal deletion syndrome found in humans. Typical facial features, palatal defects, conotruncal abnormalities of the heart, aplasia/hypoplasia of the parathyroid glands and of thymus are characteristics of this syndrome. Deletions of chromosome 22q11.2 (del22q11.2) are the leading causes of DG7VCFS. We report on a systematic search by fluorescence in situ hybridization (FISH) for deletions of chromosomes 22q11.2 in patients with a clinical suspicion or diagnosis of DG/VCFS. Using FISH we studied a series of 43 patients with suspected DG/VCFS. In this study, a total of 43 patients were investigated for the presence of a 22q11.2 deletion over a two-year period. Del22q11.2 was detected in 5 of the 43 patients tested. All patients with deletion had hypocalcemia, 80% had cardiac defects, 40% had facial dysmorphism, 40% had immunodeficiency , and 20% had otolaryngeal abnormalities. Chromosome 22q11.2 deletion is a relatively common condition and is readily diagnosed by FISH. We suggest that FISH analysis of 22q11.2 deletion should be performed in the presence of combined of hypocalcemia and congenital cardiac malformations, with or without any characteristics of the disease. This may facilitate an early diagnosis in such patients.     

Gene expression in pediatric heart disease with emphasis on conotruncal defects

Developmental abnormalities of the heart are the underlying cause of many congenital heart malformations. The embryological development of the integrated cardiovascular tissue is the result of multiple tissue and cell-to-cell interactions involving temporal and spatial events under genetic control. Recent technological advances, like microarray analysis of gene expression, are providing new tools to aid in deciphering the complex networks of gene expression that regulate cardiac development. Here, we review our current understanding of the genetics of congenital heart disorders with emphasis on gene expression studies and report preliminary data from infants with conotruncal defects. We report our microarray analysis showing over- and underexpression of individual genes and gene network interactions from dysplastic pulmonic tissue from two infants with tetralogy of Fallot compared with normal pulmonic tissue from an unaffected control infant.     

A child with chromosome 22q11.2 deletion syndrome and a bilobed gallbladder

We present an 11-year-old girl with a chromosome 22q11.2 microdeletion, velocardiofacial syndrome (VCFS), and a bilobed gallbladder as an incidental finding on abdominal sonography. The finding was confirmed by magnetic resonance cholangiopancreatography (MRCP).This is the first report of a gallbladder anomaly associated with a chromosome 22q11.2 deletion and the second report of a biliary tract anomaly associated with a mutation in the chromosome 22q11 region. We suggest that close attention be paid to the anatomy of the biliary tree in patients with mutations in the chromosome 22q11 region. Further study is warranted to determine the range and prevalence of biliary tract anomalies in this population.