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     

Facial features in children with the 22q11 deletion syndrome

AIM: To find a pattern of the most typical facial features in children with the 22q11 deletion syndrome, which could serve as an aid in identifying patients with the syndrome. METHODS: In 80 children and adolescents with the 22q11 deletion syndrome, three investigators evaluated the facial features separately using frontal and profile photographs. A patient was considered to have a given feature if at least two of the evaluators agreed. RESULTS: The most common facial features found in at least 50% of the patients were malar flatness, fullness of eyelids (hooded eyelids), broad nasal bridge/tubular nose, broad/round nasal tip, round ears, thick/overfolded helix and slightly low-set ears. These were also the most common features when all agreed, although a considerable variation in the assessment by the three evaluators was observed. CONCLUSIONS: The 22q11 deletion syndrome is a differential diagnosis in children with a variety of symptoms and signs including congenital malformations, developmental delay and speech abnormalities. Almost all children with the syndrome show a characteristic pattern of minor facial variants, which can be difficult to recognise, unless specifically looked for. A systematic evaluation of facial features might help in identifying children with the syndrome.     

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.     

Presenting phenotype in 100 children with the 22q11 deletion syndrome

The aim of this study was to investigate and describe the presenting phenotype of children with the 22q11 deletion syndrome and to describe common clinical features that could serve as guidelines in the clinical diagnostic process preceding genetic testing. A hospital-based study of 100 consecutive children and adolescents with 22q11 deletion was initiated. The patients were divided into two groups according to age at diagnosis: before or after 2 years of age. Clinical features were grouped into a core set of eight features: cardiac defects, non-visible/hypoplastic thymus or infection problems, hypocalcaemia, feeding difficulties, cleft palate/speech-language impairment, developmental delay/learning difficulties, characteristic dysmorphic features and other malformations and deformities. The median age at diagnosis was 6.7 years. Of all patients, 26% were diagnosed in infancy and 92% had a congenital cardiac defect, whereas 54% of those diagnosed later had a cardiac defect. A cleft palate was present in 25 cases and 44 had some other malformation or deformity. All presented with a combination of many of the core features. Of those diagnosed after 2 years of age, the majority presented with speech-language impairment, developmental delay or learning difficulties and recurrent infections. Characteristic mild dysmorphic features were noticed in all children. Conclusion: In spite of variable clinical expression, children with 22q11 deletion share a number of major features and have a characteristic phenotype. A high proportion have no cardiac defect and hence a risk of diagnostic delay. Increased awareness and knowledge among general paediatricians and other specialists who meet these children early in life is needed to reduce the diagnostic delay.     

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］     

22q11缺失综合征的研究进展

22q11缺失综合征(22q11DS)是最常见的染色体微缺失疾病.它的临床表现复杂多样,可表现为心脏、颅面、四肢、免疫和内分泌等多系统的异常.其患病率约为1/2500～1/4000.22q11缺失的发病机制是缺失区域内的低拷贝重复序列之间的不对称重组,TBX1基因等被认为是其相关致病基因.     

22q11缺失综合征的研究进展

22q11缺失综合征(22q11DS)是最常见的染色体微缺失疾病.它的临床表现复杂多样,可表现为心脏、颅面、四肢、免疫和内分泌等多系统的异常.其患病率约为1/2500～1/4000.22q11缺失的发病机制是缺失区域内的低拷贝重复序列之间的不对称重组,TBX1基因等被认为是其相关致病基因.     

22q11缺失综合征的研究进展

22q11缺失综合征(22q11DS)是最常见的染色体微缺失疾病.它的临床表现复杂多样,可表现为心脏、颅面、四肢、免疫和内分泌等多系统的异常.其患病率约为1/2500～1/4000.22q11缺失的发病机制是缺失区域内的低拷贝重复序列之间的不对称重组,TBX1基因等被认为是其相关致病基因.     

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...     

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.     

Symptomatic anal anomalies in chromosome 22q11 deletion syndrome: a report of three patients

Deletion of chromosome 22q11 is a common genetic condition with varying clinical presentation ranging from neonatal fatality to patients whose presentation to medical services will be prompted after a few years by speech delay or mild developmental concerns. While most published data relating to patients with 22q11 deletions has focused on the “classical” presentation of the condition with cardiac manifestations, hypocalcaemia and velopharyngeal insufficiency, a much wider range of clinical presentations can characterise this syndrome. Anal anomalies, comprising imperforate anus and symptomatic anal stenosis, are a rarely described presentation of this multisystem disorder. In this report we document three patients presenting to paediatric services with symptoms attributed initially to symptomatic anal stenosis/atresia.     

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...     

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     

Annotation: velo-cardio-facial syndrome

BACKGROUND: Velo-cardio-facial syndrome (VCFS), the most frequent known interstitial deletion identified in man, is associated with chromosomal microdeletions in the q11 band of chromosome 22. Individuals with VCFS are reported to have a characteristic behavioural phenotype with high rates of behavioural, psychiatric, neuropsychological and linguistic disorders. METHODS: A selective literature review was undertaken. RESULTS: Children and adults with VCFS have high rates of behavioural, psychiatric and communication disorders. While VCFS children have high rates of ADHD, anxiety and affective disorders, adults have high rates of psychotic disorders, particularly schizophrenia. In addition, the presence of a chromosome 22q11 deletion is associated with specific neuropsychological and neuroanatomical abnormalities. CONCLUSIONS: People with VCFS have a characteristic behavioural phenotype with high rates of behavioural, psychiatric, neuropsychological and communication disorders. Early diagnosis and treatment within a multidisciplinary framework is of paramount importance for VCFS individuals as this will have a major effect in determining the long-term outcome in affected individuals. Longitudinal studies of VCFS children are currently under way to identify precursor symptoms and areas of dysfunction which precede the later development of major psychiatric disorder. Identification of such prodromal features in VCFS may have enormous implications for the clinical management of major psychiatric disorder in VCFS and in the wider population.     

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.     

多重连接探针扩增技术在先天性心脏病22q11微缺失/微重复综合征诊断中的应用

目的染色体22q11区域基因拷贝数异常是先天性心脏病(CHD)的遗传病因之一,由其引起的CHD预后不良。该研究主要探讨多重连接探针扩增技术用于CHD22q11微缺失或微重复遗传病因诊断的实用性,并了解22q11微缺失或微重复在CHD中的发生情况。方法选择25个位于染色体22q11低重复拷贝序列A-H区域内、7个位于其周围(CES、22q13)和16个位于4、8、10、17号染色体上的基因位点共计48个探针组成多重连接探针,对181例外科手术前的CHD儿童和14例严重CHD或包括CHD的多发性畸形胎儿进行了22q11微缺失或微重复的检测,并进行了染色体核型分析。结果195例患儿中,共检出22q11微缺失者7例(LCRA-D区6例,LCRA-C区1例),22q11微重复1例(LCRB-D区),涉及的CHD类型包括室间隔缺损、房室间隔缺损、肺动脉狭窄和法洛四联征。同时染色体核型分析还发现了6例异常:1例21q部分缺失[46,XY,21q-],1例嵌合性8-三体[47,XY,+8/46,XY(1∶2)],4例21-三体。其中1例21-三体与22q11微重复同时存在。结论染色体22q11区域高密度多重连接探针检测技术能快速、灵敏、精确定位诊断染色体22q11区域基因拷贝数异常,适合于CHD的遗传学诊断;此外,22q11微缺失或微重复引起的CHD类型多种多样,建议所有CHD患者应常规进行遗传学检测。     

多重连接探针扩增技术在先天性心脏病22q11微缺失/微重复综合征诊断中的应用

目的:染色体22q11区域基因拷贝数异常是先天性心脏病（CHD）的遗传病因之一,由其引起的CHD预后不良。该研究主要探讨多重连接探针扩增技术用于CHD 22q11微缺失或微重复遗传病因诊断的实用性,并了解22q11微缺失或微重复在CHD中的发生情况。方法:选择25个位于染色体22q11低重复拷贝序列A-H区域内、7个位于其周围（CES、22q13）和16个位于4、8、10、17号染色体上的基因位点共计48个探针组成多重连接探针,对181例外科手术前的CHD儿童和14例严重CHD或包括CHD的多发性畸形胎儿进行了22q11微缺失或微重复的检测,并进行了染色体核型分析。结果:195例患儿中,共检出22q11微缺失者7例（LCR A-D区6例,LCR A-C区1例）,22q11微重复1例（LCR B-D区）,涉及的CHD类型包括室间隔缺损、房室间隔缺损、肺动脉狭窄和法洛四联征。同时染色体核型分析还发现了6例异常：1例21q部分缺失［46,XY,21q-］,1例嵌合性8-三体［47,XY,+8/46,XY（1∶2）］,4例21-三体。其中1例21-三体与22q11微重复同时存在。结论:染色体22q11区域高密度多重连接探针检测技术能快速、灵敏、精确定位诊断染色体22q11区域基因拷贝数异常,适合于CHD的遗传学诊断;此外,22q11微缺失或微重复引起的CHD类型多种多样,建议所有CHD患者应常规进行遗传学检测。［中国当代儿科杂志,2009,11（11）：892-896］