22q11.2 deletion syndrome and congenital heart disease

The 22q11.2 deletion syndrome has an estimated prevalence of 1 in 4–6,000 livebirths. The phenotype varies widely; the most common features include: facial dysmorphia, hypocalcemia, palate and speech disorders, feeding and gastrointestinal disorders, immunodeficiency, recurrent infections, neurodevelopmental and psychiatric disorders, and congenital heart disease. Approximately 60–80% of patients have a cardiac malformation most commonly including a subset of conotruncal defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B), conoventricular and/or atrial septal defects, and aortic arch anomalies. Cardiac patients with a 22q11.2 deletion do not generally experience higher mortality upon surgical intervention but suffer more peri‐operative complications than their non‐syndromic counterparts. New guidelines suggest screening for a 22q11.2 deletion in the patient with tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, conoventricular septal defects as well as those with an isolated aortic arch anomaly. Early identification of a 22q11.2 deletion in the neonate or infant when other syndromic features may not be apparent allows for timely parental screening for reproductive counseling and anticipatory evaluation of cardiac and noncardiac features. Screening the at‐risk child or adult allows for important age‐specific clinical, neurodevelopmental, psychiatric, and reproductive issues to be addressed.     

Size of 22q deletions in four previously reported patients with conotruncal anomaly face syndrome

Conotruncal anomaly face syndrome (CTAFS) was distinguished from velo-cardio-facial syndrome (VCFS) in a bind study, yet shared the finding of 22q11.2 deletions. This work has been extended to show that the 22q11.2 deletions in CTAFS greatly overlap those found in VCFS and many DiGeorge patients. The reason for dissimilar phenotypes with apparently similar 22q11.2 deletions is not yet known.     

Velo-cardio-facial phenotype and deletion of 22q11.2 in Hungarian children

Velo-cardio-facial syndrome is a developmental disorder characterized by heart defects, specific facial features, cleft palate and learning disability. Most patients have a 3-Mb deletion in chromosomal region 22q11.2. This microdeletion has also been found in patients with isolated conotruncal malformations. Although no significant ethnic variability has been reported in the frequency 22q11.2 deletions, some recent studies question the high frequency of this as the underlying cause of velo-cardio-facial syndrome in Anglo-American populations. A screening program was initiated, including a detailed clinical assessment, followed by fluorescence in situ hybridization studies for microdeletion 22q11.2 in 24 children with congenital cardiac malformations referred consecutively to our genetics clinic. We found a high ratio of associated findings including cleft palate and developmental delay in our patient group. The clinical diagnosis of velo-cardio-facial syndrome was established in 8 patients. However, the common deletion was detected in only two children. We conclude that, although the 'velo-cardio-facial phenotype' appears to be common in Hungarian children with congenital cardiac malformations, many patients may have different etiologies other than del(22)(q11.2).     

Laryngeal atresia type III (glottic web) with 22q11.2 microdeletion: Report of three patients

The clinical manifestations of patients with a 22q11.2 deletion are highly variable and mainly include developmental defects of structures derived from the third and fourth pharyngeal pouches. Laryngeal atresia has occasionally been reported in DiGeorge syndrome as well as in velo-cardio-facial syndrome. We observed three patients with type III laryngeal atresia (glottic web) and 22q11.2 microdeletion. One patient showed a “classical” 22q11.2 deletion phenotype with clinical overlap with DiGeorge and velo-cardio-facial syndromes. However, the pattern of congenital anomalies of the two others was less specific, heart defects and minor anomalies being the only outstanding clinical manifestations suspicious for monosomy 22q11.2. Our findings suggest that laryngeal atresia represents an additional malformation which should prompt investigation of 22q11.2 deletion, especially in combination with congenital heart defects. Am. J. Med. Genet. 70:130–133, 1997. © 1997 Wiley-Liss, Inc.     

Nasal dimple as part of the 22q11.2 deletion syndrome

The phenotype of the 22q11.2 microdeletion syndrome is quite variable. We describe 2 patients with a 22q11.2 deletion and a dimpled nasal tip, which, we suggest can be the extreme of the broad or bulbous nose commonly found in the 22q11.2 deletion syndrome, and should not be confused with the more severe nasal abnormalities seen in frontonasal dysplasia. Am. J. Med. Genet. 69:290–292, 1997. © 1997 Wiley-Liss, Inc.     

Chromosome 22q11.2 deletion syndrome in African-American patients: a diagnostic challenge

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with numerous and variable clinical manifestations including conotruncal heart abnormalities, palatal anomalies, hypoparathyroidism, immune deficiency, and cognitive deficits. The clinical suspicion of this syndrome is often heightened by the presence of characteristic facial features. A previous report highlighted the under‐diagnosis of this condition in African Americans, thought to be related to a paucity of typical facial features. We ascertained the largest cohort (n = 50) of African‐American individuals with 22q11DS reported thus far, across five genetics centers in the United States and report on their facial and other phenotypic features. About of our cohort has at least one dysmorphic facial feature. Auricular abnormalities, especially small ears, are the most common dysmorphic facial feature followed by nasal and ocular abnormalities. Skeletal findings are seen in about 2/3 of our cohort, higher than the typical frequency reported in 22q11DS. Cardiac anomalies, developmental delay, and palatal abnormalities are seen at a lower frequency in our cohort. Thus, it is evident that the features traditionally associated with 22q11DS are difficult to recognize in African‐American individuals with this syndrome, due to both altered frequencies of major anomalies and a non‐classic facial appearance. Therefore, a high index of suspicion is needed to recognize 22q11DS in African‐American individuals. © 2011 Wiley‐Liss, Inc.     

Neural tube defects and deletions of 22q11

Recently we reported on three unrelated children with neural tube defects (NTDs) and deletion of 22q11. Two of these children have velo-cardio-facial syndrome and the third DiGeorge sequence. Thus, NTDs appear to be part of the clinical picture due to 22q11 deletion. To further explore this association and to clarify what findings should prompt testing for this deletion in individuals with NTDs, we have reviewed all patients in a large regional spina bifida clinic population. Two hundred ninety-five patients with NTDs were identified by chart review. Charts were reviewed for congenital heart defect, minor facial anomalies, thymic hypoplasia, cleft lip and/or palate, hypocalcemia, and a family history of a NTD, congenital heart defect, or cleft lip and/or palate. A total of 22 patients was identified with NTD and at least one more clinical trait and/or a positive family history. Sixteen children received cytogenetic and molecular testing including the three previously reported patients diagnosed with a 22q11 deletion. Results of cytogenetic and molecular studies of the remaining 13 patients were normal. Deletion of 22q11 is an infrequent cause of NTDs. We recommend testing for the 22q11 deletion in patients with a NTD and conotruncal heart defect. Testing should be considered in patients with a NTD who have a first degree relative with a conotruncal heart defect or have additional clinical findings of VCFS or DGS. © 1996 Wiley-Liss, Inc.     

Submicroscopic deletions at 22q11.2: Variability of the clinical picture and delineation of a commonly deleted region

DiGeorge anomaly (DGA) and velo-cardiofacial syndrome (VCFS) are frequently associated with monosomy of chromosome region 22q11. Most patients have a submicroscopic deletion, recently estimated to be at least 1–2 Mb. It is not clear whether individuals who present with only some of the features of these conditions have the deletion, and if so, whether the size of the deletion varies from those with more classic phenotypes. We have used fluorescence in situ hybridization (FISH) to assess the deletion status of 85 individuals referred to us for molecular analysis, with a wide range of DGA-like or VCFS-like clinical features. The test probe used was the cosmid sc11.1, which detects two loci about 2 Mb apart in 22q11.2. Twenty-four patients carried the deletion. Of the deleted patients, most had classic DGA or VCFS phenotypes, but 6 deleted patients had mild phenotypes, including 2 with minor facial anomalies and velopharyngeal incompetence as the only presenting signs. Despite the great phenotypic variability among the deleted patients, none had a deletion smaller than the 2-Mb region defined by sc11.1 Smaller deletions were not detected in patients with particularly suggestive phenotypes who were not deleted for sc11.1, even when tested with two other probes from the DGA/VCFS region. © 1995 Wiley-Liss, Inc.     

No justification of routine screening for 22q11 deletions in patients with overt cleft palate

The velo-cardio-facial syndrome (VCFS), caused by a submicroscopic deletion of chromosome 22q11, is the most common syndrome that has palatal anomalies as a major feature. A possible strategy for early detection of VCFS is routine screening for 22q11 deletions in all infants with cleft palate (CP). The purpose of this study was to evaluate whether this strategy is preferable to testing on clinical suspicion. At the Nijmegen Cleft Palate Craniofacial Center, 58 new patients with overt CP were routinely tested, using fluorescence in situ hybridization (FISH), for a 22q11 deletion. One deletion was identified in a newborn girl with an overt CP who was clinically not suspected of having VCFS. Based on this study (n = 45) and the literature (n = 54), the prevalence of 22q11 deletions among children with CP, but without any other symptoms of VCFS, is estimated to be one in 99. We take the view that this figure is rather low and that early discovery will rarely have significant clinical or genetic consequences. Because CP patients remain under medical attention, almost all of the infants with isolated CP and VCFS will be recognized as having the syndrome at a later age when additional features have developed. Therefore, we conclude that routine FISH testing for 22q11 deletions in infants with overt CP is not indicated, provided clinical follow-up is guaranteed.     

Wilms tumor in a patient with 22q11.2 microdeletion

22q11.2 deletion syndrome is the most common microdeletion syndrome. Wilms tumor is one of the most common solid tumors in childhood yet 22q11.2 deletion and Wilms tumor only once have been reported in the same patient. Here we describe a young patient with subtle clinical findings suggestive of 22q11.2 at the time of diagnosis who subsequently developed Wilms tumor. We assert the importance of a low threshold for screening for 22q11.2 deletion and the associated phenotypes and maintaining vigilance in screening for common primary malignancies in patients with known 22q11.2 deletion.     

先天性心脏病患儿22q11微缺失的定量荧光聚合酶链反应检测

目的 建立对22q11染色体微缺失进行快速批量检测的技术,用于非综合征先天性心脏病患 者染色体微缺失情况的检测.方法 采用定量荧光聚合酶链反应(quantitative fluorescent polymerase chain reaction,QF-PCR)法和8个短串联重复(short tandem repeat,STR)多态标记对79例中国汉族非综合征先天性心脏病(congenital heart defects,CHD)患者和84名正常对照者进行染色体22q11微缺失的检测.结果 缺失区域的STR标记在受检的非综合征型先天性心脏病患者中的平均杂合率为0.76,在正常对照人群中为0.79.在受检的1例法洛氏四联症患儿中检测到22q11微缺失(1.3%),经多重连接依赖探针扩增(multiplex ligation-dependent probe amplification,MLPA)技术验证结果正确.结论 采用QF-PCR法,可以高效批量地对22q11染色体微缺失进行筛查.     

微滴数字PCR技术检测先天性心脏病患儿染色体22q11．2区段微缺失CSCD

目的探索一种检测22qii．2微缺失综合征的新方法。方法针对22q11．2微缺失综合征特异缺失区内的TBX1基因和内参基因RPP30设计引物和探针,采用微滴数字PCR（dropletdigitalPCR,ddPCR）的方法计算TBX1／RPP30的比值,检测22q11．2区段微缺失。结果通过数字PCR方法计算TBX1／尺PP30的比值检测22q11．2微缺失综合征,检出3例微阵列比较基因组杂交检测结果为22q11．2微缺失综合征阳性的样本。在14例临床诊断为先天性心脏病的患儿中检测出2例22q11．2微缺失阳性样本。结论微滴数字PCR可以准确检测出22q11．2区段微缺失,可提供一种快速、经济的检测先天性心脏病相关染色体22q11．2微缺失综合征的方法。     

Microsatellite DNA markers detects 95% of chromosome 22q11 deletions

Cono-truncal cardiac malformations account for some 50% of congenital heart defects in newborn infants. Recently, hemizygosity for chromosome 22q11.2 was reported in patients with the DiGeorge/Velo-cardio-facial syndromes (DGS/VCFS) and causally related disorders. We have explored the potential use of microsatellite DNA markers for rapid detection of 22q11 deletions in 19 newborn infants referred for cono-truncal heart malformations with associated DGS/VCFS anomalies. A failure of parental inheritance was documented in 84.2% of cases (16/19). PCR-based genotyping using microsatellite DNA markers located within the commonly deleted region allowed us either to confirm or reject a 22q11 microdeletion in 94.3% of cases (18/19) within 24 hours. This test is now currently performed in the infants referred to us for a cono-truncal heart malformation as a first intention screening for 22q11 microdeletion. Am. J. Med. Genet. 68:182–184, 1997 © 1997 Wiley-Liss, Inc.     

Under-recognition of 22q11.2 deletion in adult Chinese patients with conotruncal anomalies: Implications in transitional care

22q11.2 deletion syndrome (22q11.2DS) is a multi-systemic disorder with high phenotypic variability. Under-diagnosis in adults is common and recognition of facial dysmorphic features can be affected by age and ethnicity. This study aims to determine the prevalence of undiagnosed 22q11.2DS in adult Chinese patients with conotruncal anomalies and to delineate their facial dysmorphisms and extra-cardiac manifestations. We recruited consecutively 156 patients with conotruncal anomalies in an adult congenital heart disease (CHD) clinic in Hong Kong and screened for 22q11.2DS using fluorescence-PCR and fluorescence in-situ hybridization. Assessment for dysmorphic features was performed by a cardiologist at initial screening and then by a clinical geneticist upon result disclosure. Clinical photographs were taken and childhood photographs collected. Eighteen patients (11.5%) were diagnosed with 22q11.2DS, translating into 1 previously unrecognized diagnosis of 22q11.2DS in every 10 adult patients with conotruncal anomalies. While dysmorphic features were detected by our clinical geneticist in all patients, only two-thirds were considered dysmorphic by our cardiologist upon first assessment. Evolution of facial dysmorphic features was noted with age. Extra-cardiac manifestations included velopharyngeal incompetence or cleft palate (44%), hypocalcemia (39%), neurodevelopmental anomalies (33%), thrombocytopenia (28%), psychiatric disorders (17%), epilepsy (17%) and hearing loss (17%). We conclude that under-diagnosis of 22q11.2DS in Chinese adults with conotruncal defects is common and facial dysmorphic features may not be reliably recognized in the setting of adult CHD clinic, referral for genetic evaluation and molecular testing for 22q11.2DS should be offered to patients with conotruncal defects.     

Expanding the fetal phenotype: Prenatal sonographic findings and perinatal outcomes in a cohort of patients with a confirmed 22q11.2 deletion syndrome

22q deletion syndrome (22q11.2DS) is most often correlated prenatally with congenital heart disease and or cleft palate. The extracardiac fetal phenotype associated with 22q11.2DS is not well described. We sought to review both the fetal cardiac and extracardiac findings associated with a cohort of cases ascertained prenatally, confirmed or suspected to have 22q11.2DS, born and cared for in one center. A retrospective chart review was performed on a total of 42 cases with confirmed 22q11.2DS to obtain prenatal findings, perinatal outcomes and diagnostic confirmation. The diagnosis was confirmed prenatally in 67% (28/42) and postnatally in 33% (14/42). The majority (81%) were associated with the standard LCR22A‐LCR22D deletion. 95% (40/42) of fetuses were prenatally diagnosed with congenital heart disease. Extracardiac findings were noted in 90% (38/42) of cases. Additional findings involved the central nervous system (38%), gastrointestinal (14%), genitourinary (16.6%), pulmonary (7%), skeletal (19%), facial dysmorphism (21%), small/hypoplastic thymus (26%), and polyhydramnios (30%). One patient was diagnosed prenatally with a bilateral cleft lip and cleft palate. No fetus was diagnosed with intrauterine growth restriction. The average gestational age at delivery was 38 weeks and average birth weight was 3,105 grams. Sixty‐two percentage were delivered vaginally and there were no fetal demises. A diagnosis of 22q11.2 deletion syndrome should be considered in all cases of prenatally diagnosed congenital heart disease, particularly when it is not isolated. Microarray is warranted in all cases of structural abnormalities diagnosed prenatally. Prenatal diagnosis of 22q11.2 syndrome can be used to counsel expectant parents regarding pregnancy outcome and guide neonatal management.