Cardiovascular anomalies are present in 80% of neonates with 22q11.2 deletion syndrome. Three genes in chromosome 22q11.2 (TBX1, CRKL, and ERK2) have been identified whose haploinsufficiency causes dysfunction of the neural crest cell and anterior heart field and anomalies of 22q11.2 deletion syndrome. The most common diseases are conotruncal anomalies, which include tetralogy of Fallot (TF), TF with pulmonary atresia, truncus arteriosus, and interrupted aortic arch. A high prevalence of the deletion is noted in patients with TF with absent pulmonary valve, TF associated with pulmonary atresia and major aortopulmonary collateral arteries, truncus arteriosus, and type B interruption of aortic arch. Right aortic arch, aberrant subclavian artery, cervical origin of the subclavian artery, crossing pulmonary arteries, and major aortopulmonary collateral arteries are frequently associated with cardiovascular anomalies associated with 22q11.2 deletion syndrome. Virtually every type of congenital heart defect has been described early in the context of a 22q11.2 deletion. In conclusion, conotruncal anomaly associated with aortic arch and ductus arteriosus anomalies should increase the suspicion of 22q11.2 deletion.
Congenital heart disease is present in about 80% of patients with chromosome 22q11.2 deletion syndrome (DS). Historically, DiGeorge syndrome, velocardiofacial syndrome (Shprintzen syndrome), and conotruncal anomaly face syndrome (Takao syndrome) were identified separately. However, most cases of these syndromes are caused by deletions within chromosome band 22q11.2. Developmentally, these syndromes are related to abnormalities of neural crest cells and second heart field. In early embryologic development, cranial neural crest cells migrate, distribute, and form those tissues and organs of the pharyngeal arch systems, including the aortic arch and its branches, cardiac outflow tract, thymus, parathyroid, and several parts of the palate, pharynx, and face. In the early embryo, progenitor cells, from the recently identified second heart field, migrate and distribute to the primitive heart tube and form the outflow tract. More than 35 genes are present within the commonly deleted region of chromosome 22q11.2. Two genes mainly responsible for the phenotypic features of this syndrome have been identified as TBX1 and Crkl. Although fibroblast growth factor 8 (FGF8) is not located in chromosome 22q11.2, a mouse model with the FGF8 mutation phenotypically mirrors the 22q11.2 DS in humans. TBX1 and Crkl are essential for the function of FGF8 and are important for the survival, proliferation, and migration of neural crest cells. Animal models suggest that haploinsufficiency of TBX1 plays an important role. However, other genes in the region that are also haploinsufficient may contribute to the phenotype. In addition, a recent report has shown that ERK2 is the third essential gene for FGF8 and neural crest cell development in the distal 22q11.2 location outside of the commonly deleted region. Since 1992, fluorescent in situ hybridization testing has been used to identify the deletion of chromosome 22q11.2, and congenital heart diseases associated with 22q11.2 DS have been reported extensively. Chromosome 22q11.2 DS is seen with an incidence of 1 in 4,000 to 10,000 children. This is a review of congenital heart diseases associated with 22q11.2 DS, focusing on their prevalence and characteristics.
Associated Cardiovascular Anomalies
Incidence
It should be noted that the overall estimate of how many patients with 22q11.2 deletions have congenital heart defects is likely biased with respect to (1) the degree to which asymptomatic patients with chromosomal deletions have been screened for associated aortic arch anomalies and (2) the biased ascertainment of affected infants but with the probable lack of ascertainment of minimally affected adults, that is, until they have affected children.
The largest series of 22q11.2 DS was reported by Ryan et al in a multicenter study including 545 patients from 23 European centers ( Table 1 ). Other reports include a Korean multicenter study reported by Park et al and several single-institution studies by various groups, including Matsuoka et al (Japan), McDonald-McGinn et al (Philadelphia), Marino et al (Italy), and Oskarsdottir et al (Sweden) ( Table 1 ). In each study, tetralogy of Fallot (TF) was the most prevalent heart disease, followed by TF with pulmonary atresia (PA) (ventricular septal defect [VSD] with PA), VSD, interruption of the aortic arch (type B), and truncus arteriosus. Some differing frequencies of individual diseases, including truncus arteriosus, were noted in these studies. Very probably, these differences were due not to ethnicity but instead to patient selection. As listed in Table 1 , >10 other congenital heart diseases have been linked with 22q11.2 DS. Double-outlet right ventricle and transposition of the great arteries (TGA) are occasionally seen with 22q11.2 DS. Thirteen percent to 36% of patients with normal hearts were included in these studies. These cases were identified typically during studies of the index patients’ families, and about 20% of the patients with deletion of chromosome 22q11.2 inherited the deletion, frequently inheriting it from the maternal lineage. In the other 80%, both parents had no deletion, and hence, they were sporadic cases due to de novo mutations. Some patients with normal cardiovasculature were identified with other phenotypes without cardiovascular abnormalities.
| Cardiovascular Abnormality | Ryan et al | Matsuoka et al | McDonald-McGinn et al | Oskarsdottir et al | Park et al |
|---|---|---|---|---|---|
| (n = 545) | (n = 183) | (n = 222) | (n = 100) | (n = 222) | |
| Normal heart | 110 (20%) | 23 (13%) | 58 (26%) | 36 (36%) | 32 (14%) |
| TF | 95 (17%) | 67 (39%) | 49 (22%) | 13 (13%) | 59 (27%) |
| TF + absent pulmonary valve | 2 | 2 (1%) | † | 3 (1%) | |
| TF + PA + patent ductus arteriosus | 55 (10%) | 4 (2%) | † | 5 (5%) | 15 (7%) |
| TF + PA + MAPCAs | ⁎ | >45 (25%) | † | ⁎ | 42 (19%) |
| VSD | 75 (14%) | 25 (13%) | 29 (13%) | 14 (14%) | 39 (18%) |
| Interrupted aortic arch | 74 (14%) | 7 (4%) | 35 (16%) | 6 (6%) | 10 (5%) |
| Truncus arteriosus | 51 (9%) | 4 (2%) | 16 (7%) | 10 (10%) | 1 |
| Pulmonary valve stenosis | 13 (2%) | 1 | 1 (1%) | ||
| Atrial septal defect | 8 (1%) | 2 (1%) | 7 (3%) | 4 (4%) | 7 (3%) |
| Atrioventricular septal defect | 5 (1%) | 1 | 1 | 1 | |
| Double-outlet right ventricle | 4 (1%) | 3 (2%) | 1 | 7 (3%) | |
| Transposition of the great arteries | 4 (1%) | 1 | 1 (1%) | ||
| Patent ductus arteriosus | 7 (1%) | 2 (1%) | 3 (3%) | 2 (1%) | |
| Coarctation of the aorta | 4 (1%) | 1 | 1 (1%) | 1 | |
| Others ‡ | 10 (2%) | 2 (1%) | 3 (1%) | 3 (3%) | 6 (3%) |
⁎ Included in TF + PA + patent ductus arteriosus.
‡ Nine diseases that are rarely associated with 22q11.2 DS (see Table 5 ).
Some congenital heart diseases are severe and may be fatal in utero or during the perinatal period, and such patients may not survive long enough to be checked for 22q11.2 DS. More accurate incidences of cardiovascular anomalies associated with 22q11.2 DS were assessed in a study of fetuses and neonates by Boudjemline et al. They studied all fetuses for 6 conotruncal heart anomalies and identified 54 fetuses with 22q11.2 deletion. These 6 anomalies included TF (14 fetuses [26%]), TF with absent pulmonary valve (6 fetuses [11%]), TF with PA (11 fetuses [20%]), interrupted aortic arch (10 fetuses [19%]), truncus arteriosus (9 fetuses [17%]), and TGA (4 fetuses [7%]). Compared to the postnatal frequencies, the fetal frequencies of TF and TF with PA were similar. However, the fetal frequencies of the other 4 anomalies were much higher than postnatal frequencies (see Table 1 ).
The incidence of 22q11.2 DS in each congenital heart disease was studied prospectively, and the results of the fetal study of Boudjemline et al and a neonatal study by Iserin et al are listed in Table 2 . Prospective studies at children’s hospitals were reported by Goldmuntz et al (Philadelphia) and Frohn-Mulder et al (Rotterdam, The Netherlands), and these are also listed in Table 2 . In each study, all patients with conotruncal anomalies were checked for 22q11.2 DS prospectively. Similar incidences of 22q11.2 DS in TF, interrupted aortic arch, and truncus arteriosus were reported in these 3 studies. The incidence of 22q11.2 deletion in TGA was high in the fetal study, possibly reflecting an association of its perinatal mortality.
| Disease | Fetus | Neonate | Child | Adult | |
|---|---|---|---|---|---|
| Boudjemline et al | Iserin et al | Goldmuntz et al | Frohn-Mulder et al | Beauchesne et al | |
| TF | 14/100 (14%) | 8/31 (26%) | 20/126 (16%) | 7/63 (11%) | 3/77 (4%) |
| TF + absent pulmonary valve | 6/16 (38%) | 25 (40%) | ⁎ | ⁎ | 0 |
| TF + pulmonary atresia † | 11/61 (18%) | 11/24 (46%) | ⁎ | 8/25 (32%) | 2/23 (9%) |
| Interrupted aortic arch | 10/22 (45%) | 16/18 (89%) ‡ | 12/24 (50%) | 3/5 (60%) | 0 |
| Truncus arteriosus | 9/29 (31%) | 7/17 (41%) | 10/29 (35%) | 3/15 (20%) | 1/3 (33%) |
| Transposition of the great arteries | 4/33 (12%) | § | 0/39 (0%) | 0/45 (0%) | 0 |
† Including TF + PA + patent ducts arteriosus and TF + PA + MAPCAs.
‡ Interrupted aortic arch type B.
In adults, congenital heart diseases associated with 22q11.2 DS are usually VSD and TF. Momma et al reported 34 adults with TF and 22q11.2 DS. Beauchesne et al reported a genetic study in adult patients with conotruncal anomalies at the Mayo Clinic. The frequency of 22q11.2 DS was low in adult patients with TF and was 4% in patients with TF and pulmonary stenosis and 9% in patients with TF and PA ( Table 2 ). These low frequencies of 22q11.2 DS in adult patients suggest an unfavorable outcome in patients with TF and 22q11.2 DS. Although the prognosis used to be poor, there is reason to believe it is better now. Clinical features of adults with 22q11.2 deletion were studied by Bassett et al and Fung et al of Toronto General Hospital. They identified 78 adults with 22q11.2 DS, mainly from the cardiology and psychiatry clinics. Thirty-five patients were present in the adult congenital cardiac clinic, and 31 of 35 patients had TF. The other 4 patients had VSDs or VSDs and atrial septal defects. They had no adult patients with TF with absent pulmonary valve, interrupted aortic arch, or TGA. It may reflect the poor prognosis of these diseases, or in contrast, these diseases may simply be rare in these series.
TF
TF and TF with PA are the most prevalent anomalies associated with 22q11.2 DS (see Table 1 ). The incidence of 22q11.2 DS in TF, including TF with PA, has been reported to be 10% to 21% in 5 studies. In total, 603 patients were studied, and 14% had the deletion.
TF, absent pulmonary valve, and absent ductus arteriosus is a rare and severe disease with characteristic aneurysmal dilatation of the pulmonary arteries. The frequency of 22q11.2 DS in patients with TF and absent pulmonary valve has been reported in 4 studies. In total, 17 of 39 patients (44%) had the deletion. In this complex, TF is usually associated with an absent ductus arteriosus and can be induced by neural crest cell insufficiency.
Patients with TF with PA are subdivided into 2 groups: those with patent ductus arteriosus and those with major aortopulmonary collateral arteries (MAPCAs). The prevalence of 22q11.2 DS is higher in the latter group (see Table 3 ). The prevalence of 22q11.2 DS in TF and that in TF with PA and patent ductus arteriosus are similar and <20%. In contrast, the prevalence of 22q11.2 DS in patients with TF with PA and MAPCAs was much higher, at approximately 50% ( Table 3 ). The high prevalence of 22q11.2 DS in TF with PA and MAPCAs is consistent with neural crest cell insufficiency as a cause of this complex, because insufficient neural crest cells disturb the formation of the embryonic aortic arch and the pulmonary artery system.
| Anomaly | Momma et al | Chessa et al | Hofbeck et al | Frohn-Mulder et al | Maeda et al |
|---|---|---|---|---|---|
| TF + pulmonary stenosis | 9/54 (17%) | 7/63 (11%) | 15/173 (9%) | ||
| TF + PA + patent ductus arteriosus | 2/15 (13%) | 6/27 (22%) | 0/21 (0%) | 1/9 (11%) | 4/22 (18%) |
| TF + PA + MAPCA | 21/34 (62%) | 10/13 (77%) | 10/23 (43%) | 7/16 (44%) | 9/17 (53%) |
TF with pulmonary stenosis and 22q11.2 DS is often associated with additional cardiovascular anomalies. In a study by Momma et al, the frequency of associated anomalies in patients with the deletion compared to those without deletion were as follows: right aortic arch 41% versus 18%, high aortic arch 50% versus 9%, infundibular septal defect 32% versus 5%, aberrant origin of the subclavian artery 14% versus 0%, isolated subclavian artery 14% versus 0%, and isolation of the pulmonary artery 9% versus 0%. Similarly, an increased incidence of additional cardiovascular anomalies in TF and 22q11.2 DS has been reported by some investigators but not by others. Cervical aorta and isolation of the innominate artery have been reported in association with TF and 22q11.2 DS.
TF with PA and 22q11.2 DS has more complicated pulmonary arteries compared to TF with PA lacking chromosomal deletion ( Table 4 ). Hofbeck et al studied 21 patients with TF, PA, and MAPCA. Eleven patients lacked 22q11.2 DS, and favorable pulmonary arteries permitted intracardiac repair in 64% of patients. In contrast, 10 patients were associated with 22q11.2 DS and more often had arborization anomalies of the pulmonary arteries, and biventricular repair was not possible in any of the children with 22q11.2 DS. Chessa et al also reported poorly developed pulmonary artery anatomy in TF with PA and 22q11.2 DS. Compared to the nondeletion group, the deletion group had a higher frequency of absent confluent central pulmonary artery, more frequent MAPCAs, and smaller right and left pulmonary arteries. They defined a specific phenotype in patients with the deletion: PA, VSD, and MAPCAs with complex loop morphology and small central pulmonary arteries. Surgical results for TF with PA and 22q11.2 DS have been reported in several studies and are sometimes poor because of poorly developed pulmonary arteries.
| Additional Cardiovascular Anomaly | Momma et al | Hofbeck et al | ||
|---|---|---|---|---|
| Deletion (n = 23) | No Deletion (n = 26) | Deletion (n = 10) | No Deletion (n = 11) | |
| Right aortic arch | 16 (70%) | 6 (23%) | 6 (60%) | 3 (27%) |
| High aortic arch | 10 (43%) | 4 (15%) | 6 (60%) | 0 (0%) |
| Absent central pulmonary artery confluence | 11 (48%) | 1 (4%) | 2 (20%) | 1 (9%) |
| Absent ductus arteriosus | 19 (83%) | 12 (46%) | 10 (100%) | 11 (100%) |
| Major aortopulmonary collateral arteries | 21 (91%) | 13 (50%) | 10 (100%) | 11 (100%) |
| Aberrant subclavian artery | 8 (35%) | 0 (0%) | 2 (20%) | 2 (18%) |
| Persistent left superior vena cava | 0 (0%) | 0 (0%) | 0 (0%) | 3 (27%) |
Rauch et al reported that cervical origin of the subclavian artery was present in 29% of patients with TF and PA associated with 22q11.2 DS. The cervical origin of the subclavian artery was the most specific, present in 24% of patients with 22q11.2 DS and conotruncal anomalies and in none of the patients without the deletion. An aberrant origin was less specific, associated with 30% of the patients with the deletion and 9% of the patients without the deletion. Isolation of the subclavian artery was associated in 4% of the patients with the deletion and 1% of the patients without the deletion.
The indication for genetic studies in patients with TF is higher if it is associated with multiple anomalies of the following vascular structures: the aortic arch (right, cervical, or high), the subclavian artery (isolated, cervical origin, or aberrant origin), the pulmonary artery (atresia, absent central portion, or MAPCAs), and the ductus arteriosus (absent or with absent pulmonary valve). Conversely, genetic studies are not indicated in TF if it is not associated with any of these vascular anomalies and signs and symptoms characteristic of 22q11.2 DS, including abnormal face, thymic hypoplasia, cleft palate, and hypocalcemia.
Truncus arteriosus
Truncus arteriosus is frequently associated with DiGeorge syndrome and deletion of chromosome 22q11.2. Truncus arteriosus is typically induced by neural crest cell insufficiency, and its causative role has been confirmed experimentally. The prevalence of 22q11.2 DS in patients with truncus arteriosus is reported to be 31% in the fetus and 20% to 41% in infants and children (see Table 2 ).
The following characteristic association has been reported in truncus arteriosus and 22q11.2 DS. Discontinuous pulmonary arteries (type 3 according to Van Praagh and Van Praagh ) were associated with 22q11.2 DS in 2 of 3 patients in a series by Momma et al and in 3 of 4 patients in a series by McElhinney et al. Right aortic arch and an abnormal aortic arch branching pattern were 2 to 5 times more frequent in 22q11.2 DS.
In the study of Momma et al, pulmonary stenosis was present in all 5 patients with 22q11.2 DS and in none of the 9 patients without 22q11.2 DS. Pulmonary stenosis in patients with 22q11.2 DS consisted of either tubular hypoplasia of the pulmonary arteries or localized stenosis at the junction to the truncus arteriosus. MAPCAs were present in 3 of 5 patients with 22q11.2 DS and in none of the 10 patients without 22q11.2 DS. One patient with type 1 truncus arteriosus, MAPCAs, and 22q11.2 DS showed crossing pulmonary arteries (see later discussion).
Marino et al and Formigan et al noticed severe truncal valve insufficiency in 1/3 of patients with truncus arteriosus associated with 22q11.2 DS. However, in McElhinney et al’s series, abnormalities of the truncal valve were not increased in 22q11.2 DS.
Interruption of the aortic arch
Interruption of the aortic arch occurs at 3 locations and is classified in 3 types. Their frequencies in patients with and without 22q11.2 DS have been reported in 5 studies. In total, 25 patients had type A interruption distal to the left subclavian artery, and none had the deletion. Eighty-three patients had type B interruption distal to the left common carotid artery, and 61% of these had the deletion. Type C interruption distal to the brachiocephalic artery was infrequent, with only 2 patients with 22q11.2 DS included. Later, 1 patient with type A interrupted aortic arch and 22q11.2 DS was reported. Experimentally, ablation of the neural crest cell in the chick induced type B interruption of the aortic arch, indicating that it is related to neural crest cell insufficiency.
Interruption of the aortic arch associated with 22q11.2 DS is usually associated with a large subarterial doubly committed VSD extending to the membranous septum (total outlet defect). In contrast, in patients without the deletion, total outlet defect was present only in 2 of 6 patients, and the other 4 patients had muscular VSD (1 patient), aortopulmonary window (2 patients), and atrioventricular septal defect (1 patient).
Rauch et al showed that the cervical origin of the right subclavian artery was specific for 22q11.2 DS and present in 6 of 12 patients with type B interruption and 22q11.2 DS.
Genetic investigations are indicated in type B interruption but rarely in type A and type C interruptions.
VSD
VSD is sometimes associated with 22q11.2 DS. VSDs in patients with 22q11.2 DS were variable. In 4 studies that included a total of 78 patients, various types of VSD were present, including the following: perimembranous (78%), subarterial (13%), right (posterior) malalignment type (4%), and muscular (5%).
Because of the known embryonic distribution of neural crest cells in the cardiac outflow septum, subarterial VSD may also be produced in 22q11.2 DS. The frequency of 22q11.2 DS has been studied in subarterial VSD, and variable reported proportions of the deletion include 1 of 11 patients in the United States, 4 of 5 in Italy, and none of 22 patients in Japan. It is inconclusive if subarterial VSD is common in Caucasian patients with 22q11.2 DS. Frequencies of 22q11.2 DS in patients with perimembranous, right malalignment type, or muscular VSD are also inconclusive.
McElhinney et al showed that VSD with 22q11.2 DS is associated significantly more with aortic arch anomalies and discontinuous pulmonary arteries, and these anomalies were present in 9 of 12 patients with 22q11.2 DS. These included 3 patients with cervical aortic arch associated with a right aortic arch or an aberrant aortic arch branching pattern.
Genetic studies are indicated in VSD if it is associated with other vascular anomalies or signs and symptoms that are characteristic of 22q11.2 DS.
Other congenital heart diseases
Complete TGA is occasionally associated with 22q11.2 DS. Melchionda et al studied 32 patients with complete TGA and found 4 patients with 22q11.2 DS, including 2 with simple TGA and 2 with complex TGA. Association of TGA with 22q11.2 DS was generally rare, and in a series by Goldmuntz et al, in 39 patients with TGA, none had an association with 22q11.2 DS. Associated TGA was usually complex with VSD plus pulmonary stenosis or PA.
Atrial septal defect is occasionally seen with 22q11.2 DS. Marino et al studied 28 patients with atrial septal defects and identified 2 patients with 22q11.2 DS.
Table 5 lists congenital cardiovascular anomalies that are rarely associated with chromosome 22q11.2 deletion and those anomalies that have not been reported thus far.
