European Journal of Medical Genetics 58 (2015) 75e85
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Clinical research
Associated noncardiac congenital anomalies among cases with congenital heart defects Claude Stoll*, Beatrice Dott, Yves Alembik, Marie-Paule Roth Laboratoire de Genetique Medicale, Faculte de Medecine, Strasbourg, France
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 August 2014 Accepted 3 December 2014 Available online 12 December 2014
Cases with congenital heart defects (CHD) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CHD in a defined population. The anomalies associated with CHD were collected in all live births, stillbirths and terminations of pregnancy during 26 years in 346,831 consecutive pregnancies of known outcome in the area covered by our population based registry of congenital anomalies. Of the 4005 cases with CHD born during this period (total prevalence of 115.5 per 10,000), 1055 (26.3%) had associated major anomalies. There were 354 (8.8%) cases with chromosomal abnormalities including 218 trisomies 21, and 99 (2.5%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognized dysmorphic conditions, but VACTERL association. However, other recognized dysmorphic conditions were registered including Noonan syndrome, fetal alcohol syndrome, and skeletal dysplasias. Six hundred and two (15.0%) of the cases had non syndromic, non chromosomal multiple congenital anomalies (MCA). Anomalies in the urinary tract, the musculoskeletal, the digestive, and the central nervous systems were the most common other anomalies. Prenatal diagnosis was obtained in 18.7% of the pregnancies. In conclusion the overall prevalence of associated anomalies, which was one in four infants, emphasizes the need for a thorough investigation of cases with CHD. A routine screening for other anomalies may be considered in infants and in fetuses with CHD. One should be aware that the anomalies associated with CHD can be classified into a recognizable anomaly, syndrome or pattern in one out of nine cases with CHD. Ó 2014 Elsevier Masson SAS. All rights reserved.
Keywords: Congenital heart defects Congenital heart disease Cardiac anomalies Noncardiac anomalies Syndromes Surveillance Ascertainment Etiology
1. Introduction Studies of other defects associated with specific congenital anomalies may be helpful to understand embryonic development, identify the causes of congenital anomalies, determine recurrence risks, and guide expectations for the efficacy of prevention strategies [Stevenson et al., 2004]. Congenital heart defects are one of the most common congenital anomaly, representing approximately 45% of all prenatally diagnosed anomalies [Stoll et al., 2001] with a reported rate per 10,000 live births or total births varying from 43 to 124 [Lowry et al., 2013]. CHD occur in as many as 1 in 100 live births and in 1 in 500 fetal ultrasonographic examination [Meberg et al., 2007; Tegnander et al., 2006]. Many cases with CHD will have a coexisting defect involving noncardiac structures.
Individual cases of CHD may differ widely in their cause. Specific genetic factors, such as chromosomal abnormalities and inherited mutations in developmental genes, or environmental influences on fetal development i.e. medications [Stoll et al., 1989] may form the underlying cause. Although it has long been known that CHD are frequently associated with other congenital anomalies, their reported frequency and the type of associated anomalies observed vary considerably among different studies. Using data from our surveillance system of congenital anomalies over a 26-year period, we evaluated the nature and frequency of anomalies associated with CHD to identify recognizable conditions and specific patterns of associated anomalies, which could give hints about the pathogenesis of CHD.
2. Material and methods * Corresponding author. Laboratoire de Génétique Médicale, Faculté de Médecine 11, rue Humann, 67085 Strasbourg Cedex, France. Tel.: þ33 3 68 85 32 07; fax: þ33 3 68 85 31 79. E-mail address: [email protected] (C. Stoll). http://dx.doi.org/10.1016/j.ejmg.2014.12.002 1769-7212/Ó 2014 Elsevier Masson SAS. All rights reserved.
Cases with anomalies for this study were derived from 346,674 consecutive pregnancies of known outcome, including live births and stillbirths, and 157 terminations of pregnancy for fetal
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abnormality regardless of gestational age, registered by our registry of congenital anomalies described previously [Stoll and Roth, 1985]. Minor anomalies were excluded according to EUROCAT [2009] guidelines for registration of congenital anomalies (http://www. eurocat-network.eu). Cases born in 11 maternity hospitals were examined from January 1, 1979 to December 31, 2004. The region of investigation was the city of Strasbourg, France (an urban area), and the area defined by the Departement du Bas-Rhin, in which Strasbourg is situated (a rural area). Newborn pulse oximetry screening was not used in the region under study. All newborns were registered within the first 8 days postpartum, as were all fetuses aborted because of anomalies discovered at prenatal diagnosis. As everywhere in our country, no delivery took place at home in the area under study. All cases with CHD and associated anomalies, live births, stillbirths and elective terminations of pregnancy for fetal anomaly were examined by a clinical geneticist. CHD diagnoses were confirmed by echocardiography, cardiac catheterization, surgery and/or autopsy. Common to most studies, patent ductus arteriosus was included in full-term infants in whom the defect persisted for a minimum of 3 months or required surgery. Patent foramen ovale versus atrial septal defect (ASD) was excluded in full-term infants if closed within 3 months or was 1,200,000 LB, FD, SB 7984 z66.5 2289 (29)
2000e2005 3,327,591 LB, FB, TOP 26,598 80.3d 7404 (28)
2004e2008 ? LB, CICU 141 ? 80 (57)
1995e2002 ? LB, SB, TOP 3751 124 867 (23)
2008e11 ? LB, Biobank 2339 ? 803 (34)
1983e2013 ? SB, FD, Autopsy 179 ? 130 (73)
1979e2004 346,831 LB, SB, TOP 4005 115.5 1055 (26)
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Study years N of births Study population Total N Prevalence Associated N (%)
[Kenna et al., 1975]
LB, live births; SB, still births; FD, fetal deaths; TB, total births; TOP, termination of pregnancy for fetal anomaly; CICU, cardiac intensive care unit. Diagnosis confirmed by invasive techniques in 388 index cases. Chromosomal anomalies were excluded. In 43 registries of congenital anomalies from 23 European countries reporting their results to EUROCAT [2009], the prevalence of CHD varied from 53.9 (Croatia) to 153.4 (Austria).
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criteria, the variability of clinical expression of associated anomalies, the difficulty to know the proportion of patients diagnosed by objective techniques, the selection of patients, the sources of ascertainment, and the sample size. In addition to these factors, autopsies were not always performed, there was not always follow-up, many authors did not report all patients born in a certain geographical area, but instead, patients referred to a certain health care facility, and there are true population differences and changes in frequency over time (EUROCAT [2009]: http:// www.eurocat-network.eu). Moreover, many of the prevalence estimates are uncertain due to small numbers. The same concerns exist for the comparisons of subgroups of associated anomalies. In this study chromosomal abnormalities were observed in 354 (8.8%) infants with CHD. The reported percentages of chromosomal abnormalities in infants with CHD vary from 3 in Northern Ireland [Hanna et al., 1994] to 33 in Norway [Tennstedt et al., 1999] and Wisconsin [Jorgensen et al., 2014] (Table 5). The low percentage of chromosomes abnormalities in Northern Ireland is explained by the fact that at that time, 1974e1978, patients with Down syndrome were not investigated by invasive heart techniques and the 3% refers to patients who had such investigations. In the autopsy group the percentages of chromosomal abnormalities in cases with CHD was high, 33 in Norway [Tennstedt et al., 1999] and Wisconsin [Jorgensen et al., 2014] (Table 5). In the other studies, the percentages of chromosomal abnormalities varied from 6 [Greenwood et al., 1975; Kenna et al., 1975; Kramer et al., 1987; Wallgren et al., 1978] to 13 [Montaña et al., 1996] and 16 [Baker et al., 2012]. In this study 62% of the chromosomal anomalies were trisomy 21. In the other series the more common chromosomal abnormality was also trisomy 21 with a percentage ranging from 15 [Tennstedt et al., 1999] to 98 [Wallgren et al., 1978] (Table 5). In our study the other chromosomal anomalies were trisomy 18 (15%), trisomy 13 (6%), Turner syndrome (3%), and chromosomal structural aberrations (14%). This figure compares well with that in other studies (Table 5) except for the study of autopsy cases of Gücer et al. [2005] who had more trisomy 18 than trisomy 21 since the latter is the more likely to survive than the former. Many syndromes, sequences, associations and spectrums were reported to be associated with CHD [Brennan and Young, 2001]. In our series 99 out of 4005 (2.5%) cases with CHD had non chromosomal recognizable conditions including VACTERL association (23%), Noonan syndrome (8%), fetal alcohol syndrome (7%), skeletal dysplasias (6%) and many other recognizable conditions such as CHARGE syndrome, de Lange syndrome, oculo-auriculo-vertebral spectrum, Williams syndrome, and HolteOram syndrome (Table 3). In the previous reports the percentage of non chromosomal recognizable conditions varied considerably (Table 5) from 1% in the studies of Pradat [1997] and of Stephensen et al. [2004] to 8% in the series of Kramer et al. [1987]. In the stillborn cohort of Jorgensen et al. [2014], most CHD (70%) were associated with other anomalies. While recognizing that these actually comprise a variety of syndromes, sequences, and associations, the authors for convenience refer to this group comprising 33% of the stillborn as “syndromic”. As in this series, VACTERL association was also the most common recognizable non chromosomal condition in the other studies with a percentage ranging from 3 [Eskedal et al., 2004; Kramer et al., 1987] to 38 [Miller et al., 2011] (Table 5). In the older series (Table 5), Di George was a clinical diagnosis with a percentage ranging from 1 [Bower and Ramsay, 1994] to 8 [Ferencz et al., 1987]. The use of new cytogenetic methods i.e. FISH increased the rate of detection of 22q11.2 deletion as, for example, in the study of Fung et al. [2013] in which 19% of the cases tested were carrier of a 22q11.2 deletion.
In this study, among the MCA, septal defects were the most common CHD (58.6% including VSD 38.0% and ASD 20.6%) followed by RVOTO (9.7%), LVOTO (8.3%) and conotruncal defects (6.9%). This differs from the literature in which Lowry et al. [2013] reported conotruncal defects as being the most frequent in their MCA group and Gücer et al. [2005] reported VSD and Miller et al. [2011] ASD. However, Miller et al. [2011] included known associations in their MCA and Gücer et al. [2005] included minor anomalies, syndromes and chromosomal anomalies [Lowry et al., 2013]. There is no agreement in the literature as to which associated anomalies are most common in cases with CHD and MCA. In this study (Table 3) the most common associated anomalies were renal, musculoskeletal, digestive, ear, face and neck, central nervous, genital, abdominal wall, and eye. The most common anomalies among renal anomalies were renal agenesis, ureteral anomalies, hydronephrosis and cystic kidney; among musculoskeletal anomalies limb reduction defects, polydactyly, spine, rib, sternum anomalies and syndactyly; among digestive system anomalies anal atresia and malrotation; among central nervous system hydrocephaly, arhinencephaly, agenesis of corpus callosum; among ear, face and neck ear anomaly, facial dysmorphism and hypertelorism; among genital anomaly internal female genitalia anomaly and hypospadias, and among abdominal wall anomalies omphalocele and gastroschisis. In the other previous 25 studies available (Table 5) the most common associated anomalies were musculoskeletal anomalies in 12 series, gastrointestinal anomalies in 4 studies, urinary anomalies in 3 studies, and orofacial anomalies in 2 studies. However, it is difficult to compare our results with those of other studies as, for example some authors include the patients with isolated CHD in the total number of patients. Other reasons for the discrepancies between the reported studies and this study were aforementioned. In order to evaluate cases and to compare studies, it is necessary to standardize the methods of case classification. Congenital anomalies and associated anomalies must be grouped into meaningful syndromes and conditions. Methods for case classification into isolated, multiple and syndrome categories were described [Rasmussen et al., 2003]. Consideration of these guidelines will lead to more comparable case groups, an important element of careful studies aimed at identifying etiology of congenital anomalies. The causes of CHD include [Brennan and Young, 2001] chromosomal abnormalities; dominant or recessive genes (single gene determination); familial inheritance in the absence of single gene determination; teratogenic exposures (i.e. ethanol, sodium valproate, retinoic acid, lithium, rubella, cytomegalovirus, and maternal diabetes); and unknown causes. CHD are often associated with known syndromes, sequences, associations, spectrums and related anomalies (i.e., VACTERL association, Noonan syndrome). The prenatal exposure to teratogens may be preventable. Moreover, some observational studies showed a preventive effect of multivitamins in the early pregnancy particularly in conotruncal defects [Botto et al., 1996]. More recently, in Hungary, CsàkySzunyogh et al. [2013] showed that high doses of medically recorded folic acid in early pregnancy were able to reduce the birth prevalence of conotruncal defects, and this reduction was significant in transposition of the great arteries as well. However, the preventive effect of high doses of folic acid for CHD is not yet proven [Bedard et al., 2013]. The molecular basis for CHD remains unknown. A discussion of the molecular basis of CHD is beyond the scope of this paper. In short, Lalani et al. [2013] identified 55 copy number variants (CNV) >50 kb in length that were present in subjects with CHD and extracardiac anomalies and were absent in controls and they delineate regions within previously reported structural variants
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Table 5 Review of literature: recognizable and nonrecognizable conditions in cases with congenital heart defects and associated malformations: N (%). The number of cases are under the authors names. The percentage after total is a percentage of the total number of cases. For nonrecognizable conditions some authors reported the number of anomalies, this number is then in bold type whereas for authors reporting the number of cases, this number is in plain type. [Kenna et al., 1975] 1081
[Greenwood et al., 1975] 1566
[Gallo et al., 1976] 1354
Recognizable conditions Chromosomal abnormalities Trisomy 21 57 (93) 63 (71) 78 (91) Trisomy 18 7 (8) 6 (7) Trisomy 13 5 (6) 2 (2) Turner syndrome 5 (6) Deletions 22q11.2 Other 4 (7) 9 (10) Total 61(6) 89 (6) 86 (6) Nonchromosomal conditions VACTERL association Noonan syndrome 1(2) OAVS 1 (2) De Lange syndrome 2 (5) HolteOram syndrome 1 (2) Di George syndrome 3 (7) Williams syndrome Other 10 (23) Teratogena 25 (58) Total 43 (3) Non recognizable conditions: congenital anomalies by organ system (recognizable conditions excluded) Musculoskeletal 67 (18) 137 (26) 62 (8) Urinary 47 (13) 83b (16) 110(14) Genital 19 (5) 57 (7) Gastrointestinal 31 (8) 65 (12) 152(19) Central nervous system 40 (11) 107 (20) 44 (6) Respiratory 32 (9) 58 (11) 109(14) Eye 10 (3) Ear Orofacial 30 (8) 18 (2) Abdominal wall 5 (1) Diaphragme 4 (1) Other 86 (23) 78 (14) 238(30) Total 371(15) 528 (17) 790(27) [Kramer et al., 1987] 1016
[Stoll et al., 1989] 801
Recognizable conditions Chromosomal abnormalities Trisomy 21 43 (77) 45 (62) Trisomy 18 2 (4) 15 (21) Trisomy 13 7 (10) Turner syndrome 3 (5) 1 (1) Deletions 22q11.2 Other 8 (14) 4 (6) Total 56 (6) 72 (9) Nonchromosomal conditions VACTERL association 2 (3) 2 (10) Noonan syndrome 14 (18) 1 (5) OAVS De Lange syndrome HolteOram syndrome 2 (3) 1 (5) Di George syndrome Williams syndrome 5 (6) Other 29 (37) 16 (80) a Teratogen 29 (37) Total 79 (8) 20 (2) Non recognizable conditions: congenital anomalies by organ system (recognizable conditions Musculoskeletal 27 (40) 46 (21) Urinary 8 (12) 45 (21) Genital 11 (5) Gastrointestinal 9 (13) 37 (17) Central nervous system 15 (22) 22 (11) Respiratory 9 (13) Eye 8 (4) Ear Orofacial 32 (15) Abdominal wall
[Wallgren et al., 1978] 1000
[Ferencz et al., 1987] 1494
55 (98)
1 (2)
145(78) 10 (5) 15 (8) 7 (4)
56 (6)
10 (5) 187(13) 8 (9) 4 (4)
4 (4) 7 (8) 4 (4) 64 (70) 91 (6)c
152 (13) 68 (9) 54 (7) 25 (3)
16 (13) 13 (10) 5 (4) 19 (15) 9 (7) 3 (2) 7 (6)
35 (4) 23 (3) 19 (2) 120 (15) 787(38)
3 (2) 6 (5) 2 (2) 43 (34) 126 (8)
[Kidd et al., 1993] 1479
[Bower and Ramsay, 1994] 1787
[Hanna et al., 1994] 972d
106 (75)
99 (65) 23 (15) 9 (6) 5 (3)
4 (33)
35 (25) 141(10)
16 (11) 152 (9)
8 (66) 12 (3)
33 (2) excluded)
138(18) 153b (19)
18 (21) 4 (5) 1 (1) 3 (4) 3 (4) 1 (1) 5 (6) 39 (46) 13 (15) 87 (5)
3 (38) 1 (12) 1 (12)
2 (25) 1 (12) 8 (2) 22 (20) 20 (18) 1 (1) 33 (30) 6 (6) 14e (13)
(continued on next page)
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Table 5 (continued )
Diaphragme Other Total
[Kenna et al., 1975] 1081
[Greenwood et al., 1975] 1566
[Gallo et al., 1976] 1354
[Wallgren et al., 1978] 1000
[Ferencz et al., 1987] 1494
68 (7)
17 (8) 218 (14)
189 (13)
211 (12)
12 (11) 108 (18)
[Grech and Gatt, 1999] 231
[Tennstedt et al., 1999] 129
[Calzolari et al., 2003] 1549
19 (15) 11 (9) 6 (5) 3 (2)
115 (76) 11 (7) 6 (4)
4 (3) 43 (33)
20 (13) 152 (10)
[Montaña et al., 1996] 1589
[Pradat, 1997] 2618
Recognizable conditions Chromosomal abnormalities Trisomy 21 19(90) Trisomy 18 1 (5) Trisomy 13 Turner syndrome Deletions 22q11.2 Other 1 (5) Total 206 (13) 21 (9) Nonchromosomal conditions VACTERL association 1 (25) Noonan syndrome 5 (19) 2 (50) OAVS 2 (7) De Lange syndrome 1 (4) HolteOram syndrome 1 (25) Di George syndrome 8 (30) Williams syndrome 2 (7) Other 9 (33) a Teratogen Total 27 (1) 4 (2) Non recognizable conditions: congenital anomalies by organ system (recognizable conditions excluded) Musculoskeletal 10.9% 133 (15) 4 (29) Urinary 80 (9) 1 (7) Genital 37 (4) Gastrointestinal 11.8% 127 (15) 1 (7) Central nervous system 10% 30 (3) 1 (7) Respiratory 22 (2) 1 (7) Eye 24 (3) 1 (7) Ear 31 (4) Orofacial 120 (14) 2 (14) Abdominal wall 37 (4) Diaphragme 21 (2) Other 204 (24) 3 (21) Total 560 (35) 866(26) 14 (6) [Eskedal et al., 2004] 3527
[Stephensen et al., 2004] 740
[Gücer et al., 2005] 305
Recognizable conditions Chromosomal abnormalities Trisomy 21 286 (94) 28 (78) 7 (29) Trisomy 18 7 (2) 10 (42) Trisomy 13 3 (1) 6 (25) Turner syndrome 8 (3) Deletions 22q11.2 Other 8 (22) 1(4) Total 304 (9) 36 (5) 24 (8) Nonchromosomal conditions VACTERL association 5 (6) Noonan syndrome 17 (19) 4 (44) OAVS 1(8) De Lange syndrome 1(8) HolteOram syndrome 3 (3) Di George syndrome 16 (18) 1(8) Williams syndrome 21 (24) 3 (33) Other 27 (30) 2 (22) 9 (75) Teratogena Total 89 (3) 9 (1) 12 (4) Non recognizable conditions: congenital anomalies by organ system (recognizable conditions excluded) Musculoskeletal 41(15) Urinary 34 (10) 7b (16) 46b (17) Genital 45 (13) Gastrointestinal 119 (34) 5 (11) 34 (13) Central nervous system 16 (6) 18 (41) 32 (12) Respiratory 40 (15) Eye
42 Syndromes 17 Sequences
10 69 (5) 10 (8) 34b (26) 31 (24) 40 (31) 14 (11)
45 48 24 31
(25) (27) (16) (17)
129 (66)
4 (2) 9 (5) 18 (10) 179 (12)
[Wojtalik et al., 2005] 1856
[Meberg et al., 2007] 662
5
31 (60) 9 (17) 3 (6) 2 (4) 7 (13) 52 (8) 3 (11) 1 (4)
4 (15) 3 (11) 14 (54) 1 (4) 26 (4) 20 (20) 22 (22) 35 (35) 14 (14) 4 (4)
22 (25) 8 (9) 13 (15) 9 (10) 12 (13) 2 (2) 3 (3)
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Table 5 (continued )
Ear Orofacial Abdominal wall Diaphragme Other Total
[Kenna et al., 1975] 1081
[Greenwood et al., 1975] 1566
[Gallo et al., 1976] 1354
34 (10)
6 (14)
60 (22)
[Wallgren et al., 1978] 1000
[Ferencz et al., 1987] 1494
3 (3)
6 (7) 8 (9) 4 (4)
20 (6) 86 (24) 354 (10)
8 (18) 44 (6)
14 (5) 267 (46)
98 (4)
2 (2) 89 (10)
[Dadvand et al., 2009] 5715
[Dilber and Malci c, 2010] 1480
[Miller et al., 2011] 7984
[Baker et al., 2012] 141g
[Lowry et al., 2013] 3751
8 (36)
218 (61) 40 (11) 13 (4) 24 (7) 16 (4) 49 (14) 360 (10)
Recognizable conditions Chromosomal abnormalities Trisomy 21 365 (55) 97 (90) 536 (56) Trisomy 18 80 (12) 3 (3) 134 (14) Trisomy 13 32 (5) 2 (2) 63 (7) Turner syndrome 6 (6) Deletions 22q11.2 54 (6) Other 188 (28) 162 (17) Total 665 (12) 108 (7) 949 (12) Nonchromosomal conditions VACTERL association 2 (6) 62 (39) Noonan syndrome 3 (10) OAVS De Lange syndrome HolteOram syndrome Di George syndrome 11 (35) Williams syndrome 6 (19) Other 9 (29) 89f (55) Teratogena 10 (6) Total 31 (2) 161 (2) Non recognizable conditions: congenital anomalies by organ system (recognizable conditions excluded) Musculoskeletal 242 (36) 378 (21) Urinary 184 (28) 9b (12) 249 (14) Genital 160 (9) Gastrointestinal 178 (27) 18 (24) 272 (15) Central nervous system 10 (13) 251 (15) Respiratory 113 (6) Eye 103 (6) Ear 65 (4) Orofacial 24 (32) 108 (6) Abdominal wall 44 (2) Diaphragme 37 (2) Other 64 (10) 15 (20) 13 (1) Total 668 (12) 76 (5) 1793 (14) [Fung et al., 2013] 2339
1 (5) 5 (23) 8 (36) 22 (16)
24 (16) 12 (8) 6 (4) 4 (3) 4 (3)
88 (59) 11 (7) 149 (4)
31(53)
27 (47)
58 (41)
[Jorgensen et al., 2014] 179
Recognizable conditions Chromosomal abnormalities Trisomy 21 105(47) 18 (30) Trisomy 18 16 (27) Trisomy 13 1(0.5) Turner syndrome 9 (4) 5 (8) Deletions 22q11.2 Other 108 (48) 20 (34) Total 223 (10) 59 (33) Nonchromosomal conditions VACTERL association 4 (4) 6 (10) Noonan syndrome 15 (14) 2 (3) OAVS 4 (4) De Lange syndrome HolteOram syndrome Di George syndrome 43 (40) 3 (5) Williams syndrome 9 (8) Other 33 (30) 44 (76) Teratogena 4 (7) Total 108 (5) 59 (33) Non recognizable conditions: congenital anomalies by organ system (recognizable conditions excluded) Musculoskeletal 112 (24) Urinary 21 (4) Genital 21 (4) Gastrointestinal 58 (12)
130 (30) 75 (14) 37 (7) 62 (11) 59 (11) 22 (4) 14 (3) 13 (2) 42 (8) 44 (8) 25 (5) 24 (4) 547 (9) [This study] 4005
218 (62) 53 (15) 22 (6) 10 (3) 20 (6) 31 (9) 354 (9) 23 (23) 8 (8) 3 (3) 3 (3) 2 (2) 4 (4) 3 (3) 44 (44) 9 (9) 99 (3) 217 (18) 238 (20) 58 (5) 196 (16) (continued on next page)
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Table 5 (continued ) [Fung et al., 2013] 2339 Central nervous system Respiratory Eye Ear Orofacial Abdominal wall Diaphragme Other Total a b c d e f g
[Jorgensen et al., 2014] 179
[This study] 4005
12 (7)
116 (10) 21 (2) 42 (4) 132 (11) 37 (3) 44 (4) 27 (2) 69 (6) 1197 (15)
29 (6) 40 (8) 96 (20)e 21(4)
74 (16) 472 (20)
Including fetal alcohol syndrome. Urinary and Genital. 17 suspected syndromes. Associated anomalies were analyzed in 368 index patients. Eye and Ear. Including 66 single gene determined syndromes. Screening modalities included karyotype, fluorescent in situ hybridization for 22q11.2 deletion, renal ultrasound, and head ultrasound.
known to cause CHD. Unfortunately, our study was performed before the array CGH technology was available. A large number of mouse knockout studies have identified more than 300 genes with offspring manifesting a phenotypic spectrum which mimics the human CHDs and numerous candidate genes have been discussed [Blue et al., 2012]. Al Turqui et al. [2014] showing that rare variants in NR2F2 cause CHD in humans added NR2F2 to the short list of genes that have been shown, when mutated, to interfere with normal heart development and that lead to CHD in both mice and humans: TBX5, TBX1, TBX3, NKX2-5, and GATA 4. Another gene, ADAP2 can be added to this list [Venturin et al., 2014]. The potential limitations of the present study include the small number of cases in some categories of CHD and the lack of molecular studies of the patients with CHD. However, the study was performed in a homogeneous population, and complete ascertainment was obtained. The strength of our study involves a well-defined population in which all cases were referred to the Registry of Congenital Anomalies including live births, stillbirths, and termination of pregnancies, live born infants were followed up until 2 years of age, the cases were reported by several sources, every patient was examined by a clinical geneticist, and the registration was active. In conclusion, we have determined a frequency of congenital anomalies associated with CHD of 26%. This result was derived from a geographically-based cohort of close to 350,000 pregnancies. The associated anomalies underscore the need for thorough evaluation and careful characterization of cases with CHD. A multidisciplinary approach is needed to comprehensively cover all aspects of these often complicated cases. A routine screening for other congenital anomalies, especially of the renal, musculoskeletal, digestive, ear, face and neck, and central nervous system need to be considered in cases with CHD, and genetic counseling seems warranted in most of these complicated cases. Pediatricians, pediatric cardiologists, geneticists and birth defects surveillance programs should be aware that the anomalies associated with CHD can be classified into a recognizable anomaly syndrome or pattern in at least 11% of the cases. Conflicts of interest The authors declare there are no conflicts of interest. References Al Turki S, Manickaraj AK, Mercer CL, Gerety SS, Hitz MP, Lindsay S, et al. Rare variants in NR2F2 cause congenital heart defects in humans. Am. J. Hum. Genet. 2014;94:574e85. Baker K, Sanchez-de-Toledo J, Munoz R, Orr R, Kiray S, Shiderly D, et al. Critical congenital heart disease-utility of routine screening for chromosomal and other extracardiac malformations. Congenit. Heart Dis. 2012;7:145e50.
Bedard T, Lowry RB, Sibbald B, Harder JR, Trevenen C, Horobec V, et al. Folic acid fortification and the birth prevalence of congenital heart defect cases in Alberta, Canada. Birth Defects Res. A Clin. Mol. Teratol. 2013;97:564e70. Blue GM, Kirk EP, Sholler GF, Harvey RP, Winlaw DS. Congenital heart disease: current knowledge about causes and inheritance. Med. J. Aust. 2012;197:155e9. Bosi G, Scorrano M, Tosato G, Forini E, Chakrokh R, the Working Party of the Italian society of pediatric Cardiology. The Italian Multicentre study on epidemiology of congenital heart disease: first step of the analysis. Cardiol. Young 1999;9: 291e9. Botto LD, Khoury MJ, Mulinare J, Erickson JD. Periconceptional multivitamin use and occurrence of conotruncal heart defects: results from a population-based casee control study. Pediatrics 1996;9:911e7. Botto LD, Lin AE, Riehle-Colarusso T, Malik S, Correa A. National Birth Defects Prevention Study, Seeking causes: classifying and evaluating congenital heart defects in etiologic studies. Birth Defects Res. A Clin. Mol. Teratol. 2007;79: 714e27. Bound JP, Logan WFWE. Incidence of congenital heart disease in Blackpool, 1957e 1971. Br. Heart J. 1977;39:445e50. Bower C, Ramsay JM. Congenital heart disease: a 10 year cohort. J. Paediatr. Child Health 1994;30:414e8. Brennan P, Young ID. Congenital heart malformations: aetiology and associations. Semin. Neonatol. 2001;6:17e25. Calzolari E, Garani G, Cocchi G, Magnani C, Rivieri F, Neville A, et al. Congenital heart defects: 15 years of experience of the EmiliaeRomagna Registry (Italy). Eur. J. Epidemiol. 2003;18:773e80. Carlgren L-E. Incidence of congenital heart disease in children born in Gothenburg, 1941e1950. Br. Heart J. 1959;21:40e50. Csáky-Szunyogh M, Vereczkey A, Kósa Z, Gerencsér B, Czeizel AE. Risk and protective factors in the origin of conotruncal defects of heartea population-based caseecontrol study. Am. J. Med. Genet. Part A 2013;161A:2444e52. Dadvand P, Rankin J, Shirley MD, Rushton S, Pless-Mulloli T. Descriptive epidemiology of congenital heart disease in Northern England. Pediatr. Perinat. Epidemiol. 2009;23:58e65. Dickinson DF, Arnold R, Wilkinson JL. Congenital heart disease among 160 480 liveborn children in Liverpool 1960 to 1969. Implications for surgical treatment. Br. Heart J. 1981;46:55e62. Dilber D, Malci c I. Spectrum of congenital heart defects in Croatia. Eur. J. Pediatr. 2010;169:543e50. Eskedal L, Hagemo P, Eskild A, Aamodt G, Seiler KS, Thaulow E. A population-based study of extra-cardiac anomalies in children with congenital cardiac malformations. Cardiol. Young 2004;14:600e7. EUROCAT Special Report. Congenital Heart Defects in Europe 2000e2005. EUROCAT Central Registry, University of Ulster; March 2009. www.eurocat.ulster.ac.uk/ pdf/Special-Report. EUROCAT: http://www.eurocat-network.eu/. 2009 Feldt RH, Avasthey P, Yoshimasu F, Kurland LT, Titus JL. Incidence of congenital heart disease in children born to residents of Olmstead County, Minnesota, 1950e 1969. Mayo Clin. Proc. 1971;46:794e9. Ferencz C, Rubin JD, McCarter RJ, Brenner JI, Neill CA, Perry LW, et al. Congenital heart disease: prevalence at livebirth. The Baltimore-Washington Infant Study. Am. J. Epidemiol. 1985;121:31e6. Ferencz C, Rubin JD, McCarter RJ, Boughman JA, Wilson PD, Brenner JI, et al. Cardiac and noncardiac malformations observations in a population-based study. Teratology 1987;35:367e78. Ferencz C, Correa-Villasenor A. Epidemiology of cardiovascular malformations: the state of the art. Cardiol. Young 1991;1:264e84. Fung A, Manlhiot C, Naik S, Rosenberg H, Smythe J, Lougheed J, et al. Impact of prenatal risk factors on congenital heart disease in the current era. J. Am. Heart Assoc. 2013;2:e000064. Fyler DC. Report of the New England regional infant cardiac program. Pediatrics 1980;65(2 Pt 2):375e461.
C. Stoll et al. / European Journal of Medical Genetics 58 (2015) 75e85 Gallo P, Nardi F, Marinozzi V. Congenital extracardial malformations accompanying congenital heart disease. G. Ital. Cardiol. 1976;6:450e9. Greenwood RD, Rosenthal A, Parisi L, Fyler DC, Nadas AS. Extracardiac abnormalities in infants with congenital heart disease. Pediatrics 1975;55:485e92. Grech V, Gatt M. Syndromes and malformations associated with congenital heart disease in a population-based study. Int. J. Cardiol. 1999;68:151e6. Güçer S, Ýnce T, Kale G, Akçören Z, Özkutlu S, Talim B, et al. Noncardiac malformations in congenital heart disease: a retrospective analysis of 305 pediatric autopsies. Turk. J. Pediatr. 2005;47:159e66. Hanna EJ, Nevin NC, Nelson J. Genetic study of congenital heart defects in Northern Ireland (1974e1978). J. Med. Genet. 1994;31:858e63. Hoffman JIE, Christianson R. Congenital heart disease in a cohort of 19,502 births with long-term follow-up. Am. J. Cardiol. 1978;42:641e7. Jorgensen M, McPherson E, Zaleski C, Shivaram P, Cold C. Stillbirth: the heart of the matter. Am. J. Med. Genet. A 2014;164A:691e9. Källen K, Robert E, Mastroiacovo P, Castilla EE, Kallen B. CHARGE association in newborns: a registry-based study. Teratology 1999;60:334e43. Källen K, Mastroiacovo P, Castilla EE, Robert E, Kallen B. VATER non-random association of congenital malformations: study based on data from four malformation registers. Am. J. Med. Genet. 2001;101:26e32. Kenna AP, Smithells RW, Fielding DW. Congenital heart disease in Liverpool: 1960e 69. Q. J. Med. 1975;44:17e44. Kidd SA, Lancaster PA, McCredie RM. The incidence of congenital heart defects in the first year of life. J. Paediatr. Child Health 1993;29:344e9. Kirby ML. Cardiac morphogenesis e recent research advances. Pediatr. Res. 1987;21: 219e24. Kramer HH, Majewski F, Trampisch HJ, Rammos S, Bourgeois M. Malformation patterns in children with congenital heart disease. Am. J. Dis. Child. 1987;141: 789e95. Lalani SR, Shaw C, Wang X, Patel A, Patterson LW, Kolodziejska K, et al. Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities. Eur. J. Hum. Genet. 2013;21:173e81. Laursen HB. Some epidemiological aspects of congenital heart disease in Denmark. Acta Paediatr. Scand. 1980;69:619e24. Lowry RB, Bedard T, Sibbald B, Harder JR, Trevenen C, Horobec V, et al. Congenital heart defects and major structural noncardiac anomalies in Alberta, Canada, 1995e2002. Birth Defects Res. A Clin. Mol. Teratol. 2013;97:79e86. Meberg A, Hals J, Thaulow E. Congenital heart defectsechromosomal anomalies, syndromes and extracardiac malformations. Acta Paediatr. 2007;96:1142e5. Miller A, Riehle-Colarusso T, Alverson CJ, Frias J, Correa A. Congenital heart defects and major structural noncardiac anomalies, Atlanta, Georgia, 1968 to 2005. J. Pediatr. 2011;159:70e8. Mitchell SC, Korones SB, Berendes HN. Congenital heart disease in 56,109 births. Circulation 1971;43:323e32.
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Montaña E, Khoury MJ, Cragan JD, Sharma S, Dhar P, Fyfe D. Trends and outcomes after prenatal diagnosis of congenital cardiac malformations by fetal echocardiography in a well defined birth population, Atlanta, Georgia, 1990e1994. J. Am. Coll. Cardiol. 1996;28:1805e9. Pexieder T, Bloch D. EUROCAT Working Party on Congenital Heart Disease. EUROCAT Subproject on epidemiology of congenital heart disease: first analysis of the completed study. In: Clark EB, Marwald RR, Takao A, editors. Developmental mechanisms of heart disease. NY: Futura, Armonk; 1995. pp. 655e68. Pradat P. Noncardiac malformations at major congenital heart defects. Pediatr. Cardiol. 1997;18:11e8. Rasmussen SA, Olney RS, Holmes LB, Lin AE, Keppler-Noreuil KM, Moore CA. Guidelines for case classification for the national birth defects prevention study. Birth Defects Res. A Clin. Mol. Teratol. 2003;67:193e201. Riehle-Colarusso T, Strickland MJ, Reller MD, Mahle WT, Botto LD, Siffel C, et al. Improving the quality of surveillance data on congenital heart defects in the metropolitan Atlanta congenital defects program. Birth Defects Res. A Clin. Mol. Teratol. 2007;79:743e53. Stephensen SS, Sigfusson G, Eiriksson H, Sverrisson JT, Torfason B, Haraldsson A, et al. Congenital cardiac malformations in Iceland from 1990 through 1999. Cardiol. Young 2004;14:396e401. Stevenson RE, Seaver LH, Collins JS, Dean GH. Neural tube defects and associated anomalies in South Carolina. Birth Defects Res. A Clin. Mol. Teratol. 2004;70:554e8. Stoll C, Roth M-P. The Northeastern France birth defects monitoring system. In: Marois M, editor. Prevention of physical and mental congenital defects, Part B. New York: Alan R. Liss; 1985. pp. 157e62. Stoll C, Dott B, Roth MP, Alembik Y, De Geeter B. Risks factors in congenital heart diseases. Eur. J. Epidemiol. 1989;5:382e91. Stoll C, Garne E, Clementi M, and the EUROSCAN study group. Evaluation of prenatal diagnosis of associated congenital heart diseases by fetal ultrasonographic examination in Europe. Prenat. Diagn. 2001;21:243e52. Tegnander E, Williams W, Johansen OJ, Blaas HG, Eik-Nes SH. Prenatal detection of heart defects in a non-selected population of 30,149 fetuses-detection rates and outcome. Ultrasound Obstet. Gynecol. 2006;27:252e65. Tennstedt C, Chaoui R, Körner H, Dietel M. Spectrum of congenital heart defects and extracardiac malformations associated with chromosomal abnormalities: results of a seven year necropsy study. Heart 1999;82:34e9. Venturin M, Carra S, Gaudenzi G, Brunelli S, Gallo GR, Moncini S, et al. ADAP2 in heart development: a candidate gene for the occurrence of cardiovascular malformations in NF1 microdeletion syndrome. J. Med. Genet. 2014;51:436e43. Wallgren EI, Landtman B, Rapola J. Extracardiac malformations associated with congenital heart disease. Eur. J. Cardiol. 1978;7/1:15e24. skia W, Henschkea J, Wroneckie K, Siwin skac A, Wojtalik M, Mrówczyn skia M, et al. Congenital heart defect with associated malformations in Piaszczyn children. J. Pediat. Surg. 2005;40:1675e2180.
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Clinical research
Associated noncardiac congenital anomalies among cases with congenital heart defects Claude Stoll*, Beatrice Dott, Yves Alembik, Marie-Paule Roth Laboratoire de Genetique Medicale, Faculte de Medecine, Strasbourg, France
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 August 2014 Accepted 3 December 2014 Available online 12 December 2014
Cases with congenital heart defects (CHD) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CHD in a defined population. The anomalies associated with CHD were collected in all live births, stillbirths and terminations of pregnancy during 26 years in 346,831 consecutive pregnancies of known outcome in the area covered by our population based registry of congenital anomalies. Of the 4005 cases with CHD born during this period (total prevalence of 115.5 per 10,000), 1055 (26.3%) had associated major anomalies. There were 354 (8.8%) cases with chromosomal abnormalities including 218 trisomies 21, and 99 (2.5%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognized dysmorphic conditions, but VACTERL association. However, other recognized dysmorphic conditions were registered including Noonan syndrome, fetal alcohol syndrome, and skeletal dysplasias. Six hundred and two (15.0%) of the cases had non syndromic, non chromosomal multiple congenital anomalies (MCA). Anomalies in the urinary tract, the musculoskeletal, the digestive, and the central nervous systems were the most common other anomalies. Prenatal diagnosis was obtained in 18.7% of the pregnancies. In conclusion the overall prevalence of associated anomalies, which was one in four infants, emphasizes the need for a thorough investigation of cases with CHD. A routine screening for other anomalies may be considered in infants and in fetuses with CHD. One should be aware that the anomalies associated with CHD can be classified into a recognizable anomaly, syndrome or pattern in one out of nine cases with CHD. Ó 2014 Elsevier Masson SAS. All rights reserved.
Keywords: Congenital heart defects Congenital heart disease Cardiac anomalies Noncardiac anomalies Syndromes Surveillance Ascertainment Etiology
1. Introduction Studies of other defects associated with specific congenital anomalies may be helpful to understand embryonic development, identify the causes of congenital anomalies, determine recurrence risks, and guide expectations for the efficacy of prevention strategies [Stevenson et al., 2004]. Congenital heart defects are one of the most common congenital anomaly, representing approximately 45% of all prenatally diagnosed anomalies [Stoll et al., 2001] with a reported rate per 10,000 live births or total births varying from 43 to 124 [Lowry et al., 2013]. CHD occur in as many as 1 in 100 live births and in 1 in 500 fetal ultrasonographic examination [Meberg et al., 2007; Tegnander et al., 2006]. Many cases with CHD will have a coexisting defect involving noncardiac structures.
Individual cases of CHD may differ widely in their cause. Specific genetic factors, such as chromosomal abnormalities and inherited mutations in developmental genes, or environmental influences on fetal development i.e. medications [Stoll et al., 1989] may form the underlying cause. Although it has long been known that CHD are frequently associated with other congenital anomalies, their reported frequency and the type of associated anomalies observed vary considerably among different studies. Using data from our surveillance system of congenital anomalies over a 26-year period, we evaluated the nature and frequency of anomalies associated with CHD to identify recognizable conditions and specific patterns of associated anomalies, which could give hints about the pathogenesis of CHD.
2. Material and methods * Corresponding author. Laboratoire de Génétique Médicale, Faculté de Médecine 11, rue Humann, 67085 Strasbourg Cedex, France. Tel.: þ33 3 68 85 32 07; fax: þ33 3 68 85 31 79. E-mail address: [email protected] (C. Stoll). http://dx.doi.org/10.1016/j.ejmg.2014.12.002 1769-7212/Ó 2014 Elsevier Masson SAS. All rights reserved.
Cases with anomalies for this study were derived from 346,674 consecutive pregnancies of known outcome, including live births and stillbirths, and 157 terminations of pregnancy for fetal
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abnormality regardless of gestational age, registered by our registry of congenital anomalies described previously [Stoll and Roth, 1985]. Minor anomalies were excluded according to EUROCAT [2009] guidelines for registration of congenital anomalies (http://www. eurocat-network.eu). Cases born in 11 maternity hospitals were examined from January 1, 1979 to December 31, 2004. The region of investigation was the city of Strasbourg, France (an urban area), and the area defined by the Departement du Bas-Rhin, in which Strasbourg is situated (a rural area). Newborn pulse oximetry screening was not used in the region under study. All newborns were registered within the first 8 days postpartum, as were all fetuses aborted because of anomalies discovered at prenatal diagnosis. As everywhere in our country, no delivery took place at home in the area under study. All cases with CHD and associated anomalies, live births, stillbirths and elective terminations of pregnancy for fetal anomaly were examined by a clinical geneticist. CHD diagnoses were confirmed by echocardiography, cardiac catheterization, surgery and/or autopsy. Common to most studies, patent ductus arteriosus was included in full-term infants in whom the defect persisted for a minimum of 3 months or required surgery. Patent foramen ovale versus atrial septal defect (ASD) was excluded in full-term infants if closed within 3 months or was 1,200,000 LB, FD, SB 7984 z66.5 2289 (29)
2000e2005 3,327,591 LB, FB, TOP 26,598 80.3d 7404 (28)
2004e2008 ? LB, CICU 141 ? 80 (57)
1995e2002 ? LB, SB, TOP 3751 124 867 (23)
2008e11 ? LB, Biobank 2339 ? 803 (34)
1983e2013 ? SB, FD, Autopsy 179 ? 130 (73)
1979e2004 346,831 LB, SB, TOP 4005 115.5 1055 (26)
C. Stoll et al. / European Journal of Medical Genetics 58 (2015) 75e85
Study years N of births Study population Total N Prevalence Associated N (%)
[Kenna et al., 1975]
LB, live births; SB, still births; FD, fetal deaths; TB, total births; TOP, termination of pregnancy for fetal anomaly; CICU, cardiac intensive care unit. Diagnosis confirmed by invasive techniques in 388 index cases. Chromosomal anomalies were excluded. In 43 registries of congenital anomalies from 23 European countries reporting their results to EUROCAT [2009], the prevalence of CHD varied from 53.9 (Croatia) to 153.4 (Austria).
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criteria, the variability of clinical expression of associated anomalies, the difficulty to know the proportion of patients diagnosed by objective techniques, the selection of patients, the sources of ascertainment, and the sample size. In addition to these factors, autopsies were not always performed, there was not always follow-up, many authors did not report all patients born in a certain geographical area, but instead, patients referred to a certain health care facility, and there are true population differences and changes in frequency over time (EUROCAT [2009]: http:// www.eurocat-network.eu). Moreover, many of the prevalence estimates are uncertain due to small numbers. The same concerns exist for the comparisons of subgroups of associated anomalies. In this study chromosomal abnormalities were observed in 354 (8.8%) infants with CHD. The reported percentages of chromosomal abnormalities in infants with CHD vary from 3 in Northern Ireland [Hanna et al., 1994] to 33 in Norway [Tennstedt et al., 1999] and Wisconsin [Jorgensen et al., 2014] (Table 5). The low percentage of chromosomes abnormalities in Northern Ireland is explained by the fact that at that time, 1974e1978, patients with Down syndrome were not investigated by invasive heart techniques and the 3% refers to patients who had such investigations. In the autopsy group the percentages of chromosomal abnormalities in cases with CHD was high, 33 in Norway [Tennstedt et al., 1999] and Wisconsin [Jorgensen et al., 2014] (Table 5). In the other studies, the percentages of chromosomal abnormalities varied from 6 [Greenwood et al., 1975; Kenna et al., 1975; Kramer et al., 1987; Wallgren et al., 1978] to 13 [Montaña et al., 1996] and 16 [Baker et al., 2012]. In this study 62% of the chromosomal anomalies were trisomy 21. In the other series the more common chromosomal abnormality was also trisomy 21 with a percentage ranging from 15 [Tennstedt et al., 1999] to 98 [Wallgren et al., 1978] (Table 5). In our study the other chromosomal anomalies were trisomy 18 (15%), trisomy 13 (6%), Turner syndrome (3%), and chromosomal structural aberrations (14%). This figure compares well with that in other studies (Table 5) except for the study of autopsy cases of Gücer et al. [2005] who had more trisomy 18 than trisomy 21 since the latter is the more likely to survive than the former. Many syndromes, sequences, associations and spectrums were reported to be associated with CHD [Brennan and Young, 2001]. In our series 99 out of 4005 (2.5%) cases with CHD had non chromosomal recognizable conditions including VACTERL association (23%), Noonan syndrome (8%), fetal alcohol syndrome (7%), skeletal dysplasias (6%) and many other recognizable conditions such as CHARGE syndrome, de Lange syndrome, oculo-auriculo-vertebral spectrum, Williams syndrome, and HolteOram syndrome (Table 3). In the previous reports the percentage of non chromosomal recognizable conditions varied considerably (Table 5) from 1% in the studies of Pradat [1997] and of Stephensen et al. [2004] to 8% in the series of Kramer et al. [1987]. In the stillborn cohort of Jorgensen et al. [2014], most CHD (70%) were associated with other anomalies. While recognizing that these actually comprise a variety of syndromes, sequences, and associations, the authors for convenience refer to this group comprising 33% of the stillborn as “syndromic”. As in this series, VACTERL association was also the most common recognizable non chromosomal condition in the other studies with a percentage ranging from 3 [Eskedal et al., 2004; Kramer et al., 1987] to 38 [Miller et al., 2011] (Table 5). In the older series (Table 5), Di George was a clinical diagnosis with a percentage ranging from 1 [Bower and Ramsay, 1994] to 8 [Ferencz et al., 1987]. The use of new cytogenetic methods i.e. FISH increased the rate of detection of 22q11.2 deletion as, for example, in the study of Fung et al. [2013] in which 19% of the cases tested were carrier of a 22q11.2 deletion.
In this study, among the MCA, septal defects were the most common CHD (58.6% including VSD 38.0% and ASD 20.6%) followed by RVOTO (9.7%), LVOTO (8.3%) and conotruncal defects (6.9%). This differs from the literature in which Lowry et al. [2013] reported conotruncal defects as being the most frequent in their MCA group and Gücer et al. [2005] reported VSD and Miller et al. [2011] ASD. However, Miller et al. [2011] included known associations in their MCA and Gücer et al. [2005] included minor anomalies, syndromes and chromosomal anomalies [Lowry et al., 2013]. There is no agreement in the literature as to which associated anomalies are most common in cases with CHD and MCA. In this study (Table 3) the most common associated anomalies were renal, musculoskeletal, digestive, ear, face and neck, central nervous, genital, abdominal wall, and eye. The most common anomalies among renal anomalies were renal agenesis, ureteral anomalies, hydronephrosis and cystic kidney; among musculoskeletal anomalies limb reduction defects, polydactyly, spine, rib, sternum anomalies and syndactyly; among digestive system anomalies anal atresia and malrotation; among central nervous system hydrocephaly, arhinencephaly, agenesis of corpus callosum; among ear, face and neck ear anomaly, facial dysmorphism and hypertelorism; among genital anomaly internal female genitalia anomaly and hypospadias, and among abdominal wall anomalies omphalocele and gastroschisis. In the other previous 25 studies available (Table 5) the most common associated anomalies were musculoskeletal anomalies in 12 series, gastrointestinal anomalies in 4 studies, urinary anomalies in 3 studies, and orofacial anomalies in 2 studies. However, it is difficult to compare our results with those of other studies as, for example some authors include the patients with isolated CHD in the total number of patients. Other reasons for the discrepancies between the reported studies and this study were aforementioned. In order to evaluate cases and to compare studies, it is necessary to standardize the methods of case classification. Congenital anomalies and associated anomalies must be grouped into meaningful syndromes and conditions. Methods for case classification into isolated, multiple and syndrome categories were described [Rasmussen et al., 2003]. Consideration of these guidelines will lead to more comparable case groups, an important element of careful studies aimed at identifying etiology of congenital anomalies. The causes of CHD include [Brennan and Young, 2001] chromosomal abnormalities; dominant or recessive genes (single gene determination); familial inheritance in the absence of single gene determination; teratogenic exposures (i.e. ethanol, sodium valproate, retinoic acid, lithium, rubella, cytomegalovirus, and maternal diabetes); and unknown causes. CHD are often associated with known syndromes, sequences, associations, spectrums and related anomalies (i.e., VACTERL association, Noonan syndrome). The prenatal exposure to teratogens may be preventable. Moreover, some observational studies showed a preventive effect of multivitamins in the early pregnancy particularly in conotruncal defects [Botto et al., 1996]. More recently, in Hungary, CsàkySzunyogh et al. [2013] showed that high doses of medically recorded folic acid in early pregnancy were able to reduce the birth prevalence of conotruncal defects, and this reduction was significant in transposition of the great arteries as well. However, the preventive effect of high doses of folic acid for CHD is not yet proven [Bedard et al., 2013]. The molecular basis for CHD remains unknown. A discussion of the molecular basis of CHD is beyond the scope of this paper. In short, Lalani et al. [2013] identified 55 copy number variants (CNV) >50 kb in length that were present in subjects with CHD and extracardiac anomalies and were absent in controls and they delineate regions within previously reported structural variants
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Table 5 Review of literature: recognizable and nonrecognizable conditions in cases with congenital heart defects and associated malformations: N (%). The number of cases are under the authors names. The percentage after total is a percentage of the total number of cases. For nonrecognizable conditions some authors reported the number of anomalies, this number is then in bold type whereas for authors reporting the number of cases, this number is in plain type. [Kenna et al., 1975] 1081
[Greenwood et al., 1975] 1566
[Gallo et al., 1976] 1354
Recognizable conditions Chromosomal abnormalities Trisomy 21 57 (93) 63 (71) 78 (91) Trisomy 18 7 (8) 6 (7) Trisomy 13 5 (6) 2 (2) Turner syndrome 5 (6) Deletions 22q11.2 Other 4 (7) 9 (10) Total 61(6) 89 (6) 86 (6) Nonchromosomal conditions VACTERL association Noonan syndrome 1(2) OAVS 1 (2) De Lange syndrome 2 (5) HolteOram syndrome 1 (2) Di George syndrome 3 (7) Williams syndrome Other 10 (23) Teratogena 25 (58) Total 43 (3) Non recognizable conditions: congenital anomalies by organ system (recognizable conditions excluded) Musculoskeletal 67 (18) 137 (26) 62 (8) Urinary 47 (13) 83b (16) 110(14) Genital 19 (5) 57 (7) Gastrointestinal 31 (8) 65 (12) 152(19) Central nervous system 40 (11) 107 (20) 44 (6) Respiratory 32 (9) 58 (11) 109(14) Eye 10 (3) Ear Orofacial 30 (8) 18 (2) Abdominal wall 5 (1) Diaphragme 4 (1) Other 86 (23) 78 (14) 238(30) Total 371(15) 528 (17) 790(27) [Kramer et al., 1987] 1016
[Stoll et al., 1989] 801
Recognizable conditions Chromosomal abnormalities Trisomy 21 43 (77) 45 (62) Trisomy 18 2 (4) 15 (21) Trisomy 13 7 (10) Turner syndrome 3 (5) 1 (1) Deletions 22q11.2 Other 8 (14) 4 (6) Total 56 (6) 72 (9) Nonchromosomal conditions VACTERL association 2 (3) 2 (10) Noonan syndrome 14 (18) 1 (5) OAVS De Lange syndrome HolteOram syndrome 2 (3) 1 (5) Di George syndrome Williams syndrome 5 (6) Other 29 (37) 16 (80) a Teratogen 29 (37) Total 79 (8) 20 (2) Non recognizable conditions: congenital anomalies by organ system (recognizable conditions Musculoskeletal 27 (40) 46 (21) Urinary 8 (12) 45 (21) Genital 11 (5) Gastrointestinal 9 (13) 37 (17) Central nervous system 15 (22) 22 (11) Respiratory 9 (13) Eye 8 (4) Ear Orofacial 32 (15) Abdominal wall
[Wallgren et al., 1978] 1000
[Ferencz et al., 1987] 1494
55 (98)
1 (2)
145(78) 10 (5) 15 (8) 7 (4)
56 (6)
10 (5) 187(13) 8 (9) 4 (4)
4 (4) 7 (8) 4 (4) 64 (70) 91 (6)c
152 (13) 68 (9) 54 (7) 25 (3)
16 (13) 13 (10) 5 (4) 19 (15) 9 (7) 3 (2) 7 (6)
35 (4) 23 (3) 19 (2) 120 (15) 787(38)
3 (2) 6 (5) 2 (2) 43 (34) 126 (8)
[Kidd et al., 1993] 1479
[Bower and Ramsay, 1994] 1787
[Hanna et al., 1994] 972d
106 (75)
99 (65) 23 (15) 9 (6) 5 (3)
4 (33)
35 (25) 141(10)
16 (11) 152 (9)
8 (66) 12 (3)
33 (2) excluded)
138(18) 153b (19)
18 (21) 4 (5) 1 (1) 3 (4) 3 (4) 1 (1) 5 (6) 39 (46) 13 (15) 87 (5)
3 (38) 1 (12) 1 (12)
2 (25) 1 (12) 8 (2) 22 (20) 20 (18) 1 (1) 33 (30) 6 (6) 14e (13)
(continued on next page)
82
C. Stoll et al. / European Journal of Medical Genetics 58 (2015) 75e85
Table 5 (continued )
Diaphragme Other Total
[Kenna et al., 1975] 1081
[Greenwood et al., 1975] 1566
[Gallo et al., 1976] 1354
[Wallgren et al., 1978] 1000
[Ferencz et al., 1987] 1494
68 (7)
17 (8) 218 (14)
189 (13)
211 (12)
12 (11) 108 (18)
[Grech and Gatt, 1999] 231
[Tennstedt et al., 1999] 129
[Calzolari et al., 2003] 1549
19 (15) 11 (9) 6 (5) 3 (2)
115 (76) 11 (7) 6 (4)
4 (3) 43 (33)
20 (13) 152 (10)
[Montaña et al., 1996] 1589
[Pradat, 1997] 2618
Recognizable conditions Chromosomal abnormalities Trisomy 21 19(90) Trisomy 18 1 (5) Trisomy 13 Turner syndrome Deletions 22q11.2 Other 1 (5) Total 206 (13) 21 (9) Nonchromosomal conditions VACTERL association 1 (25) Noonan syndrome 5 (19) 2 (50) OAVS 2 (7) De Lange syndrome 1 (4) HolteOram syndrome 1 (25) Di George syndrome 8 (30) Williams syndrome 2 (7) Other 9 (33) a Teratogen Total 27 (1) 4 (2) Non recognizable conditions: congenital anomalies by organ system (recognizable conditions excluded) Musculoskeletal 10.9% 133 (15) 4 (29) Urinary 80 (9) 1 (7) Genital 37 (4) Gastrointestinal 11.8% 127 (15) 1 (7) Central nervous system 10% 30 (3) 1 (7) Respiratory 22 (2) 1 (7) Eye 24 (3) 1 (7) Ear 31 (4) Orofacial 120 (14) 2 (14) Abdominal wall 37 (4) Diaphragme 21 (2) Other 204 (24) 3 (21) Total 560 (35) 866(26) 14 (6) [Eskedal et al., 2004] 3527
[Stephensen et al., 2004] 740
[Gücer et al., 2005] 305
Recognizable conditions Chromosomal abnormalities Trisomy 21 286 (94) 28 (78) 7 (29) Trisomy 18 7 (2) 10 (42) Trisomy 13 3 (1) 6 (25) Turner syndrome 8 (3) Deletions 22q11.2 Other 8 (22) 1(4) Total 304 (9) 36 (5) 24 (8) Nonchromosomal conditions VACTERL association 5 (6) Noonan syndrome 17 (19) 4 (44) OAVS 1(8) De Lange syndrome 1(8) HolteOram syndrome 3 (3) Di George syndrome 16 (18) 1(8) Williams syndrome 21 (24) 3 (33) Other 27 (30) 2 (22) 9 (75) Teratogena Total 89 (3) 9 (1) 12 (4) Non recognizable conditions: congenital anomalies by organ system (recognizable conditions excluded) Musculoskeletal 41(15) Urinary 34 (10) 7b (16) 46b (17) Genital 45 (13) Gastrointestinal 119 (34) 5 (11) 34 (13) Central nervous system 16 (6) 18 (41) 32 (12) Respiratory 40 (15) Eye
42 Syndromes 17 Sequences
10 69 (5) 10 (8) 34b (26) 31 (24) 40 (31) 14 (11)
45 48 24 31
(25) (27) (16) (17)
129 (66)
4 (2) 9 (5) 18 (10) 179 (12)
[Wojtalik et al., 2005] 1856
[Meberg et al., 2007] 662
5
31 (60) 9 (17) 3 (6) 2 (4) 7 (13) 52 (8) 3 (11) 1 (4)
4 (15) 3 (11) 14 (54) 1 (4) 26 (4) 20 (20) 22 (22) 35 (35) 14 (14) 4 (4)
22 (25) 8 (9) 13 (15) 9 (10) 12 (13) 2 (2) 3 (3)
C. Stoll et al. / European Journal of Medical Genetics 58 (2015) 75e85
83
Table 5 (continued )
Ear Orofacial Abdominal wall Diaphragme Other Total
[Kenna et al., 1975] 1081
[Greenwood et al., 1975] 1566
[Gallo et al., 1976] 1354
34 (10)
6 (14)
60 (22)
[Wallgren et al., 1978] 1000
[Ferencz et al., 1987] 1494
3 (3)
6 (7) 8 (9) 4 (4)
20 (6) 86 (24) 354 (10)
8 (18) 44 (6)
14 (5) 267 (46)
98 (4)
2 (2) 89 (10)
[Dadvand et al., 2009] 5715
[Dilber and Malci c, 2010] 1480
[Miller et al., 2011] 7984
[Baker et al., 2012] 141g
[Lowry et al., 2013] 3751
8 (36)
218 (61) 40 (11) 13 (4) 24 (7) 16 (4) 49 (14) 360 (10)
Recognizable conditions Chromosomal abnormalities Trisomy 21 365 (55) 97 (90) 536 (56) Trisomy 18 80 (12) 3 (3) 134 (14) Trisomy 13 32 (5) 2 (2) 63 (7) Turner syndrome 6 (6) Deletions 22q11.2 54 (6) Other 188 (28) 162 (17) Total 665 (12) 108 (7) 949 (12) Nonchromosomal conditions VACTERL association 2 (6) 62 (39) Noonan syndrome 3 (10) OAVS De Lange syndrome HolteOram syndrome Di George syndrome 11 (35) Williams syndrome 6 (19) Other 9 (29) 89f (55) Teratogena 10 (6) Total 31 (2) 161 (2) Non recognizable conditions: congenital anomalies by organ system (recognizable conditions excluded) Musculoskeletal 242 (36) 378 (21) Urinary 184 (28) 9b (12) 249 (14) Genital 160 (9) Gastrointestinal 178 (27) 18 (24) 272 (15) Central nervous system 10 (13) 251 (15) Respiratory 113 (6) Eye 103 (6) Ear 65 (4) Orofacial 24 (32) 108 (6) Abdominal wall 44 (2) Diaphragme 37 (2) Other 64 (10) 15 (20) 13 (1) Total 668 (12) 76 (5) 1793 (14) [Fung et al., 2013] 2339
1 (5) 5 (23) 8 (36) 22 (16)
24 (16) 12 (8) 6 (4) 4 (3) 4 (3)
88 (59) 11 (7) 149 (4)
31(53)
27 (47)
58 (41)
[Jorgensen et al., 2014] 179
Recognizable conditions Chromosomal abnormalities Trisomy 21 105(47) 18 (30) Trisomy 18 16 (27) Trisomy 13 1(0.5) Turner syndrome 9 (4) 5 (8) Deletions 22q11.2 Other 108 (48) 20 (34) Total 223 (10) 59 (33) Nonchromosomal conditions VACTERL association 4 (4) 6 (10) Noonan syndrome 15 (14) 2 (3) OAVS 4 (4) De Lange syndrome HolteOram syndrome Di George syndrome 43 (40) 3 (5) Williams syndrome 9 (8) Other 33 (30) 44 (76) Teratogena 4 (7) Total 108 (5) 59 (33) Non recognizable conditions: congenital anomalies by organ system (recognizable conditions excluded) Musculoskeletal 112 (24) Urinary 21 (4) Genital 21 (4) Gastrointestinal 58 (12)
130 (30) 75 (14) 37 (7) 62 (11) 59 (11) 22 (4) 14 (3) 13 (2) 42 (8) 44 (8) 25 (5) 24 (4) 547 (9) [This study] 4005
218 (62) 53 (15) 22 (6) 10 (3) 20 (6) 31 (9) 354 (9) 23 (23) 8 (8) 3 (3) 3 (3) 2 (2) 4 (4) 3 (3) 44 (44) 9 (9) 99 (3) 217 (18) 238 (20) 58 (5) 196 (16) (continued on next page)
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C. Stoll et al. / European Journal of Medical Genetics 58 (2015) 75e85
Table 5 (continued ) [Fung et al., 2013] 2339 Central nervous system Respiratory Eye Ear Orofacial Abdominal wall Diaphragme Other Total a b c d e f g
[Jorgensen et al., 2014] 179
[This study] 4005
12 (7)
116 (10) 21 (2) 42 (4) 132 (11) 37 (3) 44 (4) 27 (2) 69 (6) 1197 (15)
29 (6) 40 (8) 96 (20)e 21(4)
74 (16) 472 (20)
Including fetal alcohol syndrome. Urinary and Genital. 17 suspected syndromes. Associated anomalies were analyzed in 368 index patients. Eye and Ear. Including 66 single gene determined syndromes. Screening modalities included karyotype, fluorescent in situ hybridization for 22q11.2 deletion, renal ultrasound, and head ultrasound.
known to cause CHD. Unfortunately, our study was performed before the array CGH technology was available. A large number of mouse knockout studies have identified more than 300 genes with offspring manifesting a phenotypic spectrum which mimics the human CHDs and numerous candidate genes have been discussed [Blue et al., 2012]. Al Turqui et al. [2014] showing that rare variants in NR2F2 cause CHD in humans added NR2F2 to the short list of genes that have been shown, when mutated, to interfere with normal heart development and that lead to CHD in both mice and humans: TBX5, TBX1, TBX3, NKX2-5, and GATA 4. Another gene, ADAP2 can be added to this list [Venturin et al., 2014]. The potential limitations of the present study include the small number of cases in some categories of CHD and the lack of molecular studies of the patients with CHD. However, the study was performed in a homogeneous population, and complete ascertainment was obtained. The strength of our study involves a well-defined population in which all cases were referred to the Registry of Congenital Anomalies including live births, stillbirths, and termination of pregnancies, live born infants were followed up until 2 years of age, the cases were reported by several sources, every patient was examined by a clinical geneticist, and the registration was active. In conclusion, we have determined a frequency of congenital anomalies associated with CHD of 26%. This result was derived from a geographically-based cohort of close to 350,000 pregnancies. The associated anomalies underscore the need for thorough evaluation and careful characterization of cases with CHD. A multidisciplinary approach is needed to comprehensively cover all aspects of these often complicated cases. A routine screening for other congenital anomalies, especially of the renal, musculoskeletal, digestive, ear, face and neck, and central nervous system need to be considered in cases with CHD, and genetic counseling seems warranted in most of these complicated cases. Pediatricians, pediatric cardiologists, geneticists and birth defects surveillance programs should be aware that the anomalies associated with CHD can be classified into a recognizable anomaly syndrome or pattern in at least 11% of the cases. Conflicts of interest The authors declare there are no conflicts of interest. References Al Turki S, Manickaraj AK, Mercer CL, Gerety SS, Hitz MP, Lindsay S, et al. Rare variants in NR2F2 cause congenital heart defects in humans. Am. J. Hum. Genet. 2014;94:574e85. Baker K, Sanchez-de-Toledo J, Munoz R, Orr R, Kiray S, Shiderly D, et al. Critical congenital heart disease-utility of routine screening for chromosomal and other extracardiac malformations. Congenit. Heart Dis. 2012;7:145e50.
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