Genetic epidemiology of cardiovascular malformations

Progress in Pediatric Cardiology 20 (2005) 113 – 126 www.elsevier.com/locate/ppedcard

Genetic epidemiology of cardiovascular malformationsB Angela E. Lina,*, Holly H. Ardingerb a

b

Genetics and Teratology Unit, MassGeneral Hospital for Children, Boston, MA, United States Section of Medical Genetics and Molecular Medicine, Children’s Mercy Hospital and University of Missouri-Kansas City School of Medicine, Kansas City, MO, United States Available online 13 June 2005

Abstract Pediatric heart disease includes an array of structural and functional abnormalities ranging from cardiovascular malformations (CVMs; also known as congenital heart defects, CHDs) to cardiomyopathy, tissue dysplasia, and disorders of rhythm. This review focuses on CVMs, an extremely important group of birth defects, because of their frequent occurrence (birth prevalence slightly less that one out of a hundred), contribution to morbidity and mortality (one-third of infant deaths due to congenital anomalies), association with additional anomalies (onefourth), and frequent presentation in malformation syndromes. As such, they represent a familiar public health concern. There has been tremendous progress in the medical and surgical treatment of CVMs. Current research pursues genetic epidemiology (the interplay of genetic and environmental factors), molecular determinants, and prevention by folic acid-containing multivitamins. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Cardiac defects; Cardiovascular genetics and malformations; Congenital heart anomalies; Epidemiology; MCA/MR syndrome; Prevalence

1. Introduction

reference list includes reviews, as well as original research papers.

1.1. Definitions 1.2. Scope When it comes to matters of the heart in children, the first task is defining the specific topic [1]. What professionals and patients commonly call ‘‘congenital heart disease’’ refers to an array of structural and functional abnormalities of the heart which are present at birth, although they may not be diagnosed until later in life. Depending on personal preference, a structural defect may be called congenital heart defect, congenital heart anomaly [2], or cardiovascular malformation (CVM). The latter term calls attention to the origin as an error of organogenesis and avoids the negative connotation that some patients sense with the word ‘‘defect.’’ This article introduces the reader to genetic aspects of CVMs, with occasional mention of cardiomyopathy [3], aortic dilation, and arrhythmia. The extensive i

This work was supported by funds from the Armand Anzalone Research Fund. * Corresponding author. Genetics and Teratology Unit, Warren 801, MassGeneral Hospital for Children, 55 Fruit St., Boston, MA 02114, United States. Tel.: +1 617 726 1742; fax: +1 617 264 6803. E-mail address: [email protected] (A.E. Lin). 1058-9813/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ppedcard.2005.04.003

The genetics of CVMs calls to mind familiar clinical topics such as inheritance and recurrence risk assessment, malformation syndrome association, and molecular genetic determinants. Added to the list is genetic epidemiology, a more recent concept referring to the interaction of genetic and environmental factors in producing disease [4– 6]. Birth defects, especially CVMs, have benefited from this approach. Frequency is the first epidemiologic concept to be discussed (defined typically as birth prevalence), but other important issues include birth defects monitoring programs that collect information on CVMs, ongoing research to evaluate risk factors, and the hope of prevention. 2. How common are CVMs? 2.1. Reporting methods and research design The frequency of birth defects such as CVMs is typically reported as birth prevalence, in contrast to either incidence

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(new cases during a defined time period) or prevalence (existing cases over a time period) [6]. Because the births being ascertained by newborn surveillance registries cannot enumerate all conceptuses, birth prevalence is viewed as an approximation of an incidence rate that would be used for other diseases [5– 8]. An exhaustive review of prevalence rates from around the world was assembled by Rosenthal [8], with a complementary review of prenatal frequencies (including fetal deaths) provided by Hoffman [9]. Table 1 adapts recent data from Botto and Correa [2] comparing prevalence rates of CVMs from the Baltimore– Washington Infant Study [10,11] and the Metropolitan Atlanta Congenital Defect Program. The reported birth prevalence of CVMs has apparently increased to approximately 1/110 [12]. Births with CVMs are generally usually identified by population-based birth defects monitoring programs, which are usually affiliated with state departments of public health. Other programs pool data from regional [10 – 12] or national databases [13], which are themselves usually based at state surveillance programs. Rarely, prevalence is calculated from hospital-based registries such as the

Table 1 Adaptation of Table 1 in Botto and Correa [2] comparing the prevalence of CVMs from the two largest population-based studies CVM

Prevalence (per 10,000 births) Metropolitan Atlanta Congenital Defect Program, 1995 – 1997

Heterotaxy, l-TGA Outflow tract defects, total Tetralogy of Fallot d-TGA Double outlet right ventricle Truncus arteriosus Atrioventricular septal defect With Down syndrome Without Down syndrome Ebstein anomaly Total APVR Right-sided obstruction Peripheral pulmonic stenosis Pulmonic stenosis, atresia Pulmonic atresia/intact septum Tricuspid atresia Left-sided obstruction Coarctation of the aorta Hypoplastic left heart Aortic valve stenosis Aortic arch atresia or hypoplasia Septal defects Ventricular septal defect Atrial septal defect Patent ductus arteriosus Other major heart defects Total

Baltimore – Washington Infant Study, 1981 – 1989

1.6

1.4

4.7 2.4 2.2 0.6

3.3 2.3 0.7 0.5

2.4 1.0 0.6 0.6

2.3 1.0 0.6 0.7

7.0 5.9 0.6 0.3

Not available 5.4 0.6 0.4

3.5 2.1 0.8 0.6

1.4 1.8 0.8 Not available

24.9 10.0 8.1 9.7 90.2

11.2 3.2 0.9 – 48.4

APVR, anomalous pulmonary venous return; TGA, transposition of the great arteries.

Brigham-Women’s Hospital Active Malformation Surveillance Programs [14,15]. Cardiovascular malformations have been studied in clinical cohort series (e.g., association with chromosome syndromes), population-based prospective cohort or case – control studies (e.g., in utero exposure to maternal diabetes) [10,11,13,16], and randomized clinical trials (e.g., studying the impact of prenatal multivitamins) (reviewed in [17,18]). 2.2. Coding and classification The seemingly simple task of coding CVMs may affect prevalence estimates. Whether one defines hemodynamically insignificant structures (e.g., left superior vena cava, aberrant subclavian artery) as ‘‘normal variants’’ or bona fide malformations, or includes functional problems such as valve regurgitation and ventricular hypertrophy has an impact on the actual figures. The more anomalies one includes in a surveillance program, the greater the investment of labor needed to identify and abstract the charts of such patients. Criteria for the type of diagnostic test (i.e., echocardiography, catheterization, magnetic resonance imaging, surgical report, and autopsy) should be rigorous; most prevalence programs do not allow clinical diagnosis alone. Instead of coding every component of a complex heart, coding the patient based on a unifying diagnosis is preferable, a practice followed by most birth defect registries [19]. Thus, tetralogy of Fallot should be coded as a single diagnosis, not as its individual components: conoventricular ventricular septal defect, pulmonic obstruction, aortic override, and right ventricular hypertrophy. Hypoplastic left heart syndrome would not be coded additionally as mitral atresia, aortic atresia, and aortic hypoplasia. Many birth defects, such as oral clefts or limb deficiencies, can be classified into meaningful groups that promote etiologic homogeneity and facilitate the recognition of causes [20]. Beyond the simple purpose of organizing a large group of defects, CVMs can be classified—an analysis that adds a dimension beyond coding. How CVMs should be named, coded, and classified has been long debated [8,21 –25]. No single system suits all needs. The extraordinary comprehensiveness of two recent databases developed by cardiology and cardiac surgical collaborations [23,24] is more detailed than the needs of many malformation surveillance programs. One approach which has had some intuitive appeal is classifying CVMs into ‘‘families’’ based on hypothetical developmental mechanisms [25]. This system has not been completely validated, although it has been useful for association studies in patients with malformation syndromes. An evidence-based approach is being developed as part of the National Birth Defects Prevention Study (NBDPS) [21], which minimizes reliance on developmental mechanisms. For example, hearts consisting of two or more CVMs, which are not known to be part of a

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developmentally related complex, are a challenge to prioritize. Tetralogy of Fallot with complete atrioventricular canal could be viewed as a complex conotruncal defect or variant of atrioventricular canal. The approach in the NBDPS has been to categorize them as associations or complexes without assigning a developmental hierarchy [21]. 2.3. Trends over time A valuable element to the study of the frequency and mortality of CVMs is trend analysis over time. Ideally, there would be prevalence data from fetal life to adulthood. With rare exception, prevalence figures generally reflect patients ascertained in the first year of life [2,12,14]. Several generalizations can be made: The birth prevalence of CVMs has steadily increased over 30 years, but rates for severe defects (e.g., hypoplastic left heart syndrome) have not changed greatly. This contrasts with the rise in less severe defects (e.g., atrial septal defects) [2,12]. Improvements in diagnostic testing, especially echocardiography, are the likely cause of the trend. Pregnancies which end as elective termination [14,26], miscarriage, or stillbirth [14] have an impact on livebirth prevalence (reviewed in [2,8]). Intuitively, the increased use of prenatal diagnosis and the choice to terminate a pregnancy affected with a CVM would lead to a decrease in livebirth prevalence [27], and yet, prevalence is rising [2,12]. This is thought to reflect improved diagnosis, probably due to the use of echocardiography more frequently and at an earlier age [2,12]. Whether a genuine increase in CVM births is occurring will require additional epidemiologic studies. Ideally, birth defects surveillance programs should keep track of all fetuses with a CVM, including terminations, to provide the full spectrum of defect diagnoses and their outcomes. 2.4. Changing survival As important as the focus on births, attention must also be directed to the factors that influence survival and contribute to mortality [2,28,29]. Although individuals with CVMs are benefiting from improved medical and surgical care, they account for one-third of infant deaths due to congenital anomalies, and approximately one-tenth of all infant deaths [2]. In a study of national trends, the rate of death among those with CVMs is decreasing with a concomitant increase in the age at death [28]. The recognition of longer survival in individuals with multiple malformation syndromes and CVMs is an important health care issue given that their medical needs as aging adults must be addressed by non-pediatric caregivers. Among U.S. blacks, a higher mortality and slower decline in death rate among those with CVMs compared to whites have been observed [12,28]—a discrepancy of serious concern.

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3. Congenital heart anomalies associated with malformation syndromes Multiple studies have shown that CVMs are associated with non-cardiac malformations in about 25% of individuals [10], approximately 30% of whom have a recognizable syndrome. In patients hospitalized for an interventional procedure or cardiac surgery, a syndrome was identified in 39% [30]. Population-based studies have reported chromosome abnormalities in approximately 13% of newborns with CVMs [10,16]. In addition to the familiar common autosomal trisomies (involving chromosomes 21, 18, and 13), microdeletion 22q11 is an acknowledged important chromosome cause of CVMs [2,31], especially of the conotruncal type [31 – 33]. Furthermore, research often extrapolates from the observation of cytogenetic abnormalities in children with syndromic CVMs to localizing the molecular determinants of isolated CVMs [34]. Tables 2, 3, and 4 list syndromes and the type and frequency of associated congenital heart anomalies [2,11,15,17,31,35 – 97]. The reader is referred also to well-known textbooks [98,99] for more extensive descriptions about the syndromes, in general, and to chapters dealing with additional CVM syndromes, in particular [100]. The syndromes listed on the tables can be loosely categorized as being associated with: (a) ‘‘typical’’ CVMs, which are more common in the particular syndrome (e.g., atrial and ventricular septal defects in deletion 5p syndrome); (b) distinctive defects (e.g., polyvalvar nodular dysplasia in trisomy 18); or (c) relatively low frequency defects, but proportionally more common than in the general population (e.g., total anomalous pulmonary venous connection in Smith – Lemli – Opitz syndrome). Identifying a syndrome is essential to accurate genetic counseling [101]. The importance of a formal dysmorphologic evaluation cannot be overemphasized. Selected photos illustrate features of 22q11 deletion spectrum (Fig. 1), Hall –Hittner syndrome (CHARGE association) (Fig. 2), and Costello syndrome (Fig. 3). The information provided in Tables 2, 3, and 4 offers new insights that may differ from previous reviews by bringing a cardiology perspective to familiar syndromes such as valproate exposure (monotherapy only). Compared to a recent review of defects associated with valproate exposure [92], we did not include nonstructural cardiac problems, (e.g., partial right bundle branch block), auscultatory diagnoses (e.g., ventricular septal defect murmur), and variant minor anomalies (e.g., left superior vena cava). Individual papers were reviewed for anatomic details (e.g., ventricular septal defect location). For consistency, especially when the number of cases was small, CVMs were loosely grouped into ‘‘families,’’ and a single defect or defect grouping was used to identify the patient (e.g., transposition of the great arteries, ventricular septal defect, and coarctation were

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Table 2 Chromosome abnormality and contiguous gene syndromes associated with congenital heart anomalies Frequency of cardiac anomaliesa Etiology syndrome

References

All (%) Distinctive or most common

Distinguishing features

Distinctive Growth Development face delay delay or MR

Deletion 1p36

Slavotinek et al. [35]

35

All

All

All

Deletion 3p25

Green et al. [36], Robinson et al. [37]

25

Yes

All

All

Duplication 3q

Faas et al. [38]

90

Assorted CVMs

Yes

All

All

Deletion 4p

Battaglia et al. [39]

30 – 50

Yes

All

All

Deletion 4qter

Huang et al. [40]

40

Yes

Most

All

Deletion 5p (5p minus syndrome)

Wilkins et al. [41]

30 – 50

ASD2 PSV VSD PDA Right-sided obstruction mostly PS ASD VSD PDA

Obesity Cleft lip/palate Epilepsy Hearing loss Brachydactyly Ptosis Abnormal ears Postaxial Polydactyly Clinodactyly Short neck GU abnormalities Abnormal ears Cleft lip/palate GU anomalies

Yes

All

All

Deletion 8p23.1

Digilio et al. [42], Pehlivan et al. [43], Devriendt et al. [44]

65 – 80

No

Yes

All

Duplication 8q

Digilio et al. [45]

45

Short fifth finger

Yes

All

All

Deletion 10p

Van Esch et al. [46]

50

No

Most

All

Deletion 11q

Grossfeld et al. [47]

55

VSD Left-sided obstruction HLHS

Yes

Most

Most

Trisomy 13

Musewe et al. [48], Lehman et al. [49]

50 – 80

Yes

All

All

Trisomy 18

Van Praagh et al. [50] 95

Yes

All

All

Deletion 18q

Cody et al. [51]

30

All

Torfs and Christianson [52]

45 – 55

Wide-spaced nipples Yes Cleft palate GU anomalies GI malformations Yes Fifth finger clinodactyly Microbrachycephaly

All

Trisomy 21 (Down syndrome)

All

All

Tetrasomy 22p (Cat-eye syndrome)

Berends et al. [53]

50

Conotruncal, especially DORV and TOF VSD ASD PDA, HLHS AVC Polyvalvular dysplasia Polyvalvular dysplasia Conoventricular VSD TOF, DORV AVC PS ASD VSD AVC ‘‘family’’ (i.e., complete AVC, ASD primum) VSD, all locations ASD secundum PDA TOF TAVPR, PAPVR Assorted defects

Minor hand/foot anomalies Renal anomalies DiGeorge phenotype Thrombocytopenia or abnormal platelets Undescended testes Renal malformation Polydactyly Cleft lip/palate CNS and renal malformations Scalp cutis aplasia

Anal malformations Coloboma Preauricular tag/pit GU malformations

All

All

Assorted CVMs TOF/PA PDA Ebstein DCM AVC complete, partial Assorted CVMs

PS ASD2 AVC VSD Conotruncal TOF, DORV, TA VSD and/or ASD PDA

Upper extremity defects Cat-like cry Cleft lip/palate Abnormal ears Preauricular tags GU abnormalities Abnormal ears Minor hand anomalies

Overlapping fingers CNS malformations GU malformations

Yes

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Table 2 (continued) Frequency of cardiac anomaliesa Etiology syndrome

References

Der 11;22

All (%) Distinctive or most common

Distinguishing features

Distinctive Growth Development face delay delay or MR

60

Pre-auricular tag/pit Cleft palate Genital anomalies Cleft palate Hypocalcemia T-cell dysfunction Slender, long fingers (Fig. 1) Horseshoe kidney Short fourth metacarpal Lymphedema Gonadal dysgenesis Nevi, keloids

Yes

All

All

Yes

Most

Most

Often

All

Many have learning disabilities, MR occurs with ring X

Lin et al. [54], McDermid and Morrow [55] Deletion 22q11 Earing et al. [56], (DiGeorge syndrome, Botto et al. [31] velo-cardio-facial syndrome)

75 – 85

Turner syndrome

25

Lin [57]

ASD VSD PDA IAA, type B TOF TA RAA, ASCA Left-sided obstruction (e.g., BAV TASV, COA, MV anomalies, HLHS) PAPVR MVP Aortic root dilation

(1) The syndromes listed include are associated with (a) ‘‘typical’’ CVMs, but more common than in the general population; (b) distinctive defects, as well as (c) relatively low frequency defects, however, are still more common than in the general population. (2) General sources, in addition to the specific references, include Jones [98], and Burn and Goodship [100]. ASCA, aberrant subclavian artery; ASD, atrial septal defect; ASV, aortic stenosis, valvar; AVC, atrioventricular canal; BAV, bicuspid aortic valve; COA, coarctation; CVM, cardiovascular malformations; DCM, dilated cardiomyopathy; DORV, double outlet right ventricle; FAVS, facio-auriculo-vertebral spectrum; GI, gastrointestinal; GU, genitourinary; HCM, hypertrophic cardiomyopathy; HLHS, hypoplastic left heart syndrome; IAA, A/B, interrupted aortic arch, type A or B; MR, mental retardation; MS, mitral stenosis; MVP, mitral valve prolapse; OR, odds ratio; PA, pulmonary atresia; PAPVR, partial anomalous pulmonary venous return; PDA, patent ductus arteriosus; PKU, phenylketonuria; (P)PS, (peripheral) pulmonic stenosis; RAA, right aortic arch; TA, truncus arteriosus; TAVPR, total anomalous pulmonary venous return; TOF, tetralogy of Fallot; VSD, ventricular septal defect. a Frequency figures rounded.

viewed as complex transposition rather than three individual CVMs).

between non-steroidal anti-inflammatory drugs and muscular ventricular septal defects [103]. 4.2. Molecular determinants

4. Genetic and epidemiologic research 4.1. The National Birth Defects Prevention Study To facilitate the study of genetic and environmental factors associated with birth defects, including CVMs, the NBDPS was funded by Congress in 1996 [13]. The ongoing multi-state, multi-center case – control study is comprised of a number of Centers for Birth Defects Research and Prevention (originally seven) across the country, as well as the Centers for Disease Control and Prevention in Atlanta. This represents the largest collaborative study of major birth defects. Research on the genetic epidemiology of the CVMs will surpass the Baltimore –Washington Infant Study in population size [21]. However, the Baltimore –Washington Infant Study obtained cardiac diagnoses from participating cardiologists [10,11] instead of abstracted data from surveillance programs, which probably increased the accuracy of information. In addition to the large number of defects and risk factors being analyzed, the novel study design includes the collection of a DNA sample as buccal swabs [102], and rigorous classification of cases [20]. The first risk factor analysis involving CVMs from this collaboration reported that there was no significant association

The search for genes that cause or contribute to CVMs and other cardiac anomalies has proceeded at a rapid pace. The multifactorial model is being reevaluated. Although it remains a valid etiology, its widespread application to isolated non-syndromic CVMs is being reconsidered, tempered with the realization that only a small proportion of CVMs has been found to be due to monogenic cause. CVMs remain etiologically heterogeneous, and multigenic and environmental influences cannot be ignored. The starting point of molecular genetic research is often a malformation syndrome with a distinctive cardiac phenotype, and associated with a chromosome abnormality. These include the well-known autosomal trisomies, deletions, and a growing number of microdeletion syndromes [32,104 – 106]. Researchers look for the rare patient with a microdeletion, or the valuable family pedigrees in which multiple family members in several generations have similar CVMs. Attention shifts from studies of syndromes and families to isolated, apparently non-syndromic CVMs [32]. New technology has inspired novel analysis. Using a genome-wide gene expression analysis of tissue from malformed and normal hearts, a preliminary study reported specific gene expression profiles correlating to specific cardiac malformation phenotypes [107].

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Frequency of cardiac anomaliesa Etiology syndrome

References

All (%)

Distinctive or most common

Distinguishing features

Distinctive face

Growth delay

Development delay or MR

Autosomal dominant Adams – Oliver syndrome

Lin et al. [58]

20

Scalp cutis aplasia, terminal transverse limb defects

No

No

No

Alagille syndrome

McEhlinney et al. [59]

95

Left-sided obstruction (e.g., COA, parachute MV), TOF PPS, TOF/TOF with PA, ASD, VSD

Yes

Most

Rare

Char syndrome

Sweeney et al. [60]

60

PDA

Yes

No

No

Cornelia – de Lange syndrome Holt – Oram syndrome

Jackson et al. [61]

25

VSD, ASD, PS, TOF

Yes

All

All

Sletten and Pierpont [62], Bruneau et al. [63], Huang [64] Lin et al. [65], Friedman et al. [66]

80

ASD T other CVM, VSD, TA, TOF, PAPVR, conduction defect PSV ASV, COA HCM PSV, ASD AVC partial COA HCM PDA, ASD, VSD, left-sided obstruction (e.g., COA, HLHS) SVAS T PVS, PS, other left-sided obstructions (e.g., ASV, MS, COA)

Bile duct paucity, chronic cholestasis, butterfly vertebrae, posterior embryotoxon Anomalies on fifth finger, supernumerary nipple Upper limb deficiency, GI anomalies Upper limb malformation

No

No

No

Few

Few

Many associated with deletion

Yes

Most

Most

Broad thumbs and great toes

Yes

All

All

Hypercalcemia, hypodontia, hypoplastic nails

Yes

Most

All

Short limbs, polydactyly, hypoplastic nails, dental anomalies

No

All

No

Neurofibromatosis

2

Noonan syndrome

Marino et al. [67]

85

Rubenstein – Taybi syndrome

Stevens and Bhakta [68], Hanauer et al. [69]

35

Williams syndrome

Eronen et al. [70]

60

Autosomal recessive Ellis – van Creveld syndrome

Digilio et al. [71]

60

AVC ‘‘family,’’ CAVC, common atrium, ASD primum

Cafe´ au lait macules optic glioma, scoliosis, pseudarthrosis, neurofibromas Short, webbed neck; pectus deformity; cryptorchidism

A.E. Lin, H.H. Ardinger / Progress in Pediatric Cardiology 20 (2005) 113 – 126

Table 3 Mendelian gene syndromes associated with congenital heart anomalies

Lin and Slavotinek [72]

50

ASD, VSD, conotruncal

Keutel syndrome

Teebi et al. [73]

70

PPS

Smith – Lemli – Opitz syndrome

Lin et al. [74]

45

ASD, VSD, complete AVC, TAPVR

Lin et al. [75]

25

ASD, VSD, rare, variable cardiomyopathy

75

PSV, ASD2 HCM Conotrucal/arch, assorted CVMs

Costello syndrome

Noonan [76], Kavamura et al. [77] Tellier et al. [78], Graham [79], Lalani et al. [80] Lin et al. [81]

60

PHACES syndrome

Bronzetti et al. [82]

100

Ritscher – Schinzel syndrome (3C)

Leonardi et al. [83]

100

X-linked recessive Simpson – Golabi – Behmel syndrome

Suspected gene etiology Cardio-facio-cutaneous syndrome Hall – Hittner syndrome (CHARGE association)

80

PSV MV, TV, AV thickening HCM arrhythmia (atrial tachycardia) COA, IAA, type A Right, double, cervical aortic arch TOF, DORV, AVC

Diaphragmatic hernia, distal digital hypoplasia Short digits, mixed hearing loss, cartilage calcification Two to three toe syndactyly, cleft palate, lung anomalies, genital anomalies

Yes

All

All

Yes

No

All

Yes

All

All

Macrosomia, cleft palate, supernumerary nipples, hernias, hypospadias, poly/syndactyly

Yes

No

Many

Sparse, curly hair; low, rotated ears; hyperkeratosis Coloboma, choanal atresia, genital anomalies, ear anomalies (Fig. 2) Skin/joint laxity, fine/curly hair, deep palm creases, ulnar deviation, papillomata

Yes

Most

Most

Many

All

All

Yes (Fig. 3)

All

All

Posterior fossa malformations, hemangiomas, eye anomalies

No

No

No

Posterior fossa malformations, cleft palate, coloboma

Yes

Unknown

All

Abbreviations as specified in Table 2 with the addition of: TOF/PA, tetralogy of Fallot with pulmonary atresia. a Frequency figures rounded.

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Fryns syndrome

119

120

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Table 4 Maternal exposures associated with congenital heart anomalies (data from population-based case – control studies expressed as ‘‘risk’’ among exposed mothers, whereas data from clinical series are based on frequency among those manifesting embryopathy) Frequency of cardiac anomaliesa Etiology syndrome References Alcohol Diabetes

Hyperthermia, fever

All

Distinctive or most common

Carmichael et al. [84] Increased ASD, VSD, conotruncal Loffredo [17] Increased Truncus, TOF Botto and Correa [2] Heterotaxy AVC HCM Ferencz et al. [11], Increased PSV, other outflow Chambers et al. [85], defects, VSD, ASD Botto et al. [86]

Maternal PKU

Levy et al. [87]

15 – 30

Retinoic acid Rubella

Lammer et al. [88] Reef et al. [89]

25 46 – 60

Thalidomide

Lenz [90]

30

Valproate monotherapy

Ardinger et al. [91], Kozma [92]

30

Left-sided obstruction (e.g., COA, AS, MS, TOF) Conotruncal PDA, peripheral PS, PSV, polyvalvular dysplasia Conotruncal Assorted CVMs, anomalous RPA

Distinguishing features

Distinctive Growth Development face delay delay or MR

Brain Renal agenesis, sacral agenesis, neural tube defect

Yes No

Most No

Most No

Neural tube defect, limb deficiency, ear anomalies, cleft lip/palate, diaphragmatic hernia, vascular interruption defects Dysmorphic not distinctive

No

Yes

Yes

No

Yes

Yes

No No

Some Yes

Most Yes

No

Some

Rare

Yes

Some

Some

Microtia, CNS malformation Cataract ,deafness, hepatosplenomegaly Limb reduction defects, ear anomalies, eye anomalies Neural tube defect, craniosynostosis, cleft lip/palate

Abbreviations as specified in Table 2 with the addition of: RPA, right pulmonary artery. a Frequency figures rounded.

4.3. Environmental causes Discussion about environmental causes is necessary in a review of genetic aspects or causes because of the likelihood that environmental factors play a role in the occurrence of CVMs in certain genetic backgrounds (genotypes). A recent summary of candidate exposures [5] distills the list to nutritional excesses and deficiencies, maternal illness and infection, drugs, chemicals in the home or workplace, and radiation. Although the expression ‘‘environmental cause’’ conjures up the image of a toxic waste dump or smog, it refers more broadly to any factor which is not genetic. Most of the environmental causes of CVMs occur within the

Fig. 1. A 16-year-old girl with 22q11 deletion (velo-cardio-facial syndrome) and long slender fingers.

fetal – placental – maternal ‘‘environment.’’ Despite understandable public concerns, the short list of known teratogens does not include pollutants of air, water, and food. Reviews of possible environmental factors by Loffredo [17] and

Fig. 2. An 11-year-old boy with Hall – Hittner syndrome, a well-defined entity within the broader definition of the CHARGE association. He has the ear anomaly in which the pinna is square-shaped. In fact, severely malformed ears are not typical.

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tetralogy of Fallot, truncus arteriosus, and complete atrioventricular septal defect. Contrary to older reports derived from smaller uncontrolled cohorts, d-transposition of the great arteries is not strongly associated with diabetes. Recent research also implicates fever, flu, and obesity as possible risk factors [2,17]. Alcohol is frequently cited in descriptive clinical reports as being associated with CVMs, but the frequency, type, and certainty of diagnosis have been inconsistent. A recent large population-based case – control study showed an association between alcohol and conotruncal CVMs, especially with binge drinking [84]. For the vast majority of suspected risk factors, additional research derived from large population-based programs and using rigorous definitions and diagnostic criteria will be needed. Until then, cardiologists are reminded that an epidemiologic association should not be interpreted as causative. 4.4. Folic acid supplementation

Fig. 3. A 9-year-old boy with the classic facial appearance of Costello syndrome. He also has the classic cardiac phenotype (i.e., tachycardia and persistent hypertrophic cardiomyopathy; patient 9, Appendix, Lin et al. [81]).

Botto and Correa [2] point out that only ingestion of certain prescription drugs (e.g., retinoic acid) is causative of CVMs. Organic solvent exposure in the home or workplace warrants further investigation to confirm preliminary association studies [17]. Table 5 lists several exposures associated with CVMs and other anomalies. Leading the list is diabetes for which the risk is greatest in early pregnancy [2,17,108]. The Baltimore –Washington Infant Study showed the strongest association between maternal diabetes and the ‘‘early’’ malformations such as laterality and looping defects,

There is clear evidence that maternal use of multivitamin supplements containing folic acid, or folic acid alone, is associated with a reduction in occurrence of nonsyndromic neural tube defects [109]. It has been found that the risk of other birth defects, including CVMs, may also be decreased with folic acid supplements given periconceptionally [110]. The comprehensive review by Botto et al. [18] examined all major randomized trials and observational studies from 1992 to 2000. Table 6 in this article presents a condensed version of Table 2 from Botto et al. [18], which lists two negative studies [111, 112], but three [110,113,114] which support a possible overall decrease in the risk of CVMs in the range of 25– 50%. This risk reduction appears to be greater for conontruncal (outflow tract defects) and septal defects. Interpreting existing data and plans for future studies must grapple with methodology, defect classification, and etiologic heterogeneity [18].

Table 5 Syndromes in which etiology is unknown, heterogeneous, or multifactorial, associated with congenital heart anomalies Frequency of cardiac anomaliesa Etiology syndrome

References

All (%) Distinctive or most common

Hemifacial microsomia Kumar et al. [93] (Goldenhar, FAVS)

50

Heterotaxy

Lin et al. [15], Ticho et al. [94], Ware et al. [95]

¨100

VATER association

Weaver et al. [96], 50 – 70 Botto et al. [97]

Distinguishing features

VSD, conotruncal

Distinctive Growth Development face delay delay or MR

Microtia/ear tags, vertebral Yes abnormality, epibulbar dermoid Dextrocardia, d-transposition, Visceral situs; anomalies; No l-transposition, AVC, malposition; GU, brain, TAPVR, and lung; lobtion IVC interruption (varies anomalies; spleen anomalies; with asplenia or polysplenia) cleft lip/palate; biliary atresia VSD T other Vertebral malformation, GI No TOF anomalies, renal anomalies, radial deficiency

Abbreviations as specified in Table 2 with the addition of: IVC, interrupted inferior vena cava. a Frequency figures rounded.

Some

Some

No

Depends on associated brain anomaly

Some

No

122

A.E. Lin, H.H. Ardinger / Progress in Pediatric Cardiology 20 (2005) 113 – 126

Table 6 Adaptation of Table 2 in Botto et al. [18] summarizing studies of maternal multivitamin supplement use and risk of CVMs (1992 – 2000) Reference

Type of study

Exposure

RR/OR (95% CI) Type of CVM

Czeizel et al. [110]

Randomized clinical trial

Shaw et al. [113] Scanlon et al. [111] Botto et al. [114] Werler et al. [112]

Case – control, Case – control, Case – control, Case – control,

population-based population-based population-based population-based

MV with 0.8 mg of folic acid MV MV with folic acid MV MV

All

Outflow tract

VSDs

0.42 (0.19 – 0.98)

0.48 (0.04 – 5.34)

0.24 (0.05 – 1.14)

0.70 0.97 0.46 1.00

0.61 (0.38 – 0.99) 1.20 (0.80 – 1.80)

0.76 (0.60 – 0.97)

(0.46 – 1.1) (0.6 – 1.6) (0.24 – 0.86) (0.70 – 1.50)

MV, multivitamin; OR, odds ratio; RR, relative risk.

5. Recurrence risk and genetic evaluations

While the concordance rates of the various types of CVMs varied, two specific types of defects, isolated AVC and laterality defects, showed the highest concordance at 80% and 64%, respectively. Occurrence of CVMs among first-degree relatives of a proband with a CVM varies depending on the relationship. From a population-based registry of adults who survived surgery for selected major CVMs (abnormalities of situs, abnormalities of atrioventricular or ventriculoarterial connection, anomalous pulmonary venous connection, atrioventricular septal defect, or tetralogy of Fallot), the recurrence risk among offspring (4.1%) was significantly greater than among siblings (2.1%) [125]. Folic acid supplementation is recommended for all women of childbearing age to decrease the risk of having a child with a neural tube defect. An added benefit may be a decrease in the overall occurrence of CVMs.

5.1. Recurrence risk assessment

5.2. The role of the geneticist

Traditionally, CVMs were suggested to be due to a multifactorial etiology with a recurrence risk of 2– 4% [119]. The Baltimore– Washington Infant Study provided valuable information about the heritability of CVMs [120], weakening support for the additive multifactorial model in isolated CVMs of unknown etiology and suggesting a substantial genetic component in the etiology of some groups of CVMs. As an example, although the overall frequency of having a previous sibling with a CVM was 3.1% (precurrence risk), a much higher rate was observed when the proband had either hypoplastic left heart syndrome (8.0%) or coarctation of the aorta (6.3%). This apparent familial aggregation of left-sided obstructive defects has been reexamined in studies including echocardiograms on first-degree relatives [121,122]. Further analysis has suggested that in such families, the CVMs are likely due to a small number of genes [123]. Another study from the United Kingdom examined the recurrence risk of CVMs using fetal echocardiography in 6640 consecutive pregnancies where a first-degree relative had a CVM [124]. The recurrence for all CVMs was 2.7%, with a high concordance for the specific type of CVM (37%), or for CVM of the same group (44%). In families with two or more recurrences, the concordance rate was higher still (55%).

Because not all CVMs are due to multifactorial causation, a generic recurrence risk of 2 –4% should not be used casually in counseling the parents of a child with a CVM. Among patients with a CVM, a consultation with a clinical geneticist can provide valuable information. When a child is born with one or more other anomalies in addition to the CVM, the geneticist can evaluate for the presence of a recognizable syndrome, which will assist in determining in a timely manner the need for specialized genetic tests and in uncovering other anomalies that may affect the child’s cardiac status. Identification of a syndrome can give the family the most accurate risk for recurrence of a CVM in a future child. An evaluation in a genetics clinic can be helpful if a history of a CVM is found in a parent of the affected child. It must be kept in mind that the parent’s CVM may be isolated or may be syndromic given that some syndromes have only subtle manifestations with variable presentations. Testing of the patient or the parent may be recommended and prenatal ultrasound may be offered for evaluating a future pregnancy and is important regardless of whether it is the mother or the father who is affected [124]. In other families, a detailed pedigree may reveal a CVM in other

Similar to what has been found in neural tube defect studies, a derangement of maternal homocysteine metabolism and a specific mutation in the methylenetetrahydrofolate reductase (MTHFR) gene termed C677T have been reported to be more frequent in small, selected populations with CVMs [115 – 117]. This mutation is associated with elevated homocysteine levels, which can be normalized by folic acid supplementation. It is not yet certain whether the increased incidence of neural tube defects, CVMs, and other congenital defects is due to the mutation itself, elevated homocysteine levels, or some other effects on an as yet unknown gene or metabolic pathway (reviewed in [117]). One review cautions that further investigation is warranted in this area [118].

A.E. Lin, H.H. Ardinger / Progress in Pediatric Cardiology 20 (2005) 113 – 126

relatives, which may or may not substantially change the risk of recurrence. Even patients with apparently isolated, non-familial CVMs will benefit from a genetic consultation in the later teen years as they begin to contemplate starting a family. With the rapid increase in knowledge about the genetics of CVMs, families should be encouraged to inquire as to the latest information on the recurrence risk of heart defects. Formal clinical collaboration between pediatric cardiologists and geneticists has increased in recent years [126].

6. Conclusions Cardiovascular malformations are the most familiar group of congenital heart anomalies to consider because of their frequency, severity, and the burden upon medical resources and family. An appreciation of the genetic aspects of CVMs requires an understanding of their epidemiology, association with non-cardiac malformations often as malformation syndromes, risk factors, especially maternal exposures, and molecular determinants. If further research supports current evidence that they can be prevented by folic acid and/or multivitamin supplement, a powerful strategy to reduce their prevalence may be utilized.

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We thank Adolfo Correa, Lorenzo Botto, and Kathy Hoess for thoughtful discussions.

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