Obstructive left-sided congenital heart lesions exhibit familial clustering, and familial echocardiographic screening for bicuspid aortic valve has become standard practice. Hypoplastic left heart syndrome (HLHS) is a severe left-sided obstructive lesion; however, familial screening is not universally recommended. The purpose of this study was to define the incidence of cardiovascular malformations (CVMs) in first-degree relatives of HLHS probands. First-degree relatives were screened for CVM by transthoracic echocardiography. Screening was completed in 152 family members (97 parents and 55 siblings) of 52 probands. Of these, 17 of 152 (11%) had CVM. Anomalies detected included: bicuspid aortic valve in 5 (3%), isolated dilated ascending aorta in 4 (3%), coarctation of the aorta in 1, partial anomalous pulmonary venous connection in 1, anomalous, intramural coronary artery in 1, bicuspid pulmonary valve in 1, and other anomalies in 4. Most were previously undiagnosed (11 of 17, 65%). Fourteen of 52 families (27%) had ≥1 relative with CVM. Overall, 7 of 55 siblings (13%), 5 of 46 fathers (11%) and 5 of 51 mothers (10%) had CVM. Although the incidence of CVM in first-degree relatives of HLHS probands was lower in this cohort than previously reported, it remained substantial, with at least one additional member having CVM in 27% of families. The frequent occurrence of undiagnosed CVM highlights the importance of routine familial screening in HLHS. In fact, even if screening was done in childhood, it may be appropriate to screen again in the third or fourth decade to exclude isolated enlargement of the ascending aorta.
Obstructive left-sided congenital heart lesions include hypoplastic left heart syndrome (HLHS), Shone complex, coarctation of the aorta (COA), congenital aortic valve stenosis, and bicuspid aortic valve (BAV). These lesions exhibit familial clustering in epidemiologic studies such as the Baltimore Washington Infant Study and in prospective studies of patients’ first-degree family members. The incidence of BAV in first-degree relatives of affected family members has been reported to be as high as 9% to 10%. Familial echocardiographic screening for BAV and associated aortopathy has thus become standard clinical practice. The incidence of congenital cardiovascular malformations (CVMs) in first-degree relatives of patients with HLHS has been reported to be even higher than that of BAV, up to 19%. Despite this, familial screening has not been universally adopted. This study prospectively assessed the cardiac morphology of first-degree family members of HLHS probands using 2-dimensional transthoracic echocardiography. The purpose was to define the incidence of CVM and to determine if routine family screening is warranted in this population.
Methods
The Institutional Review Board at Mayo Clinic approved this study. Prospective enrollment was performed after obtaining informed consent from all participants or their legal guardians. Participants included HLHS probands and their first-degree family members, defined as parents and full siblings. Consenting probands or guardians were interviewed, and family pedigrees were constructed for all probands.
Electronic medical records of probands, including surgical reports and echocardiographic images, were reviewed to confirm HLHS diagnosis. For this study, HLHS was strictly defined to include only aortic valve stenosis or atresia, mitral valve stenosis or atresia, left ventricular hypoplasia, and hypoplasia of the ascending aorta. All probands in this cohort underwent single ventricle palliative procedures or cardiac transplantation; none were determined eligible for biventricular repair. There were no patients with known genetic syndromes (e.g., Turner syndrome, trisomy 13, and trisomy 18) included in our cohort. Chromosomal microarray was performed on all available and consenting probands.
All available and consenting first-degree family members underwent transthoracic echocardiographic examination in the Mayo Clinic Congenital Echocardiography Laboratory. All studies were reviewed by staff pediatric cardiologists; reviewing physicians were not blinded as to the screening nature of the study. Complete studies were performed in accordance with institutional protocol using 2-dimensional, M-mode, and Doppler imaging by experienced congenital cardiac sonographers. Left heart structures including aortic valve annulus, sinus of Valsalva, sinotubular junction, and midascending aortic diameters were measured. Results were indexed to body surface area and compared with published normal values. Pediatric patients were diagnosed with aortic dilatation if computed aortic Z -scores were greater than 2. BAV was diagnosed in parasternal short-axis view by assessing morphology in both systole and diastole and was classified as previously described.
Statistical analyses were performed using JMP statistical software (version 10.0). Descriptive data are presented as mean ± standard deviation; median with range; or percentage with 95% confidence interval.
Results
There were 52 HLHS probands (28 male and 24 female) included in the study. Proband left heart morphologies included: aortic and mitral atresia in 15 (29%), aortic atresia and mitral stenosis in 9 (17%), aortic stenosis and mitral atresia in 1 (2%); and aortic and mitral stenosis in 27 (52%). One-hundred fifty two of 188 first-degree family members consented and were available to undergo screening (81%; 70 males and 82 females). The mean age of screened relatives was 27.4 years (median, 31.4 years; range, 2.1 to 57.6 years). Six fathers, 1 mother, 27 full siblings, and 2 children of probands did not undergo screening (unable to contact, not locally available, did not consent, or too young for cooperation with nonsedated echocardiography). Complete screening of all first-degree family members was able to be performed for 34 of 52 families (65%).
A cardiovascular abnormality was identified by echocardiography in 17 of 152 (11.2%) first-degree family members ( Table 1 ). There was no observed differential in familial CVM based on proband HLHS morphology. Chromosomal microarray identified duplications or deletions in 9 of 48 tested probands. No significant difference in occurrence of familial CVM was observed based on proband chromosomal microarray abnormality. Abnormal microarray results were found in 15% (2 of 13) of probands with relatives found to have CVMs versus 20% (7 of 35) in families with no additional CVMs, p = 1.0. None of the identified deletions or duplications segregated with congenital heart disease. Four relatives had an isolated finding of BAV. One sibling had BAV, a dilated aortic root, and COA, resulting in a total incidence of BAV of 3.3% in this group (5 of 152). BAV morphology included fusion of the right and left coronary cusps in 3, right and noncoronary cusp fusion in 1, and left and noncoronary cusp fusion in 1.
| Echocardiographic finding | N | Relation to proband (age in years at time of echo) |
|---|---|---|
| Bicuspid aortic valve | 4 | Father (48), mother (31), 1 sister (5), 1 sister (4) |
| Dilated ascending aorta, normal aortic valve | 3 | Father (58), father (51), father (39) |
| Ventricular septal defect | 2 | Mother (24), sister (5) |
| COA, bicuspid aortic valve, dilated aortic root, accessory mitral chordal tissue | 1 | Brother (6) 2 |
| Dilated aortic root, accessory mitral chordal tissue | 1 | Brother (7) 2 |
| Bicuspid pulmonary valve | 1 | Mother (30) |
| Mitral valve prolapse with mitral regurgitation | 1 | Mother (28) |
| Anomalous origin of RCA | 1 | Mother (34) |
| Partial anomalous pulmonary venous return | 1 | Brother (7) 3 |
| Papillary fibroelastoma vs. Lambl’s | 1 | Father (29) 3 |
| Patent ductus arteriosus | 1 | Brother (9) |
| Total | 17 |
Four family members had aortic root and/or ascending aortic dilatation with normal aortic valves. All were males (3 fathers and 1 brother) and with an age range of 7 to 58 years (median, 45 years). Maximum aortic root dimension ranged from 41 to 44 mm in the adults, with midascending aortic diameters of 38 to 41 mm. The child was 7-years old and showed mild root enlargement ( Z -score, +2.1). None were hypertensive or had a history of dissection.
Overall, BAV and/or aortopathy were present in 9 of 152 (5.9%). Two patients with isolated BAV were members of the same family (mother and sister of proband). The sibling with COA, BAV, and dilated aortic root also had accessory mitral valve chordal tissue. Another sibling within the same family presenting with dilated aortic root, normal aortic valve, and accessory mitral valve chordal tissue; these findings were not present in either of the parents in this family.
Additional abnormal findings requiring follow-up included 1 mother with anomalous origin of the right coronary artery from the left aortic cusp, who had a history of chest pain with exercise. The diagnosis was previously unknown, and she subsequently underwent surgical coronary artery unroofing. One relative had a ∼3 × 5-mm mobile mass on the noncoronary cusp of the aortic valve, possibly consistent with a papillary fibroelastoma; antiplatelet therapy and close echocardiographic follow-up were recommended.
Overall, at least 1 affected family member was identified with a CVM in 14 of 52 families (26.9%). There was more than one subject with CVM in 3 of 52 families (5.8%). The pedigrees of families with ≥1 affected family member are shown in Figure 1 . Abnormalities were present in 5 of 46 fathers (10.9%), 5 of 51 mothers (9.8%), and 7 of 55 siblings (12.7%). There was no significant difference in incidence of CVM based on sex (9 of 73 males, 8 of 83 females; p = 0.6). Cardiovascular diagnoses were previously unknown in 11 of 17 relatives with CVM (65%). In those with BAV, none had greater than mild aortic stenosis or insufficiency at the time of the study.
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