9.7 Genetic Syndromes & Their Associated Cardiac Lesions
Key Takeaways
- Trisomy 21 is the strongest single syndromic predictor of atrioventricular septal defect, and these children develop elevated pulmonary vascular resistance earlier than other children with comparable shunts, which compresses the window for surgical repair.
- 22q11.2 deletion syndrome is the conotruncal syndrome: interrupted aortic arch type B, truncus arteriosus, tetralogy of Fallot, and pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals, frequently with a right aortic arch or an aberrant subclavian artery.
- Williams-Beuren syndrome deletes the elastin gene and produces supravalvar aortic stenosis with the classic hourglass narrowing at the sinotubular junction, peripheral pulmonary artery stenosis, and coronary ostial stenosis that creates a documented risk of sudden death under anesthesia.
- Noonan syndrome and the other RASopathies produce a dysplastic, thickened, poorly mobile pulmonary valve that responds less well to balloon valvuloplasty than a typical domed valve, together with hypertrophic cardiomyopathy and secundum atrial septal defect.
- Turner syndrome clusters left-sided obstructive disease: bicuspid aortic valve in roughly 30%, coarctation in roughly 10%, an elongated transverse arch, partial anomalous pulmonary venous connection, and an intrinsic aortopathy that is tracked with the ascending aortic size index rather than raw diameter.
Last updated: September 2026
9.7 Genetic Syndromes & Their Associated Cardiac Lesions
Clinical Core: Roughly 20% to 30% of congenital heart disease occurs in the setting of a recognized genetic syndrome, and the ARDMS content outline lists this explicitly as task 3.A.21. The practical consequence for a sonographer is that the syndrome changes the protocol. A referral that says "Williams syndrome" means the study is incomplete without a careful sinotubular junction and coronary ostial interrogation. A referral that says "22q11.2 deletion" means the arch sidedness and branching pattern must be nailed down. Knowing the map converts a generic screening study into a targeted one.
The Aneuploidies
| Syndrome | Cardiac lesions | Sonographic emphasis |
|---|---|---|
| Trisomy 21 (Down syndrome) — 40% to 50% have congenital heart disease | Complete atrioventricular septal defect (the signature lesion), ventricular septal defect, secundum atrial septal defect, tetralogy of Fallot with atrioventricular septal defect, patent ductus arteriosus | Define the Rastelli type of the common atrioventricular valve, the degree of ventricular balance, and the common atrioventricular valve regurgitation; estimate pulmonary artery pressure at every visit because pulmonary vascular resistance rises earlier than in other children, narrowing the repair window |
| Trisomy 18 (Edwards syndrome) | Ventricular septal defect, polyvalvular dysplasia (thickened, nodular, redundant leaflets on multiple valves), double outlet right ventricle | Polyvalvular dysplasia is close to syndrome-specific; interrogate all four valves |
| Trisomy 13 (Patau syndrome) | Ventricular septal defect, atrial septal defect, patent ductus arteriosus, hypoplastic left heart syndrome, dextrocardia | Assess left heart adequacy and ductal dependence |
| Turner syndrome (45,X) | Bicuspid aortic valve (~30%), coarctation (~10%), elongated transverse arch, partial anomalous pulmonary venous connection, aortic dilation and dissection risk | Dedicated suprasternal arch imaging; report the ascending aortic size index (diameter in cm divided by body surface area in m^2) because short stature makes raw diameters misleading |
The RASopathies
Mutations along the RAS–MAPK signaling pathway share a recognizable cardiac phenotype.
- Noonan syndrome (PTPN11, SOS1, RAF1, KRAS): dysplastic pulmonary valve stenosis in roughly 50% to 60%, hypertrophic cardiomyopathy in roughly 20%, and secundum atrial septal defect. The key practical point is that a dysplastic pulmonary valve is thickened, nodular, and immobile rather than thin and domed, so balloon valvuloplasty is markedly less effective than in typical valvar pulmonary stenosis and surgical valvotomy is more often required.
- Costello syndrome (HRAS) and cardiofaciocutaneous syndrome (BRAF, MAP2K1/2): hypertrophic cardiomyopathy, pulmonary valve stenosis, and a strong tendency to atrial tachyarrhythmia.
- LEOPARD / Noonan syndrome with multiple lentigines (PTPN11): hypertrophic cardiomyopathy and conduction abnormalities.
Deletion and Contiguous Gene Syndromes
- 22q11.2 deletion (DiGeorge, velocardiofacial) — the conotruncal syndrome. Expect interrupted aortic arch type B (interruption between the left carotid and left subclavian arteries), truncus arteriosus, tetralogy of Fallot, and pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals. A right aortic arch and an aberrant subclavian artery are common companions, so arch sidedness and branching must be defined explicitly in every study. Hypocalcemia and thymic hypoplasia complete the picture.
- Williams-Beuren syndrome (7q11.23, elastin) — an elastin arteriopathy, not an isolated valve lesion. Expect supravalvar aortic stenosis with the classic hourglass narrowing at the sinotubular junction, peripheral and branch pulmonary artery stenosis, and, critically, coronary ostial stenosis. The coronary lesion underlies the well-documented risk of sudden death during anesthesia or sedation, which makes a deliberate parasternal short-axis coronary origin interrogation a mandatory part of the study and makes the sonographer's report directly relevant to procedural safety.
- Alagille syndrome (JAG1, NOTCH2): peripheral pulmonary artery stenosis and hypoplasia, tetralogy of Fallot, plus bile duct paucity, butterfly vertebrae, and posterior embryotoxon.
- CHARGE syndrome (CHD7): conotruncal defects, aortic arch anomalies, and atrioventricular septal defect.
- Kabuki syndrome (KMT2D): left-sided obstructive lesions — coarctation, bicuspid aortic valve, hypoplastic left heart syndrome.
Single-Gene and Connective Tissue Disorders
| Disorder | Gene | Cardiac phenotype |
|---|---|---|
| Holt-Oram syndrome | TBX5 | Secundum atrial septal defect, ventricular septal defect, progressive atrioventricular conduction disease; radial ray limb anomalies |
| Ellis-van Creveld syndrome | EVC/EVC2 | Common atrium or large primum atrial septal defect |
| Marfan syndrome | FBN1 | Aortic root dilation at the sinuses of Valsalva, mitral valve prolapse |
| Loeys-Dietz syndrome | TGFBR1/2, SMAD3, TGFB2/3 | Aggressive aortopathy with arterial tortuosity; dissection at small diameters |
| Tuberous sclerosis complex | TSC1, TSC2 | Multiple cardiac rhabdomyomas |
| Friedreich ataxia | FXN | Concentric hypertrophic cardiomyopathy progressing to a dilated, burnt-out phenotype |
| Duchenne and Becker muscular dystrophy | DMD | Dilated cardiomyopathy that begins in the posterobasal and inferolateral left ventricular wall before global involvement |
| Pompe disease (glycogen storage type II) | GAA | Massive biventricular hypertrophy in infancy with a characteristically short PR interval and giant QRS voltages |
| Fabry disease | GLA | Concentric hypertrophy with the binary appearance of the endocardial border; X-linked |
| Mucopolysaccharidoses (Hurler, Hunter) | Various | Progressive mitral and aortic valve thickening with stenosis and regurgitation, and coronary narrowing |
| Barth syndrome | TAZ | Dilated cardiomyopathy and left ventricular non-compaction with neutropenia |
Teratogens and Maternal Conditions
| Exposure | Cardiac effect |
|---|---|
| Maternal pregestational diabetes | Transient asymmetric septal hypertrophy of the infant of a diabetic mother, which resolves over weeks to months; also transposition of the great arteries, ventricular septal defect, and truncus arteriosus |
| Maternal anti-Ro/SSA and anti-La/SSB antibodies (lupus, Sjögren) | Congenital complete heart block and endocardial fibroelastosis |
| Maternal phenylketonuria (uncontrolled) | Tetralogy of Fallot, ventricular septal defect, coarctation |
| Congenital rubella | Patent ductus arteriosus, peripheral pulmonic stenosis, supravalvar aortic stenosis |
| Fetal alcohol spectrum | Ventricular septal defect, atrial septal defect |
| Retinoic acid embryopathy | Conotruncal defects |
| Anticonvulsants (valproate, phenytoin) | Ventricular septal defect, atrial septal defect, coarctation |
| Lithium | Historically associated with Ebstein anomaly, though the absolute risk is now considered much lower than originally reported |
Reversing the Map: From Lesion Back to Syndrome
The exam also asks the question in the other direction. When a specific lesion is found, these syndromic associations should be actively considered and mentioned in the report:
- Complete atrioventricular septal defect → trisomy 21; also heterotaxy if the atrioventricular connection is unbalanced with anomalous venous return.
- Interrupted aortic arch type B or truncus arteriosus → 22q11.2 deletion.
- Supravalvar aortic stenosis → Williams-Beuren syndrome (or familial elastin arteriopathy).
- Dysplastic pulmonary valve with hypertrophic cardiomyopathy → Noonan syndrome and the RASopathies.
- Coarctation or bicuspid aortic valve in a girl → Turner syndrome.
- Multiple ventricular rhabdomyomas → tuberous sclerosis complex.
- Aortic root dilation in a tall adolescent → Marfan syndrome; check for ectopia lentis.
- Isolated congenital complete heart block in a structurally normal heart → maternal anti-Ro/SSA antibodies.
- Peripheral pulmonary artery stenosis with cholestasis → Alagille syndrome.
Exam-Day Traps
- Scanning a Williams syndrome patient without imaging the coronary ostia. The coronary lesion, not the supravalvar gradient, is what kills these children under anesthesia.
- Failing to define arch sidedness in a conotruncal defect. A right aortic arch reframes the entire differential toward 22q11.2 deletion and changes surgical approach.
- Treating a Noonan pulmonary valve like a typical domed valve. Report leaflet thickness, nodularity, and mobility, because those features predict a poor balloon result.
- Reporting raw aortic diameters in Turner syndrome. These patients are short; use the ascending aortic size index and consistent Z-scores.
- Assuming septal hypertrophy in an infant of a diabetic mother is hypertrophic cardiomyopathy. It is transient and regresses, but it can still produce dynamic left ventricular outflow tract obstruction in the first days of life and must be interrogated with color and continuous-wave Doppler.
Loading diagram...
Test Your Knowledge
A 5-year-old with Williams-Beuren syndrome is scheduled for dental extraction under general anesthesia, and the anesthesiologist requests a preoperative echocardiogram. Beyond quantifying the supravalvar aortic gradient, which additional interrogation is most critical to procedural safety and why?
A
B
C
D
Test Your Knowledge
A neonate has truncus arteriosus with a right aortic arch and an aberrant left subclavian artery, and is hypocalcemic in the first days of life. Which genetic diagnosis should be considered, and what additional arch finding is characteristic of the same condition?
A
B
C
D
Test Your Knowledge
An 8-month-old with Noonan syndrome has valvar pulmonary stenosis with a peak instantaneous gradient of 62 mmHg. The valve leaflets are markedly thickened and nodular with minimal excursion, and the annulus is small. How does this appearance change the expected outcome of balloon pulmonary valvuloplasty?
A
B
C
D
Test Your Knowledge
A 15-year-old girl of short stature with a webbed neck has an ascending aortic diameter of 3.2 cm and a body surface area of 1.35 m^2. A bicuspid aortic valve with right-left coronary cusp fusion is present. How should the aortic dimension be reported in this patient, and what does the value indicate?
A
B
C
D