Congenital heart disease

A newborn (or fetus) with a structural cardiac anomaly: septal defect (ASD, VSD, AVSD), conotruncal lesion (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch, transposition), left-sided obstructive lesion (HLHS, aortic stenosis, coarctation), right-sided obstructive lesion (pulmonary stenosis, atresia, Ebstein), or a laterality defect. CHD occurs in ~1% of live births. The clinical job is to decide whether this is isolated (multifactorial, ~70%) or syndromic (~30%), because syndromic CHD comes with extracardiac surveillance and reproductive counseling implications.

Three questions structure the work-up:

1. What lesion? Each anatomic class has a characteristic short list of associated syndromes. The lesion is the highest-yield clue.
2. Extracardiac features? Dysmorphic face, palatal anomaly, growth failure, hypocalcemia, hypotonia, polydactyly, radial ray anomaly, single umbilical artery, GU anomaly, cleft. Any one flips the work-up syndromic.
3. Family history. Prior child with CHD, parent with repaired or unrepaired CHD, consanguinity, recurrent miscarriage. Recurrence risk in isolated CHD is ~2-3% (higher in left-sided lesions).

Conotruncal lesions (TOF, truncus, IAA-B, TGA)

• 22q11.2 deletion syndrome (the diagnosis you cannot miss): present in 15-20% of TOF, 30-50% of interrupted aortic arch type B, and most truncus arteriosus. Adds thymic hypoplasia + hypoparathyroidism (hypocalcemia in the newborn) + palatal anomalies (overt or submucous cleft, velopharyngeal insufficiency) + characteristic face + developmental delay + psychiatric risk later. Send FISH or microarray on every conotruncal lesion.
• CHARGE syndrome (CHD7): conotruncal and aortic arch anomalies in addition to the CHARGE features.
• Alagille: see below; can include TOF.

Left ventricular outflow obstruction (HLHS, AS, CoA, BAV)

• Turner syndrome (45,X): bicuspid aortic valve (30-50%) + coarctation + HLHS + aortopathy. Karyotype every female with a left-sided lesion, even without other Turner features.
• Familial LVOTO: strong familial clustering for BAV/CoA/HLHS in some families; first-degree relatives warrant screening echo.

Septal defects (ASD, VSD, AVSD)

• Down syndrome (trisomy 21): AVSD is the classic lesion; 40-50% of trisomy 21 has CHD, of which ~40% is AVSD. Any infant with AVSD gets a karyotype.
• Holt-Oram syndrome (TBX5, AD): ASD (secundum) or VSD + radial ray anomaly (absent or hypoplastic thumb, absent radius). The upper-limb finding is the diagnostic step before any genetic test.
• Williams syndrome (7q11.23 microdeletion, sporadic): supravalvular aortic stenosis (the lesion-defining association) + elfin facies + cocktail-party personality + infantile hypercalcemia + intellectual disability. FISH for 7q11.23 elastin region.
• Noonan syndrome and RASopathies (PTPN11, SOS1, RAF1, BRAF, others; AD): pulmonary valve stenosis with a dysplastic valve + hypertrophic cardiomyopathy + ASD. Short stature, downslanting palpebral fissures, low-set posteriorly rotated ears, webbed neck.
• Alagille syndrome (JAG1, NOTCH2; AD): peripheral pulmonic stenosis (most common cardiac feature) + cholestasis from bile duct paucity + butterfly vertebrae + posterior embryotoxon + characteristic facies.

Heterotaxy and laterality defects

• See the companion clinical-presentation leaf on heterotaxy. Asplenia (right isomerism) with complex CHD or polysplenia (left isomerism) with interrupted IVC; genes include ZIC3, NODAL, LEFTY2, CFC1, GDF1; primary ciliary dyskinesia often presents with situs inversus.

Mendelian lesion-specific genes (isolated CHD)

• NKX2-5 (ASD with AV block), GATA4 (ASD, VSD, TOF, AVSD), TBX5 (Holt-Oram), CITED2, NOTCH1 (left-sided lesions, BAV).

Aneuploidy

• Trisomy 21: AVSD.
• Trisomy 18 and 13: complex CHD (VSD, polyvalvar dysplasia, DORV).

1. Echocardiogram to characterize the lesion, and detailed extracardiac exam: facies, palate, hands, growth parameters, abdominal exam for organomegaly or asymmetry, hearing screen.
2. 22q11.2 FISH or chromosomal microarray on every conotruncal lesion (and any CHD with extracardiac features).
3. Karyotype on every infant with AVSD (Down) and every female with a left-sided lesion (Turner).
4. Chromosomal microarray as first-tier genetic test for CHD plus any other anomaly.
5. Serum calcium in any conotruncal lesion (22q11.2 hypoparathyroidism).
6. Abdominal ultrasound when laterality or heterotaxy is suspected.
7. Phenotype-targeted gene panel or exome when CMA is normal but a syndrome is suspected (Noonan/RASopathy panel, Alagille, Holt-Oram).
8. Cardiology follow-up + extracardiac surveillance plan based on syndromic diagnosis (renal US for Williams, ophthalmology for Alagille, developmental surveillance for 22q11.2, etc.).