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Genetic Syndromes with Cardiac Involvement

Learning Objectives

Core Knowledge & Clinical Reasoning

  • [ ] Identify syndrome-specific cardiac lesions (Down: AVSD; Turner: BAV/CoA; Noonan: PS/HCM; Williams: supravalvar AS)
  • [ ] Apply appropriate cardiac screening protocols by syndrome (echo ALL Down syndrome infants)
  • [ ] Recognize increased pulmonary hypertension risk in Down syndrome and implications for surgical timing
  • [ ] Evaluate aortic dissection risk factors in Turner syndrome (ASI, hypertension, BAV)

Management Decisions

  • [ ] Formulate surveillance protocols specific to each syndrome
  • [ ] Determine when specialized imaging (MRI for Turner aorta) is indicated
  • [ ] Modify surgical approach based on syndrome-specific outcomes

Communication & Counseling

  • [ ] Counsel families on cardiac involvement as part of syndrome-specific anticipatory guidance
  • [ ] Address activity and sports participation recommendations by syndrome
  • [ ] Discuss genetic implications for family planning

Systems-Based Practice

  • [ ] Coordinate multidisciplinary care across cardiology, genetics, and primary care
  • [ ] Ensure appropriate transition to adult care with syndrome-specific cardiac surveillance

Key Guidelines

2020 AHA Scientific Statement: Cardiovascular Health in Turner Syndrome Circ Genom Precis Med. 2020;13:e000048

2023 Circulation Expert Consensus: Cardiovascular Complications of Down Syndrome Circulation. 2023;147:425-441

Turner Syndrome (45,X)

Epidemiology

  • Incidence: 1 in 2,500 live female births
  • CHD in 20-50%
  • Leading cause of death is cardiovascular disease

Cardiac Findings

Finding Prevalence
Bicuspid aortic valve 15-30% (30-60x population)
Coarctation of aorta 7-18%
PAPVR 13-15%
Elongated transverse arch ~50%
Aortic dilation Common

Aortic Dissection Risk

  • 164 per 100,000 patient-years (vs 6/100,000 general population)
  • Risk factors:
  • 45,X karyotype
  • BAV, coarctation
  • Hypertension
  • Pregnancy

Surveillance Protocol

  • Echo + MRI at diagnosis
  • MRI every 5-10 years if normal
  • Annual MRI if ASI >2.3 cm/m²
  • BP at every visit

See Topic 31 for comprehensive Turner CV management

Down Syndrome (Trisomy 21)

Epidemiology

  • CHD in ~50% of live births
  • Most common cause of CHD in syndromic patients

Cardiac Findings

Finding Prevalence Notes
AVSD 40-45% Most common
VSD 30-35%
ASD 10-15%
TOF 5-8%
PDA 5-10%

Screening Recommendations

  • Echo ALL infants with suspected or confirmed Down syndrome
  • ECG screening (conduction abnormalities common)
  • Physical exam alone misses ~50% of CHD

Unique Considerations

  • Higher pulmonary hypertension risk
  • Earlier age of onset
  • May limit surgical options
  • Different surgical outcomes
  • Higher risk with single-ventricle palliation
  • Generally good outcomes with biventricular repairs
  • Upper airway obstruction
  • May worsen PH
  • Consider sleep study
  • Exercise promotion
  • Important despite historical restrictions
  • Special Olympics participation encouraged

Other Syndromes (Brief Overview)

Noonan Syndrome

  • CHD: Pulmonary stenosis (most common), HCM, ASD
  • Gene: PTPN11, SOS1, RAF1, others
  • HCM may be unique phenotype

Williams Syndrome

  • CHD: Supravalvar AS, peripheral PS, coronary ostial stenosis
  • Generalized arteriopathy
  • Sudden death risk (coronary and perioperative)

22q11.2 Deletion (DiGeorge/Velocardiofacial)

  • CHD: Conotruncal defects (TOF, interrupted arch, truncus arteriosus)
  • Calcium/parathyroid abnormalities
  • Immune dysfunction

Marfan Syndrome

  • See Topics 14 and 29
  • FBN1 mutation
  • Aortic root dilation, MVP, dissection risk

Loeys-Dietz Syndrome

  • See Topics 14 and 29
  • TGFBR1/2, SMAD3
  • More aggressive aortopathy than Marfan

Board Pearls

Pearl: Echo ALL infants with Down syndrome

Physical exam alone misses ~50% of CHD

Pearl: AVSD is the most common CHD in Down syndrome

Not VSD, despite VSD being most common CHD overall

Pearl: Turner syndrome: Aortic dissection risk 27x higher

BAV in 15-30%; hypertension in >50%

Self-Assessment

Q1: A newborn with Down syndrome has a normal cardiac exam. What is the next step?

Answer **Answer**: Echocardiogram **Rationale**: Physical exam alone misses approximately 50% of CHD in Down syndrome. All infants with suspected or confirmed Down syndrome should have echocardiography regardless of physical exam findings.

Q2: What is the most common congenital heart defect in Down syndrome?

Answer **Answer**: Atrioventricular septal defect (AVSD) **Rationale**: AVSD accounts for 40-45% of CHD in Down syndrome. This is distinctive because VSD is the most common CHD in the general population, but AVSD predominates in Down syndrome.

References

  • Circulation. 2023;147:425-441 (Down syndrome)
  • Circ Genom Precis Med. 2020;13:e000048 (Turner)