What is CHARGE (Coloboma, Heart defect, Atresia choanae, Restricted growth and development, Genital abnormality, and Ear abnormality) syndrome compared to Tetralogy of Fallot (TOF)?

CHARGE Syndrome vs. Tetralogy of Fallot: Key Distinctions

CHARGE syndrome is a complex multi-system genetic disorder caused by CHD7 gene mutations affecting multiple organ systems, while Tetralogy of Fallot (TOF) is a specific isolated congenital heart defect—though TOF is actually one of the most common cardiac malformations found within CHARGE syndrome. 1

Fundamental Differences

CHARGE Syndrome: A Multi-System Genetic Disorder

CHARGE syndrome is a genetic condition characterized by autosomal dominant mutations in the CHD7 gene, presenting with a constellation of congenital abnormalities across multiple organ systems. 1 The acronym stands for:

• Coloboma of the eye
• Heart defects
• Atresia of the choanae (nasal passages)
• Restricted growth and development
• Genital abnormalities
• Ear abnormalities and deafness 1, 2

Over 75% of patients with CHARGE syndrome have CHD7 gene mutations detected, and the condition affects approximately 0.1-1.2 per 10,000 live births. 2

Cardiac Involvement in CHARGE

Congenital heart defects occur in 75-80% of CHARGE syndrome patients, with a distinctive pattern favoring conotruncal and aortic arch anomalies. 1, 3, 4 The cardiac malformations in CHARGE include:

• Conotruncal defects (42% of cardiac cases): Tetralogy of Fallot, double-outlet right ventricle, truncus arteriosus 5
• Aortic arch anomalies (36% of cardiac cases): vascular rings, aberrant subclavian artery, interrupted aortic arch 5
• Atrioventricular septal defects 4
• Ventricular and atrial septal defects 1

The most common cyanotic heart defect in CHARGE syndrome is specifically Tetralogy of Fallot. 2

Non-Cardiac Features of CHARGE

CHARGE syndrome presents with severe multi-system involvement that distinguishes it from isolated cardiac defects: 1, 2

• Intellectual disability occurs in almost all cases, with IQ ranging from normal to profound retardation 1
• Cranial nerve dysfunction affecting multiple nerves 2
• Characteristic ear malformations with conductive and/or sensorineural hearing loss 2
• Feeding difficulties requiring aggressive early intervention from specialized feeding teams 2
• Behavioral phenotype with challenging behaviors requiring specialized educational and pharmacological interventions 2

Tetralogy of Fallot: An Isolated Cardiac Malformation

TOF is a specific congenital cardiac malformation consisting of four anatomic components resulting from anterosuperior deviation of the conal septum. 1 The four components are:

1. Ventricular septal defect (VSD)—malalignment type 1
2. Right ventricular outflow tract obstruction 1
3. Overriding aorta 1, 6
4. Right ventricular hypertrophy 1, 6

TOF occurs in approximately 3 per 10,000 live births and accounts for 7-10% of all congenital cardiac malformations, making it the most common cyanotic congenital heart defect. 1, 6

Etiology and Associations

TOF etiology is multifactorial, with associations including untreated maternal diabetes, phenylketonuria, retinoic acid exposure, and chromosomal anomalies (trisomies 21,18,13, and 22q11.2 microdeletions). 6 The familial recurrence risk is 3%. 6

When TOF occurs as an isolated defect (not part of a syndrome), patients typically have normal intelligence and no extra-cardiac malformations. 1

Clinical Outcomes

TOF has excellent surgical outcomes with current management, showing greater than 85-90% survival at 30 years post-repair. 1, 6 However, long-term complications include:

• Pulmonary regurgitation requiring late reoperation 1
• RV outflow tract obstruction or aneurysm 1
• Ventricular arrhythmias with sudden cardiac death risk of 6-9% by 30 years post-surgery 1
• Progressive RV dilation and dysfunction 1

Critical Clinical Distinctions

Neurodevelopmental Outcomes

The neurodevelopmental prognosis differs dramatically between isolated TOF and CHARGE syndrome:

• Isolated TOF patients have moderate risk for developmental delays, with increasing complexity associated with more neurodevelopmental issues 1
• CHARGE syndrome patients have intellectual disability in almost all cases, representing the most severe end of the neurodevelopmental spectrum among congenital heart disease patients 1

Management Complexity

CHARGE syndrome requires intensive multi-disciplinary management far beyond cardiac care alone, including: 2

• Multiple surgical interventions across organ systems
• Feeding team intervention for nutritional support
• Audiological management for hearing loss
• Ophthalmologic care for colobomas
• Endocrine evaluation for genital abnormalities
• Specialized educational services
• Behavioral and pharmacological interventions

In contrast, isolated TOF management focuses primarily on cardiac surgical repair and long-term cardiology follow-up. 1

Genetic Counseling Implications

CHARGE syndrome is caused by de novo CHD7 mutations in most cases, while TOF can occur sporadically or as part of various genetic syndromes (22q11.2 deletion being most common). 2, 6 When TOF presents in the context of multiple congenital anomalies, genetic evaluation should specifically assess for CHARGE syndrome versus 22q11.2 deletion syndrome (DiGeorge), as these are distinct conditions requiring different management approaches. 1, 3

Common Pitfall to Avoid

Do not assume that a patient with TOF and additional anomalies automatically has CHARGE syndrome—the cardiac pattern in CHARGE favors conotruncal defects including TOF, but the diagnosis requires meeting major and minor criteria (four major characteristics OR three major and three minor characteristics). 1, 2 The major criteria include choanal atresia, coloboma, characteristic ear anomalies, and cranial nerve dysfunction—not just the presence of heart disease. 2