Tetralogy of Fallot

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Introduction

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease (CHD) presenting after the neonatal period1,2. It accounts for between 7% to 10% of all congenital cardiac defects.3

The word ‘tetralogy’ refers to something made up of four parts. Therefore, Tetralogy of Fallot is characterised by four defects. Three of the defects are anatomical: ventricular septal defect (VSD), pulmonary stenosis and an overriding aorta. The fourth defect is a physiological adaptation which is right ventricular hypertrophy.

Tetralogy of Fallot is sometimes referred to as ‘blue baby syndrome.

You might also be interested in our medical flashcard collection which contains over 1000 flashcards that cover key medical topics.

Aetiology

Causes of Tetralogy of Fallot

There is no single cause for Tetralogy of Fallot. Instead, the development of TOF is multifactorial. However, Tetralogy of Fallot is associated with various genetic conditions.

Down’s syndrome

Down’s syndrome (trisomy 21) is a genetic disorder caused by a third copy of chromosome 21.

Down’s syndrome causes delays in physical growth, intellectual disability, and characteristic facial features. About 40% of those with Down’s syndrome are born with a form of congenital heart disease. Lesions include Tetralogy of Fallot, atrial septal defect and ventricular septal defects.4

DiGeorge syndrome

DiGeorge syndrome is caused by a microdeletion on the long arm of chromosome 22. It is also known as 22q11.2 deletion syndrome.

DiGeorge syndrome is autosomal dominant and occurs in about 1 in 4000 people.3

The salient features of DiGeorge syndrome are summarised as CATCH-22:

  • Cardiac abnormalities (commonly Tetralogy of Fallot)
  • Abnormal facies (cleft palate, hypertelorism and short philtrum)
  • Thymic aplasia/hypoplasia
  • Cleft palate
  • Hypocalcaemia/hypoparathyroidism

CHARGE syndrome

CHARGE is a complex syndrome with a wide range of mental and physical disabilities. It is caused by a mutation of CHD7 on chromosome 8 in 80 to 90% of cases. CHARGE syndrome occurs in 1:10 000 to 1:15 000 live births.6

Clinical features of CHARGE syndrome include:

  • Colomba
  • Heart defects
  • Atresia choanae (bone blocking the nasal passage which causes difficulty breathing)
  • Restriction of growth and development
  • Ear abnormalities and deafness

VACTERL association

VACTERL association is a condition that is characterised by the presence of a group of congenital malformations.7

The exact cause is unknown but microdeletions of the FOX gene cluster at 16q24.1 have been reported to cause VACTERL associations.8 It occurs in 1 per 10000 to 40000 live births.

Patients need to have at least three of the following characteristics to make a diagnosis of VACTERL association:

  • Vertebral defects
  • Anal atresia
  • Cardiac defects
  • Tracheoesophageal fistula
  • Renal anomalies
  • Limb abnormalities

Associated congenital defects

Tetralogy of Fallot can be associated with the presence of other congenital cardiac abnormalities:9

  • Right aortic arch (25%)
  • Abnormal coronary artery anatomy (5 to 10%)
  • Pulmonary atresia
  • Aorticopulmonary collateral vessels
  • Patent ductus arteriosus
  • Atrioventricular septal defect
  • Atrial defect
  • Absent pulmonary valve

Pathophysiology

There are four components of Tetralogy of Fallot (Figure 1):

  • Ventricular septal defect
  • Pulmonary artery stenosis
  • Overriding aorta
  • Right ventricular hypertrophy
Tetralogy of Fallot
Figure 1. Tetralogy of Fallot diagram.

Development of Tetralogy of Fallot

The development of Tetralogy of Fallot begins in utero and is caused by a single developmental error.14

Normally, the primitive truncus arteriosus is split in two by the evolving spiral septum. However, in Tetralogy of Fallot, the truncus arteriosus fails to divide. Therefore, the spiral septum cannot fuse with the growing muscular ventricular septum causing a ventricular septal defect.

There is narrowing of the pathway from the right ventricle to the pulmonary artery which causes pulmonary artery stenosis

In addition, the aortic root is enlarged and extends over the right ventricle outflow tract causing the overriding aorta.

Finally, right ventricular hypertrophy occurs as a physiological adaptation to increased afterload in the heart. A right-sided aortic arch, coronary artery abnormalities and additional VSDs are associated abnormalities.

Fetal circulation

When the fetus is in the womb, its lungs are not in use. This is because circulating blood bypasses the lungs. Fetal blood is oxygenated at the feto-maternal interface and shunted from the right atrium to the left atrium via the foramen ovale. The oxygenated blood moves from the left atrium to the left ventricle and into the aorta to the rest of the body.

When deoxygenated blood returns from the foetal body it enters the right atrium and flows into the right ventricle.

In an adult, blood would then flow to the lungs to be oxygenated. However, in the fetus blood bypasses the lungs and flows through the ductus arteriosus into the descending aorta.

The descending aorta connects to the umbilical arteries and the deoxygenated blood flows back to the placenta.

The deoxygenated blood is oxygenated again in the feto-maternal interface at the level of the placenta. The oxygenated blood travels across the placenta into the foetus’s right atrium. The cycle repeats.

Fetal circulation
Figure 2. Normal fetal circulation.

Right to left shunt and cyanosis

When a baby takes its first breath, the lungs expand reducing resistance to blood flow and allowing for more flow from the right ventricle. The ductus arteriosus and foramen ovale close as they are not required. The baby’s circulation is now the same as an adult’s circulation.

However, in Tetralogy of Fallot, this is not the case. Firstly, the ventricular septal defect allows the mixing of oxygenated and deoxygenated blood.

This means deoxygenated blood enters the aorta and is pumped to the rest of the body. The tissues receive poorly oxygenated blood resulting in cyanosis.

Secondly, the overriding aorta means that the aortic valve is placed further to the right than normal, above the VSD. The aorta is also enlarged. When the right ventricle contracts and pumps blood upwards, the aorta is in the direction of travel of that blood. Therefore, more deoxygenated blood enters the aorta from the right side of the heart.

Thirdly, pulmonary stenosis means there is greater resistance to the flow of blood from the right ventricle into the pulmonary artery.

Instead of deoxygenated blood flowing through the pulmonary artery to the lungs, blood is pushed through the VSD into the aorta. The pulmonary stenosis along with the overriding aorta causes deoxygenated blood to be shunted from the right to the left side of the heart causing cyanosis.

Fourthly, the right ventricle is pumping blood into the pulmonary artery under great resistance due to pulmonary stenosis, and due to pressures from the left ventricle being directly transmitted to the right ventricle because of the open VSD. This puts increased strain on the right ventricle causing right ventricular hypertrophy.

The degree of cyanosis is related to the severity of the pulmonary stenosis.

Tetralogy of Fallot blood flot
Figure 3. Comparison of Tetralogy of Fallot with a normal heart.

Risk factors

Risk factors for ToF include:13

  • 1st-degree family history of congenital heart disease
  • A parent with Tetralogy of Fallot
  • A parent with DiGeorge syndrome
  • Foetal exposure to teratogens in utero (e.g. alcohol, warfarin and trimethadione)
  • Poorly controlled maternal diabetes
  • Maternal intake of retinoic acid
  • Congenital Rubella infection
  • Increased maternal age (over 40 years old)

Clinical features

Clinical features will vary depending on the subtype of TOF. 

There are three major subtypes of TOF:15

  1. TOF with a milder form of pulmonary stenosis
  2. TOF with pulmonary atresia
  3. TOF with absent pulmonary valve

TOF with a milder form of pulmonary stenosis

Children born with mild pulmonary stenosis are usually asymptomatic at birth. As the child and the heart grows, the symptoms develop. Around the age of 1 to 3 years, the child develops cyanosis.

TOF with pulmonary atresia

Children who are born with moderate to severe pulmonary stenosis will present within the first few weeks of life with cyanosis and respiratory distress.

TOF with absent pulmonary valve

This is caused by TOF with pulmonary atresia or TOF with an absent pulmonary valve.

In TOF with an absent pulmonary valve, the pulmonary valve is markedly dysplastic and is effectively regurgitant to a moderate or severe degree. This causes enlargement of the branch pulmonary arteries as well as the right ventricle.

The branch pulmonary arteries enlarge so much sometimes that they may obstruct the tracheal tree and there may be associated tracheo or bronchomalacia as a result.

The deoxygenated blood can only flow into the lungs via a patent ductus arteriosus. The child will develop cyanosis and respiratory distress within the first few hours of life.

Clinical examination

Typical findings on general examination may include:

  • Central cyanosis
  • Clubbing (Figure 4)
  • Respiratory distress

Typical findings on cardiovascular examination may include:

  • Thrill
  • Heave (due to right ventricular hypertrophy)
  • An ejection systolic murmur loudest in the 2nd intercostal space, upper left sternal edge (pulmonary area)
  • Ejection click due to the closure of the dilated aortic valve in diastole
  • Single S2 due to closure of the aortic valve in diastole with reduced pulmonary valve closure due to PA stenosis
  • Continuous murmur at the left upper sternal edge if there is a patent ductus arteriosus
Clubbing and cyanosis
Figure 4. Digital clubbing with cyanotic nail beds in an adult with tetralogy of Fallot

Differential diagnoses

Differential diagnoses to consider include other types of cyanotic congenital heart disease:

  • Transposition of the Great Arteries (TGA)
  • Total anomalous pulmonary venous drainage (TAPVD)
  • Hypoplastic left heart syndrome (HLHS)
  • VSD with Eisenmenger syndrome
Cyanotic congenital heart disease: 6Ts

The ‘6Ts’ can be used to recall the differential diagnoses of cyanotic lesions:

  • Tetralogy of Fallot
  • Transposition of great arteries
  • Truncus arteriosus
  • Total anomalous pulmonary venous connection
  • Tricuspid valve abnormalities
  • Ton of others – hypoplastic left heart, double outlet right ventricle, pulmonary atresia

For more information, see the Geeky Medics guide to congenital heart disease


Investigations

Many cases of Tetralogy of Fallot are identified through antenatal screening.

A foetal echocardiogram can be used to identify Tetralogy of Fallot.16 Foetuses with Tetralogy of Fallot can present with a ventricular septal defect or an overriding aorta on ultrasound.17

During a newborn baby check, an ejection systolic murmur caused by pulmonary stenosis may be heard.

Bedside investigations

Relevant bedside investigations include:

  • Pulse oximetry
  • ECG: to detect heart chamber enlargement and arrhythmia. TOF may present with right axis deviation and right ventricular hypertrophy

Laboratory investigations

Relevant laboratory investigations include:

  • Genetic testing: if a genetic syndrome is suspected (e.g. Down’s syndrome, DiGeorge syndrome)

Imaging investigations

Relevant imaging investigations include:

  • Chest X-ray: to visualise the structure of the heart and the lungs. Findings may include a boot-shaped heart (due to RVH) or reduced pulmonary vascular markings (due to reduced pulmonary blood flow)
  • Cardiac MRI: used to determine the anatomy of the lesion and the cardiac function
  • Cardiac catheterisation: to evaluate the structure and haemodynamic physiology of the heart and help to plan for surgery. Cardiac catheterisation may also be used to deliver therapy such as stent angioplasty of the ductus arteriosus, or stent angioplasty to the right ventricular infundibulum in babies who exhibit hypercyanotic spells.

Management

Surgical intervention typically occurs within the first year of life. Some patients receive a bridging procedure before complete repair of the Tetralogy of Fallot.18

In some infants, a prostaglandin infusion is given to maintain a patent ductus arteriosus. This allows blood to flow from the aorta back to the pulmonary arteries thereby maintaining the blood flow to the pulmonary circulation. This is necessary when there is not enough forward flow from the heart through the pulmonary valve into the lungs.

Surgical bridging procedures

Bridging is used in infants who have poor pulmonary artery anatomy or co-morbidities who are not suitable to undergo surgical repair immediately. Bridging procedures help relieve cyanosis and defers the need for complete surgical repair.

Blalock-Taussig shunt

A Blalock-Taussig (BT) shunt is placed as a form of intermediate management until a complete repair can be conducted. It allows babies to grow so they are better suited for their complete repair. A BT shunt is usually performed in the first weeks of life.

The BT shunt mimics a patent ductus arteriosus and increases pulmonary blood flow before a complete repair can be performed. There are two ways of performing a BT shunt:

  1. Anastomosis of the subclavian artery to the pulmonary artery: this allows more blood to be oxygenated by the lungs as the high-pressure arterial system forces blood through the lungs. It also promotes the growth of the pulmonary arteries which will make the complete repair easier
  2. Modified BT shunt: this is an artificial shunt made from synthetic material (usually Gore-Tex)

There are other forms of bridging including a right ventricle to pulmonary artery conduit (to bypass the right ventricle outflow tract obstruction) or pulmonary artery band (minimises pulmonary overloading).

Surgical repair

The timing of the repair will depend on the severity of the symptoms, but the usual rule is no younger than 3 months and no older than 4 years. Children must be fit enough to undergo the complete repair.

The complete repair is performed under cardiopulmonary bypass. A midline sternotomy incision is performed. The right ventricle outflow tract/pulmonary artery stenosis is resected. The pulmonary artery is enlarged and the VSD is closed with a patch.

The pulmonary valve may also be repaired (surgeons make an effort to preserve the function of the pulmonary valve, so-called valve preserving surgery).

After surgery children are looked after in a cardiac intensive care unit (CICU).


Complications

Complications of surgical repair

Despite surgical repair of a Tetralogy of Fallot patients can still experience long-term complications.

The most common late complication is significant pulmonary regurgitation.19 This leads to right ventricular dilatation and dysfunction. The enlarged right ventricle may interact with the left ventricle and disrupt left ventricular filling or systolic function.

Some patients can also experience arrhythmias such as ventricular tachycardia, atrial flutter and atrial fibrillation.19

In addition, pulmonary artery stenosis may persist due to incomplete resection of the obstruction, or it may recur as muscle bundles in the right ventricular infundibulum hypertrophy over time.

Cyanotic (‘tet’) spells

A cyanotic or ‘tet’ spell is a complication of an unrepaired Tetralogy of Fallot. A ‘tet’ spell is a sudden episode of profound cyanosis and hypoxia and can be fatal.20

They tend to occur in young children between the ages of 2 months and 2 years. During the ‘tet spell’ the child will become cyanotic, dyspnoeic, and irritable. In severe cases, a ‘tet spell’ can cause reduced consciousness, seizures and potentially death.

There are several causes of a ‘tet’ spell:

  1. Decrease in oxygen saturations (e.g. crying, or other forms of emotional or physical distress or defecating)
  2. Decrease in systemic vascular resistance (e.g. playing)
  3. Increase in pulmonary vascular resistance
  4. Tachycardia
  5. Hypovolaemia

It is thought that an increase in right to left shunting and a fall in arterial oxygen saturations causes a cyanotic spell.

After the initial drop in arterial oxygen saturation, there is an increase in right ventricular outflow tract obstruction, an increase in pulmonary vascular resistance and/or a decrease in systemic resistance.

This creates a vicious cycle which stimulates the respiratory centre. This causes hyperpnea and an increase in adrenergic tone with circulating catecholamines.

The increase in circulating catecholamines causes increased contractility which leads to increased outflow tract obstruction.

On auscultation of the heart during a tet spell, there will be a reduced/absent murmur due to decreased pulmonary blood flow and a tightly ‘shut’ infundibulum.

How to manage a ‘tet spell’

Children with Tetralogy of Fallot will manage a ‘tet spell’ themselves by squatting or bringing their knees to their chest. Squatting increases the systemic vascular resistance which pushes blood into the pulmonary vessels.

Management should include:20

  1. Position the child with their knees at their chest
  2. Oxygen
  3. Morphine: decreases respiratory drive
  4. Intravenous fluids: increase pre-load which increases the volume of blood which flows into the pulmonary vessels
  5. Beta-blockers (propranolol): relaxes the right ventricle infundibulum and improves the flow of blood to the pulmonary vessels
  6. Phenylephrine infusion: increases systemic vascular resistance
  7. Emergency ventricular outflow tract stent or BT shunt
  8. Sodium bicarbonate if there is metabolic acidosis

Arrhythmias

Adults with Tetralogy of Fallot can experience arrhythmias. Atrial and ventricular enlargement as well as the scars caused by surgical intervention form the substrate for arrhythmias. Atrial fibrillation and atrial flutter are most common.

Sinus rhythm can be restored by medications, catheter ablation or electrical cardioversion. In the case of ventricular tachyarrhythmias, an implantable cardioverter-defibrillator may be needed.

Other complications

Other complications of Tetralogy of Fallot include:

Prognosis

Around 90% of children with a surgically repaired Tetralogy of Fallot survive into adulthood.21  However, the prognosis of Tetralogy of Fallot depends on the severity. Without surgical treatment the prognosis is poor. 

Patients with Tetralogy of Fallot require lifelong follow-up (including ECGs, echocardiography and exercise testing). Further procedures (e.g. stenting for pulmonary stenosis) may be required into adulthood. 


Key points

  • Tetralogy of Fallot is the most common cyanotic congenital heart disease presenting after the neonatal period
  • Tetralogy of Fallot is comprised of ventricular septal defect, pulmonary stenosis, overriding aorta and right ventricular hypertrophy
  • Tetralogy of Fallot is associated with Down’s syndrome, DiGeorge syndrome, and other cardiac malformations
  • Tetralogy of Fallot causes a right to left cardiac shunt which causes cyanosis
  • Other clinical findings may include clubbing, respiratory distress and cardiac murmurs
  • Most cases of Tetralogy of Fallot are identified on antenatal screening or on a newborn baby check
  • Surgical intervention for Tetralogy of Fallot should occur within the first year of life
  • Bridging procedures (e.g., BT shunt/stent) can be used when a child cannot undergo surgical repair immediately
  • ‘Tet’ spells can occur in Tetralogy of Fallot, they are episodes of profound cyanosis and hypoxia
  • There are many complications of Tetralogy of Fallot which include arrhythmias, sudden cardiac death, heart failure and infective endocarditis
  • Long-term follow-up with a paediatric and adult congenital cardiology specialist is required and patients may need repeat procedures in adulthood
  • 90% of patients with a surgically repaired Tetralogy of Fallot survive into adulthood

Reviewer

Dr Gruschen Veldtman

Consultant in Adult Congenital Cardiology


Editor

Dr Chris Jefferies


References

  1. Marcdante, K. and R.M. Kliegman, Nelson essentials of pediatrics e-book. 2014: Elsevier Health Sciences.
  2. Baumgartner, H., et al., 2020 ESC Guidelines for the management of adult congenital heart disease: The Task Force for the management of adult congenital heart disease of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Adult Congenital Heart Disease (ISACHD). European Heart Journal, 2020. 42(6): p. 563-645.
  3. Diaz-Frias, J. and M. Guillaume, Tetralogy of Fallot. 2021: StatPearls Publishing, Treasure Island (FL).
  4. CJ, E., The consequences of chromosome imbalance: principles, mechanisms and models. Cambridge. Cambridge Unversity Press. . 2007: p. 255-256.
  5. MedlinePlus, 22q11.2 deletion syndrome. Genetic Conditions. Genetics. . 2019.
  6. Blake, K.D. and C. Prasad, CHARGE syndrome. Orphanet Journal of Rare Diseases, 2006. 1(1): p. 34.
  7. Solomon, B.D., The etiology of VACTERL association: Current knowledge and hypotheses. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 2018. 178(4): p. 440-446.
  8. Shaw-Smith, C., Genetic factors in esophageal atresia, tracheo-esophageal fistula and the VACTERL association: Roles for FOXF1 and the 16q24.1 FOX transcription factor gene cluster, and review of the literature. European Journal of Medical Genetics, 2010. 53(1): p. 6-13.
  9. Zhao, Y., et al., Prenatal and Postnatal Survival of Fetal Tetralogy of Fallot. Journal of Ultrasound in Medicine, 2016. 35(5): p. 905-915.
  10. Puia-Dumitrescu, M., et al., Survival, Morbidities, and Developmental Outcomes among Low Birth Weight Infants with Congenital Heart Defects. Am J Perinatol, 2021. 38(13): p. 1366-1372.
  11. Van Der Linde, D., et al., Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. Journal of the American College of Cardiology, 2011. 58(21): p. 2241-2247.
  12. Tatewaki, H. and A. Shiose, Pulmonary valve replacement after repaired Tetralogy of Fallot. General Thoracic and Cardiovascular Surgery, 2018. 66(9): p. 509-515.
  13. Starr, J.P., Tetralogy of Fallot: Yesterday and Today. World Journal of Surgery, 2010. 34(4): p. 658-668.
  14. Sarris, G.E., et al., Results of surgery for Ebstein anomaly: A multicenter study from the European Congenital Heart Surgeons Association. The Journal of Thoracic and Cardiovascular Surgery, 2006. 132(1): p. 50-57.e4.
  15. Farouk, A., et al., Individualized approach to the surgical treatment of tetralogy of Fallot with pulmonary atresia. Cardiology in the Young, 2009. 19(1): p. 76-85.
  16. A, W., Tetralogy of Fallot- antenatal. Case Study Radiopaedia 2020.
  17. Lee, W., et al., Tetralogy of Fallot: prenatal diagnosis and postnatal survival. Obstet Gynecol, 1995. 86(4 Pt 1): p. 583-8.
  18. Jonas, R.A., Early Primary Repair of Tetralogy of Fallot. Seminars in Thoracic and Cardiovascular Surgery: Pediatric Cardiac Surgery Annual, 2009. 12(1): p. 39-47.
  19. Apitz, C., G.D. Webb, and A.N. Redington, Tetralogy of Fallot. The Lancet, 2009. 374(9699): p. 1462-1471.
  20. Sharkey, A.M. and A. Sharma, Tetralogy of Fallot: Anatomic Variants and Their Impact on Surgical Management. Seminars in Cardiothoracic and Vascular Anesthesia, 2012. 16(2): p. 88-96.
  21. Smith, C.A., et al., Long-term Outcomes of Tetralogy of Fallot: A Study From the Pediatric Cardiac Care Consortium. JAMA Cardiology, 2019. 4(1): p. 34-41.

Image references

  • Figure 1. LadyofHats. Tetralogy of Fallot. License: [Public domain]
  • Figure 2. OpenStax. Fetal Circulatory System. License: [CC BY]
  • Figure 3. LadyofHats. Blue baby syndrome. License: [Public domain]
  • Figure 4.Herbert L. Fred, MD and Hendrik A. van Dijk. Digital clubbing with cyanotic nail beds in an adult with tetralogy of Fallot. License: [CC BY-SA]

 

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