TETRALOGY OF FALLOT

Tetralogy of Fallot has four major components:

· Pulmonary valve stenosis

· valvular in 25% of the cases,

· infundibular in 25%, A fibromuscular or fibrous hypertrophy of the infundibular region can be seen in the infundibular stenosis.

· both valvular and infundibular in 50% of the cases.

· highly variable, from mild stenosis to cases in which pulmonary valve atresia is present. These cases are called “pseudotruncus”, since they functionally behave as a common truncus

· The pulmonary stenosis may be progressive and can progress all the way to pulmonary valve atresia at birth.

· High interventricular septal defect

· perimembranous and usually wide

· Aortic root overriding the ventricular septal defect

· Concentric hypertrophy or the right ventricle.

TYPES OF TETRALOGY

Four types of Fallot have been described depending on the severity or extent of the anatomical defects.

1. The “extreme” Fallot or “pseudotruncus”:

· pulmonary stenosis is so severe that the pulmonary artery is almost atresic or absent.

2. The “classic” Fallot:

· pulmonary stenosis and overriding of the aorta above the ventricular septal defect can be seen.

3. The “pink” Fallot:

· a small defect is present.

· mild pulmonic stenosis and a discrete overriding of the aorta over the interventricular septal defect.

4. The “pentalogy” of Fallot:

· an interauricular septal defect is seen in addition to the four typical components.

PREVALENCE

· Tetralogy of Fallot represents 15% of all the congenital heart disease.

· In a recent study by Boudjemline et al., in a series of 337 cases of conotruncal heart disease:

1. tetralogy of Fallot - 56% of these cases

2. vascular malposition 16%

3. coarctation with or without interruption of the aortic arch 14%

4. truncus arteriosus 9%

5. agenesis of the pulmonary valves 5%

· Sex ratio: Slight predominance of males over females.

ETIOLOGY

Several genes, separately or in combination, could contribute to these defects. The 22q11 deletion has been associated with congenital conotruncal heart defects, as well an intrafamilial variability of cardiac involvement. There is a reported case of monozygotic twins, both with tetralogy of Fallot, in whom prenatal diagnosis found 22q11 micro deletion.

Alcohol, anti-convulsivants, thalidomide and maternal hyperphenylalaninemia and phenylketonuria have been described as teratogens to tetralogy of Fallot

PATHOGENESIS

• Tetralogy of Fallot is due to an abnormal embryological development of the heart in which an unequal conotruncal division results in a small pulmonary artery and a great aortic artery.

• The incomplete embryologic rotational process of the conotruncal septum explains the lack of alignment of this septum with the interventricular septum in tetralogy of Fallot. The incomplete rotational process of the aortic artery explains its dextroposition, its overriding location above the interventricular septum and its relationship with the right ventricle.
• The normal rotational process of the conotruncal septum does not take place the way it should, and a lesser than 180-degree rotary motion is responsible for the dextroposition of the aortic artery.
• The pulmonary artery remains in an anterior position in relation to the aorta (this differentiates tetralogy of Fallot from complete transposition of the great vessels, where the position of the pulmonary and aortic arteries is inverted).
• Under normal circumstances one septum is continuous with the other. The abnormal alignment process produces a defect of tissue between the septa, causing the interventricular communication.
• Pulmonary infundibular stenosis is at least partly due to anterior deviation of the infundibular septum, which in itself narrows the subpulmonary outflow tract. This furthers the malalignment of the septa.

ULTRASOUND

• The four-chamber view may look normal if the interventricular defect and overriding aorta is not seen.
• Dilated aorta overriding the interventricular septum (1,2). Beware of a common artifact that resembles overriding aorta (3).

• Aortic root dilatation, not seen in all cases, has been considered a marker of tetralogy offallot, but a normal size does not exclude the diagnosis.

• Perimembranous VSD.
• Mildly stenotic RV outflow tract.
• No RV hypertrophy in the mid second trimester (develops after birth).
• Inverse relationship between the size of the ascending aorta and pulmonary artery (often a marked disproportion).
• A large aortic root is an important diagnostic clue (4).
• Color Doppler may demonstrate:

• Reverse flow in the ductus arteriosus to the main pulmonary artery (ductal-dependent circulation, which denotes poor prognosis).
• In pulmonary stenosis and atresia, the stenotic jet, even small, is identified by demonstration of high velocities and turbulence in the main pulmonary artery.
• The overriding of the aorta with blood entering from both ventricles into the aorta is visible as a “Y” shaped image in color Doppler during the systolic phase.
• Pulmonary artery stenosis is not always present at initial ultrasound examination, but this finding can develop or worsen during in-utero life.
• Main pulmonary artery size, main pulmonary artery/aortic diameter ratio and pattern of pulmonary artery growth may be predictive of the severity of postnatal pulmonary outflow obstruction. Pulmonary artery atresia and progressive pulmonary artery stenosis can develop in utero in some fetuses with tetralogy of Fallot.
• Doppler studies demonstrate increased peak velocities in the pulmonary artery, due to the RV outflow tract obstruction (stenosis).
• Doppler studies may demonstrate no flow in the pulmonary artery if complete atresia is present.

• During the prenatal period, the concentric hypertrophy of the right ventricle is not seen.
• Cardiac failure is never seen in fetal life unless there is an absent pulmonary valve present (massive regurgitation to the RV and RA).

Case 1
Case 2

• Hydrops fetalis and polyhydramnios can occasionally be seen, especially in severe cases with absent pulmonary valve (which occurs in 3-6% of patients with tetralogy of Fallot) and pulmonary artery aneurysm, in which the mediastinal structures can be compressed. The aneurysm may be seen as a cystic, pulsatile dilatation, without definite valve echoes.

DIFFERENTIAL DIAGNOSIS

• VSD. In cases of minor forms of right outflow tract obstruction and overriding aorta, differentiation may be difficult.
• Truncus arteriosus. In those cases in which the pulmonary artery is not imaged, differentiation between pulmonary atresia with VSD and truncus may be extremely difficult.
• Pseudo-overriding of the aorta
• Double outlet right ventricle.

ASSOCIATIONS

• Bicuspid aortic valve (40%).
• Left pulmonary artery stenosis (40%).
• Absent pulmonary valve (2%).
• Right-sided aortic arch (35%).
• Left superior vena cava.
• Absent ductus arteriosus (15%).
• ASD (25%)
• Absent pulmonary valve with pulmonary aneurysm
• Tracheo-esophageal fistula.
• Down syndrome.
• Forked ribs, scoliosis.
• Coronary artery anomalies in 10% (single right coronary artery or left anterior descending coronary artery arises from right coronary artery).
• CHARGE association.
• Other reported anomalies include Prune Belly syndrome and DiGeorge sequence.
• Abnormal karyotype in 8% of all cases
• Azancot et al. in a recent study of 44 cases of non-isolated tetralogy of Fallot, found genetic anomalies in 18 of the fetuses (10 trisomies, including five trisomies 21 and 5 structural abnormalities including 2 micro-deletions 22q11 and 1 deletion of chromosome 8p23.1 and 3 mendelian syndromes), with an overall incidence of malformations of 61%.

Type	Anomalies (8% of cases)
Cardiovascular	Absent ductus arteriosus (15%) Absent pulmonary valve with pulmonary aneurysm Anomalies of the left heart Atrial septal defect Atrioventricular canal Ductus arteriosus Infundibular hypertrophy Left superior vena cava Pulmonary hypoplasia/atresia Right sided aortic arch (20%) Valvular agenesis Venous anomalies
Extracardiac abnormalities	Prune Belly Shprintzen (velo-cardio-facial) syndrome Hypoparathyroidism DiGeorge sequence
Chromosome anomalies (8%)	Trisomy 13 Trisomy 18 Trisomy 21 Monosomy X Micro-deletions 22q11 Deletion of chromosome 8p23.1

HEMODYNAMICS

Pulmonary blood flow is supplied retrograde through the ductus arteriosus with absence of RV hypertrophy or IUGR.

POSTNATAL

• The variable resistance created by the stenotic pulmonary artery, prevents the venous flow of the right heart from moving freely towards the pulmonary circulation, and the wide interventricular defect allows it into the left ventricle and aorta, creating the right to left shunt.
• In utero, this is not a problem for the fetus, since normal blood oxygenation takes place in the utero-placental unit.
• In the classic Fallot, systemic hypoxia is the most important problem after birth and the admixture explains the cyanosis in the affected individuals.
• The severity of both, the pulmonary artery stenosis and the aortic overriding above the interventricular septum, will determine the degree of hypoxia and cyanosis of the newborn.
• In mild cases cyanosis may be absent.
• The more severe the pulmonary stenosis the greater the size of the ascending aorta (both aortic and pulmonary flow will be directed through it).
• After birth, right ventricular hypertension and subsequent concentric hypertrophy of the right ventricle occurs due to:
• the right ventricle is subjected to the left ventricular and aortic pressures due to the large interventricular septal defect

resistance to flow due to the pulmonary stenosis

PROGNOSIS

In early life the prognosis will be determined by the presence of associated anomalies and fetal syndromes in which cases the survival rate is only 10%. In isolated cases of tetralogy of Fallot, the survival rate reaches 85%.

Those cases with severe pulmonary stenosis or atresia, aneurysm of the pulmonary artery associated with hydrops fetalis and polyhydramnios, and great overriding aorta above the interventricular septal defect, will eventually have cardiac failure and may die in utero. Those that do not die in utero will be cyanotic after birth and will have short life expectancy.

Those cases of mild to moderate pulmonary stenosis with discrete overriding aorta will have the best prognosis and surgical results. The cyanosis after birth may be gentle or absent, and a normal life span may be achieved.

Recurrence risk: In cases of a sibling with Tetralogy of Fallot, the recurrence risk is estimated in 2%.

REFERENCES

1. Kleinman CS, Donnerstein RL, DeVore GR et.al. Fetal echocardiography for evaluation of in utero congestive heart failure. N Engl J Med 1982;306:568-575.
2. Sanders SP, Bierman FZ, Williams RG. Conotruncal malformations: diagnosis in infancy using subxiphoid 2-dimensional echocardiography. Am J Cardiol 1982;50:1361-1367.
3. DeVore GR, Siassi B, Platt LD. Fetal echocardiography VIII. Aortic root dilatation - a marker for tetralogy of Fallot. Am J Obstet Gynecol 1988;159:129-136.