DEFINITION
Tetralogy of Fallot (TOF) is a congenital heart defect which is classically understood to involve four anatomical abnormalities of the heart (although only three of them are always present): pulmonary stenosis, an opening in the interventricular septum, malposition of the aorta over both ventricles, and hypertrophy of the right ventricle. It is the most common cyanotic heart defect, and the most common cause of blue baby syndrome.
EPIDEMIOLOGY
The approximate incidence of tetralogy of Fallot (TOF) of about 400 per million live births marks it as the most common complex or cyanotic defect. Corrective surgery for TOF now permits over 85% of such children to survive into adulthood. Approximately 50% of patients with TOF are women, and it was one of the first disorders to be surgically palliated or repaired. (Fallot's tetralogy and pregnancy: Prognostication and prophesy, 2004)
SYMPTOMS
- The clinical features of tetralogy of Fallot are directly related to the severity of the anatomic defects. Infants often display the following:
- Difficulty with feeding,
- Failure to thrive
- Episodes of bluish pale skin during crying or feeding ("Tet" spells)
- Exertional dyspnea, usually worsening with age
- Physical findings include the following:
- Most infants are smaller than expected for age
- Cyanosis of the lips and nail bed is usually pronounced at birth
- After age 3-6 months, the fingers and toes show clubbing
- A harsh systolic ejection murmur (SEM) is heard over the pulmonic area and left sternal border
- During cyanotic episodes, murmurs may disappear
- The following may also be noted:
figura1. clubbing fingers
DIAGNOSIS
Patients with a Fallot's tetralogy proved by a haemodynamic and angiographic examination are studied by echography, a non invasive technique. The diameters of the right and left ventricles, of the left atrium and of the aorta are measured. The movements of the interventricular septum and the position of the aorta in relation to it are analysed. Moreover, by scanning of the left ventricle an opening is looked for in the septum. The ventricular septal defect together with a dilatation of the right ventricle and a more or less intense dilatation of the root of the aorta are found in all cases. An aorta overriding the septum is observed, and this is the more obvious the older the child.There are therefore echocardiographic criteria making it possible to diagnose Fallot's tetralogy. These criteria are the more obvious the older the child.
Before more sophisticated techniques became available, chest x-ray was the definitive method of diagnosis. The abnormal "coeur-en-sabot" (boot-shaped) appearance of a heart with tetralogy of Fallot is classically visible via chest x-ray, although most infants with tetralogy may not show this finding. (Study of tetralogy of Fallot by echocardiography, 2001)
PATHOGENESIS
Its cause is thought to be due to environmental or genetic factors or a combination. It is often associated with:
- DiGeorge syndrome (22q11 deletions in isolated and syndromic patients with tetralogy of Fallot, 2006)
- Down Syndrome (Cardiac Malformations Associated with Down's Syndrome, 2004)
- Maternal phenylketonuria (Maternal phenylketonuria syndrome: Congenital heart defects, 2007)
The following table shows the main characteristics of the above-mentioned genetic diseases:
| Genetic disease | Location of the mutation | Type mutation |
| DiGeorge syndrome | Chromosome 22 | Deletion of a portion of chromosome 22 |
| Down syndrome | Chromosome 21 | Trisomy |
| Maternal phenylketonuria | Chromosome 12 | Point mutation of certain DNA bases |
Specific genetic associations include:
• JAG1
Jagged1 is a direct Notch target in smooth muscle, resulting in a positive feedback loop and lateral induction that propagates a wave of smooth muscle differentiation during aortic arch artery development. In vivo, it is shown that Notch inhibition in cardiac neural crest impairs Jagged1 messenger RNA expression and results in deficient smooth muscle differentiation and resultant aortic arch artery defects. (Notch Activation of Jagged1 Contributes to the Assembly of the Arterial Wall, 2012)
Evaluation of candidate loci in a large kindred segregating autosomal dominant ToF with reduced penetrance culminated in identification of a missense mutation (G274D) in JAG1, the gene encoding jagged1, a Notch ligand expressed in the developing right heart. Mutation carriers manifested cardiac disease, including classic ToF, ventricular septal defect with aortic dextroposition and isolated peripheral pulmonic stenosis (PPS). All forms of ToF are represented, including variants with pulmonic stenosis, pulmonic atresia and absent pulmonary valve. The glycine corresponding to position 274 is highly conserved in other epidermal growth factor-like domains of jagged1 and in those of other proteins. Its substitution in other proteins has been associated with mild or atypical variants of disease. These data support either a relative loss-of-function or a gain-of-function pathogenetic mechanism in this family and suggest that JAG1 mutations may contribute significantly to common variants of right heart obstructive disease. (Familial Tetralogy of Fallot caused by mutation in the jagged1 gene, 2010)
• NKX2-5
Heart formation in Drosophila is dependent on the homeobox gene tinman. The homeobox gene Nkx2-5 is closely related to tinman and is the earliest known marker for cardiogenesis in vertebrate embryos. (Building the heart piece by piece:modularity of cis-elements regulating Nkx2-5 transcription, 2000)
Recent reports have implicated mutations in the transcription factor NKX2.5 as a cause of tetralogy of Fallot (TOF). Patients were screened for NKX2.5 alterations by conformation-sensitive gel electrophoresis and sequencing of fragments with aberrant mobility. It was found that NKX2.5 mutations are the first gene defects identified in nonsyndromic TOF patients. NKX2.5 mutation is present in ≥4% of TOF patients. (NKX2.5 Mutations in Patients With Tetralogy of Fallot, 2001)
• ZFPM2
ZFPM2 is a transcription regulator that plays a central role in heart morphogenesis and development of coronary vessels from epicardium, by regulating genes that are essential during cardiogenesis. (Functions of ZFPM2, 2002)
Two out of 47 patients with sporadic tetralogy of Fallot (TOF), the most common cyanotic conotruncal heart defect (CTD), showed heterozygous missense mutations of the ZFPM2/FOG2 gene. Knockout mice carrying mutations in the ZFPM2/FOG2 gene have similarly been found to exhibit TOF. ZFPM2/FOG2 gene mutations may contribute to some sporadic cases of TOF. (Mutations of ZFPM2/FOG2 gene in sporadic cases of tetralogy of Fallot, 2003)
• VEGF
The importance of vascular endothelial growth factor-A (VEGF) and subsequent Notch signaling in cardiac outflow tract development is generally recognized. Although genetic heterogeneity and mutations of these genes in both humans and mouse models relate to a high susceptibility to develop outflow tract malformations such as tetralogy of Fallot and peripheral pulmonary stenosis.The increase of VEGF and Notch signaling during right ventricular outflow tract development can lead to abnormal development of both cushion and myocardial structures. Defective right ventricular outflow tract development as presented provides new insight in the etiology of tetralogy of Fallot. (Tetralogy of Fallot and Alterations in Vascular Endothelial Growth Factor-A Signaling and Notch Signaling in Mouse Embryos Solely Expressing the VEGF120 Isoform,2005)
By using a multi-genetic approach, it was recently discovered that VEGF might be a modifier of the cardiac birth defects in subjects with isolated, non-syndromic TOF. common polymorphisms in the VEGF promoter (−2578A, −1154A) and leader sequence (−634G), known to lower vascular endothelial growth factor (VEGF) levels, increase the risk for TOF. (Low expression VEGF haplotype increases the risk for tetralogy of Fallot: a family based association study, 2004)
Protein Aminoacids Percentage
The Protein Aminoacids Percentage gives useful information on the local environment and the metabolic status of the cell (starvation, lack of essential AA, hypoxia)
Protein Aminoacids Percentage (Width 700 px)
PATHOFISIOLOGY
Tetralogy of Fallot involves four heart malformations which present together:
figura2. Tetrology of Fallot
A) Pulmunar infudibular stenosis: a narrowing of the right ventricular outflow tract. It can occur at the pulmonary valve (valvular stenosis) or just below the pulmonary valve(infundibular stenosis).
B) Overrinding aorta: an aortic valve with biventricular connection is situated above the ventricular septal defect and connected to both the right and the left ventricle.
C) Ventricular septal defect: a hole between the two bottom chambers (ventricles) of the heart.
D) Right ventricular hypertrophy: the right ventricle is more muscular than normal, causing a characteristic boot-shaped (coeur-en-sabot) appearance as seen by chest X-ray.
(Tetralogy of Fallot, Pathofisiology, 2010)
COMPLICATIONS
In addition, tetralogy of Fallot may present with other anatomical anomalies, including:
1. stenosis of the left pulmonary artery, in 40% of patients
2. a bicuspid pulmonary valve, in 60% of patients
3. right-sided aortic arch, in 25% of patients
4. coronary artery anomalies, in 10% of patients
5. a patent foramen ovale or atrial septal defect, in which case the syndrome is sometimes called a pentalogy of Fallot
6. an atrioventricular septal defect
7. partially or totally anomalous pulmonary venous return
8. forked ribs and scoliosis
(Tetralogy of Fallot, Addictional abnormalities, 2010)
THERAPY
Emergency management of tet spells:
Prior to corrective surgery, children with tetralogy of Fallot may be prone to consequential acute hypoxia (tet spells), characterized by sudden cyanosis and syncope. These may be treated with beta-blockers such as propranolol, but acute episodes may require rapid intervention with morphine to reduce ventilatory drive and a vasopressor such as epinephrine, phenylephrine, or norepinephrine to increase blood pressure. Oxygen (100%) is effective in treating spells because it is a potent pulmonary vasodilator and systemic vasoconstrictor. This allows more blood flow to the lungs. There are also simple procedures such as squatting and the knee chest position which increases aortic wave reflection, increasing pressure on the left side of the heart, decreasing the right to left shunt thus decreasing the amount of deoxygenated blood entering the systemic circulation. (Squatting: the hemodynamic change is induced by enhanced aortic wave reflection, 2002)
Palliative surgery:
The procedure palliative surgery is not curative. It is, in fact, a temporary measure, pending the baby's heart may grow and be ready for the intracardiac repair.
The procedure involves the application of a bypass, or shunt, which connects the aorta to the pulmonary artery. This communication is also known as anastomosis and promotes blood flow to the lungs. When you decide to intervene with the intracardiac repair, the bypass is removed. (Palliative surgery in tetralogy of Fallot, 2010)
Total surgical repair:
Total repair of tetralogy of Fallot initially carried a high mortality risk. This risk has gone down steadily over the years. Surgery is now often carried out in infants one year of age or younger with less than 5% perioperative mortality. (Tetralogy of fallot repair in patients 40 years or older, 2010
