tetralogy of fallot tetralogy of fallot tetralogy of fallot (tof), formerly known as steno-fallot tetralogy, is a congenital heart defect characterized by four specific cardiac defects. classically, the four defects are: pulmonary stenosis, which is narrowing of the exit from the right ventricle; a ventricular septal defect, which is a hole allowing blood to flow between the two ventricles; right ventricular hypertrophy, which is thickening of the right ventricular muscle; and an overriding aorta, which is where the aorta expands to allow blood from both ventricles to enter. not to be confused with teratology. tetralogy of fallotother namesfallot’s syndrome, fallot’s tetrad, steno-fallot tetralogydiagram of a healthy heart and one with tetralogy of fallotspecialtycardiac surgery, pediatricssymptomsepisodes of bluish color to the skin, difficulty breathing, heart murmur, finger clubbingcomplicationsirregular heart rate, pulmonary regurgitationusual onsetfrom birthcausesunknownrisk factorsalcohol, diabetes, >40, rubella during pregnancydiagnostic methodbased on symptoms, echocardiogramdifferential diagnosistransposition of the great arteries, eisenmenger syndrome, ebstein anomalytreatmentopen heart surgeryfrequency1 in 2,000 babies at birth, children may be asymptomatic or present with many severe symptoms. later in infancy, there are typically episodes of bluish colour to the skin due to a lack of sufficient oxygenation, known as cyanosis. when affected babies cry or have a bowel movement, they may undergo a "tet spell" where they turn cyanotic, have difficulty breathing, become limp, and occasionally lose consciousness. other symptoms may include a heart murmur, finger clubbing, and easy tiring upon breastfeeding. the cause of tetralogy of fallot is typically not known. risk factors include a mother who uses alcohol, has diabetes, is over the age of 40, or gets rubella during pregnancy.: 62 it may also be associated with down syndrome and other chromosomal defects that cause congenital heart defects. tof is typically treated by open heart surgery in the first year of life. the timing of surgery depends on the baby's symptoms and size. the procedure involves increasing the size of the pulmonary valve and pulmonary arteries and repairing the ventricular septal defect. in babies who are too small, a temporary surgery may be done with plans for a second surgery when the baby is bigger. with proper care, most people who are affected live to be adults. long-term problems may include an irregular heart rate and pulmonary regurgitation. the prevalence of tof is estimated to be anywhere from 0.02 to 0.04%. though males and females were initially thought to be affected equally, more recent studies have found males to be affected more than females. it is the most common complex congenital heart defect, accounting for about 10 percent of cases. it was initially described in 1671 by niels steensen. a further description was published in 1888 by the french physician étienne-louis arthur fallot, after whom it is named. the first total surgical repair was carried out in 1954. signs and symptoms digital clubbing with cyanotic nail beds in an adult with tetralogy of fallot tetralogy of fallot results in low oxygenation of blood. this is due to a mixing of oxygenated and deoxygenated blood in the left ventricle via the ventricular septal defect (vsd) and preferential flow of the mixed blood from both ventricles through the aorta because of the obstruction to flow through the pulmonary valve. the latter is known as a right-to-left shunt. infants with tof – a cyanotic heart disease – have low blood oxygen saturation. blood oxygenation varies greatly from one patient to another depending on the severity of the anatomic defects. typical ranges vary from 60% to around 90%. depending on the degree of obstruction, symptoms vary from no cyanosis or mild cyanosis to profound cyanosis at birth. if the baby is not cyanotic, then it is sometimes referred to as a "pink tet". other symptoms include a heart murmur which may range from almost imperceptible to very loud, difficulty in feeding, failure to gain weight, retarded growth and physical development, labored breathing (dyspnea) on exertion, clubbing of the fingers and toes, and polycythemia. the baby may turn blue with breastfeeding or crying. those born with tetralogy of fallot are more likely to experience psychiatric disorders such as attention deficit hyperactivity disorder (adhd) in later life, potentially due to underlying genetic changes that predispose to both conditions. tet spells infants and children with unrepaired tetralogy of fallot may develop "tet spells". these are acute hypoxia spells, characterized by shortness of breath, cyanosis, agitation, and loss of consciousness.: 200 this may be initiated by any event – such as anxiety, pain, dehydration, or fever – leading to decreased oxygen saturation or that causes decreased systemic vascular resistance, which in turn leads to increased shunting through the ventricular septal defect. typically, these spells decrease in frequency after the first four years of life. clinically, tet spells are characterized by a sudden, marked increase in cyanosis followed by syncope.: 200 older children will often squat instinctively during a tet spell. this increases systemic vascular resistance and allows for a temporary reversal of the shunt. it increases 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. cause while the specific causes of tof have not been fully identified, there are various environmental or genetic factors that have been associated with tof. so far, around 20% of overall chd cases have been due to known causes such as genetic defects and teratogens which are various factors causing embryo development abnormalities or birth defects. however, the other 80% of cases have little known about their cause. genetic factors linked to tof include various gene mutations or deletions. gene deletions associated with tof include chromosome 22 deletion as well as digeorge syndrome. specific genes associations with tof include: jag1 codes for ligands within the notch family of proteins and is highly expressed in the developing heart. mutations of the jag1 gene can lead to abnormal heart development associated with tof. nkx2-5 codes for cardiac morphogenesis regulators to allow for proper heart development. defects in this gene typically causes septal defects and has been associated with around 4% of all tof cases. zfpm2 is another cardiac regulator involved in regulation of gata4. mutations of the zfpm2 gene lead to reduced gata production and have been seen in some tof cases. vegf a well-known endothelial growth factor involved in the vascularization of the heart. decreased vegf expression has been shown to be a modifier of tof. notch1 is involved in the vascularization of tissues and is the most common site of genetic variations involved with tof, accounting for 7% of all tof cases. tbx1 expresses progenitors involved with the development of the right ventricle. chromosome 22q11 deletions also deleting tbx1 gene have been seen in 17% tof cases. flt4 gene expression leads to vascular endothelial growth factor receptor 3 (vegfr-3) which helps vascularization. mutations of this gene have been associated with tof, accounting for 2.4% of all cases. foxc2 is another gene involved in embryonic development of the cardiac system. mutations of this gene have been shown to result in dysfunctional lymphatic syndrome and tof. gata4 aids in cardiac development by helping increase the production of cardiomyocytes. mutations of this gene have been seen in various familial tof cases often lasting 2-3 generations. flna is a protein coded by the gene of the same name that crosslinks actin filaments into networks in cytoplasm and helps anchor membrane proteins for the actin cytoskeleton. mutations of this gene were seen to cause tof in some patients. the environmental factors that have been studied to potentially be associated with tof include: maternal alcohol consumption: during embryonic development, many of the body’s processing and filtration systems are not fully developed. fetal body is unable to process alcohol as well as adults which can lead to improper development, including cardiogenesis. while no conclusive evidence has been found between effects of alcohol consumption and tof, maternal alcohol consumption has been seen in various patients with tof. maternal smoking: maternal smoking has been associated with various fetal complications such as premature delivery and low birth weight which can lead to tof. in the famous baltimore-washington study, it was reported that smoking more than one pack per day while pregnant was associated with two specific cardiac deflects, both part of tof: pulmonary stenosis and transposition with vsd. maternal diabetes: maternal diabetes, diabetes mellitus, and gestational diabetes are well-known risk factors of fetal chd, including tof. maternal diabetes has been shown to increase the risk of cardiovascular deformations, namely the transposition of great arteries, one of the four deformations in tof. studies have also looked at whether diabetes increases the risk of malformation or poor sugar regulation and have found that sugar regulation does not significantly affect cardiac malformations. retrospective studies have shown that diabetic mothers with good glucose control still retained the elevated chd risk. rubella: rubella is characterized as mild, contagious viral disease with often unnoticed consequences. infection with rubella during the first trimester has been seen to cause various fetal malformations, including tof. maternal age: older maternal age, especially after 35 can have various pregnancy risks due to existing co-morbidities such as hypertension, diabetes, hypothyroidism, and consanguinity. these risk factors can effect fetal development and lead to various fetal conditions such as chd (including tof), down syndrome and autism. embryology studies show that anterior malalignment of the aorticopulmonary septum results in the clinical combination of a ventricular septal defect (vsd), pulmonary stenosis, and an overriding aorta.: 200 right ventricular hypertrophy develops progressively from resistance to blood flow through the right ventricular outflow tract. pathophysiology in healthy individuals, the human heart develops around the 20th day of gestation, when the outer endocardial tubes merge into a single cardiac tube. thereafter, the cardiac tube begins to fold, developing into the atrium and ventricle. the right ventricle is dominant prior to birth, receiving 65% of the venous return to the heart, and is the main contributor of blood flow to the lower part of the body, the placenta, and the lungs. though the exact cause of tof is unknown, an association that has been observed is an anterior deviation of the infundibular septum that results in a misaligned vsd, with an overriding aorta causing a subsequent right ventricular obstruction. different factors such as pulmonary stenosis can also contribute with the right ventricular outflow obstruction. during tet spells, a decrease in systemic vascular resistance or an increase in pulmonary resistance would be physiologically observed. the main anatomic defect in tof is the anterior deviation of the pulmonary outflow septum. this defect results in narrowing of the right ventricular outflow tract (rvot), override of the aorta, and a vsd. four malformations "tetralogy" denotes four parts, here implying the syndrome's four anatomic defects. this is not to be confused with the similarly named teratology, a field of medicine concerned with abnormal development and congenital malformations (including tetralogy of fallot). below are the four heart malformations that present together in tetralogy of fallot: heart with tetralogy of fallot a: pulmonary stenosis; b: overriding aorta; c: ventricular septal defect (vsd); d: right ventricular hypertrophy normal heart condition description pulmonary infundibular 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). infundibular pulmonic stenosis is mostly caused by the overgrowth of the heart muscle wall (hypertrophy of the septoparietal trabeculae), however, the events leading to the formation of the overriding aorta are also believed to be a cause. the pulmonic stenosis is the major cause of the malformations, with the other associated malformations acting as compensatory mechanisms to the pulmonic stenosis. the degree of stenosis varies between individuals with tof and is the primary determinant of symptoms and severity. this malformation is infrequently described as sub-pulmonary stenosis or subpulmonary obstruction. overriding aorta an aortic valve with biventricular connection, that is, it is situated above the ventricular septal defect and connected to both the right and the left ventricle. the degree to which the aorta is attached to the right ventricle is referred to as its degree of "override." the aortic root can be displaced toward the front (anteriorly) or directly above the septal defect, but it is always abnormally located to the right of the root of the pulmonary artery. the degree of override is extremely variable, with 5-95% of