Pathophysiology, clinical features, and

diagnosis of tetralogy of Fallot

Authors: Thomas Doyle, MD, Ann Kavanaugh-McHugh, MD
Section Editors: Heidi M Connolly, MD, FACC, FASE, John K Triedman, MD
Deputy Editor: Carrie Armsby, MD, MPH

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.

Literature review current through: Nov 2019. | This topic last updated: Nov 27, 2018.

INTRODUCTION

Tetralogy of Fallot (TOF) includes the following major features (figure 1) [1]:

● Right ventricular outflow tract obstruction

● Intraventricular communication

● Deviation of the origin of the aorta to the right

● Concentric right ventricular hypertrophy

The pathophysiology, clinical features, and diagnosis of TOF will be reviewed here.
The management and outcome of TOF are discussed separately. (See
"Management and outcome of tetralogy of Fallot".)

TOF with pulmonary atresia is discussed separately. (See "Tetralogy of Fallot with
pulmonary atresia and major aortopulmonary collateral arteries
(TOF/PA/MAPCAs)".)

EPIDEMIOLOGY
The prevalence of TOF in the United States is approximately 4 to 5 per 10,000 live
births [2,3]. This defect accounts for approximately 7 to 10 percent of cases of
congenital heart disease and is one of the most common congenital heart lesions
requiring intervention in the first year of life [4]. TOF occurs equally in males and
females [5].

ANATOMY

The exact embryologic abnormality that accounts for TOF is unknown. What is
recognized is that during development, there is anterior and cephalad deviation of
the infundibular septum. This results in a malaligned ventricular septal defect
(VSD), with the aortic root overriding the defect and leading to subsequent right
ventricular outflow obstruction (figure 1). The ensuing right ventricular hypertrophy
is thought to be a response to the large VSD and right ventricular outflow
obstruction with resultant systemic right ventricular systolic pressure.

Ventricular septal defect — The VSD in TOF is most commonly a single large

malaligned subaortic defect located in the perimembranous region of the septum
(image 1). The VSD can extend into the muscular septum. There are rarely other
muscular ventricular septal defects. (See "Isolated ventricular septal defects in
infants and children: Anatomy, clinical features, and diagnosis".)

Right ventricular outflow obstruction — The right ventricular outflow obstruction is

often at multiple levels (image 2):

● The anterior and cephalad deviation of the infundibular septum results in

subvalvar obstruction

● Hypertrophy of muscular bands in this region can further accentuate

subvalvar obstruction
 ● The pulmonary valve annulus is usually hypoplastic, although in some
instances it is of normal size

● The pulmonary valve itself is frequently bicuspid and stenotic

In addition, it is not uncommon to identify an area of supravalvar narrowing in the

main pulmonary artery at the sinotubular ridge. There may also be further
obstruction at the branch pulmonary arteries. These may be diffusely hypoplastic
or have focal areas of stenosis, most commonly at the proximal branch pulmonary
arteries. The proximal left pulmonary artery near the site of ductal insertion is a
frequent location for stenosis (image 3A-B).

Overriding aorta — Overriding aorta is a congenital anomaly, in which the aorta is

displaced to the right over the VSD rather than the left ventricle. This results in
blood flow from both ventricles into the aorta.

The degree of aortic override of the VSD can vary widely and is one of the major
factors used by some groups to differentiate between TOF and double outlet right
ventricle. If one defines double outlet right ventricle as the absence of
aortic/mitral valve fibrous continuity, then the degree of override is not relevant to
diagnosis. If, however, one defines double outlet right ventricle as a condition with
greater than 50 percent aortic override, then, by definition, the degree of aortic
override in TOF is limited.

Associated cardiac features — There are a number of frequently associated

anatomic features that are important to look for when evaluating a patient with
TOF, since they affect therapy. Associated cardiac anomalies occur in
approximately 40 percent of patients with TOF [6]:

● Approximately 25 percent of patients have a right aortic arch. This is

particularly important to identify if one is contemplating a palliative shunt.
 ● Abnormalities of the coronary arteries, such as the left anterior descending
arising from the right coronary artery, are seen in approximately 10 percent of
patients [6,7]. These are important to identify prior to complete repair, since
the course of the artery may run directly across the right ventricular outflow
tract; inadvertent transection could have catastrophic consequences.

● Occasionally, patients have significant aorticopulmonary collateral vessels

that may require attention prior to or at the time of surgery.

● A patent ductus arteriosus, multiple ventricular defects, and complete

atrioventricular septal defects may be present.

● Infrequently, aortic valve regurgitation is present due to aortic cusp prolapse.

GENETIC FACTORS

Although TOF may present as part of a known syndrome, this lesion typically
occurs sporadically without other anomalies.

Surveys of patients with nonsyndromic TOF have reported the following genetic
abnormalities:

● In one study of 114 patients with nonsyndromic TOF, 4 percent of patients had
mutations in transcription factor NKX2.5., which appears to have a role in
cardiac development [8].

● In genome-wide surveys of patients with nonsyndromic TOF and their parents,

de novo copy number variants were estimated to be present in approximately
10 percent of sporadic cases of TOF compared with less than 0.1 percent in
controls at several chromosomal locations [9]. Several reports have
associated TOF with mutations in TBX1 and ZFPM2 [10-12].
 ● MTHFR polymorphism has also been associated with an increased risk of
development of TOF [13].

Further investigation is required to determine the role of these mutations and

polymorphisms in the evolution of TOF.

Approximately 15 percent of patients with TOF present with associated syndromes

[10,14-20]:

● Down syndrome (trisomy 21). (See "Down syndrome: Clinical features and
diagnosis".)

● Alagille syndrome (mutations in JAG1). TOF as the sole manifestation of

JAG1 mutations without other evidence of Alagille syndrome has also been
reported [21]. (See "Inherited disorders associated with conjugated
hyperbilirubinemia", section on 'Alagille syndrome'.)

● DiGeorge and velocardiofacial syndromes (deletion on chromosome 22q11).

There may be susceptibility genes for TOF within the latter region of
chromosome 22q11 in children without extracardiac anomalies [19,22,23],
and 22q11.2 deletion syndrome is unrecognized in many adult patients with
TOF [24]. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and
diagnosis".)

PATHOPHYSIOLOGY

The physiologic consequences of TOF are largely dependent upon the degree of
right ventricular outflow obstruction. Since the VSD is typically large and
unrestrictive, the pressure in the right ventricle reflects that of the left ventricle. As
a result, the direction of blood flow across the VSD will be determined by the path
of least resistance for blood flow, not by the size of the VSD. If the resistance to
blood flow across the obstructed right ventricular outflow tract (RVOT) is less than
the resistance to flow out of the aorta into the systemic circulation, blood will
naturally shunt from the left ventricle to the right ventricle and into the pulmonary
bed. In this situation, there is predominately a left-to-right shunt and the patient
will be acyanotic.

As the degree of right ventricular outflow obstruction increases, the resistance to

blood flow into the pulmonary bed also increases. If the right ventricular
obstruction is significant enough to increase resistance, it will be easier for blood
to cross the VSD from the right ventricle into the left ventricle and go out the aorta,
which now becomes the path of least resistance. This right-to-left shunt across
the VSD results in a large volume of desaturated blood entering the systemic
circulation causing cyanosis (figure 1). In patients with unrepaired TOF, chronic
cyanosis can result in erythrocythemia.

One of the physiologic characteristics of TOF is that the RVOT can fluctuate. An
individual with minimal cyanosis can develop a dynamic increase in right
ventricular outflow tract obstruction with a subsequent increase in right-to-left
shunt and the development of cyanosis. In the most dramatic situation, there can
be near occlusion of the RVOT with profound cyanosis. These episodes are often
referred to as "tet spells" or "hypercyanotic spells." (See 'Tet spells' below.)

CLINICAL FEATURES

Presentation — The clinical presentation of the patient with TOF is dependent

upon the degree of right ventricular outflow obstruction:

● Infants with severe obstruction and inadequate pulmonary flow typically

present in the immediate newborn period with profound cyanosis and require
intervention.

● Infants with mild to moderate obstruction and balanced pulmonary and

systemic flow may be asymptomatic initially. They may be referred for
 cardiology evaluation and diagnosed during evaluation of a murmur noted in
the nursery or in the course of well child care. These children are referred to
as "pink tets"). Importantly, the degree of right ventricular outflow tract (RVOT)
obstruction is progressive over time. An initially asymptomatic and acyanotic
child may gradually develop increasing cyanosis and/or present with
hypercyanotic ("tet") spells when the gradually increasing RVOT obstruction is
abruptly and dynamically increased during periods of excitement, agitation, or
hypovolemia. (See 'Tet spells' below.)

● Infants with minimal obstruction are also asymptomatic initially. They may
develop symptoms of pulmonary overcirculation and heart failure in the first
four to six weeks after birth as the initially elevated perinatal pulmonary
vascular resistance falls to normal.

In addition, some affected newborns will be detected by an evaluation prompted

by a failed pulse oximetry screening test. (See "Newborn screening for critical
congenital heart disease using pulse oximetry".)

In general, the earlier the onset of cyanosis, the more likely that severe RVOT
stenosis or atresia is present.

In the contemporary era in the United States, most children are diagnosed in
infancy; however, this is not true in regions of the world where access to health
care is more limited. Rarely, and most often in the course of relocation from those
regions, older children with unrepaired TOF may present, usually with some degree
of baseline cyanosis, often limiting their own activities to prevent hypercyanotic
episodes.

Tet spells — Patients with unrepaired TOF are at risk for episodic hypercyanotic
("tet”) spells in which there can be transient near occlusion of the RVOT with
profound cyanosis. The exact etiology of these episodes is unclear, although there
have been a number of proposed mechanisms, including increased infundibular
contractility, peripheral vasodilatation, hyperventilation, and stimulation of right
ventricular mechanoreceptors [25].

Tet spells typically arise when the infant becomes agitated or upset. They may
also occur in the setting of pain, fever, anemia, hypovolemia, after a bowel
movement, after feeding, or, in older children with uncorrected TOF, after vigorous
exercise [26]. They tend to occur more commonly in the morning and after feeding,
though they can arise at any time [6].

Tet spells are characterized by hyperpnea (rapid and deep respirations), irritability,
inconsolability, and progressively severe cyanosis. An older child experiencing a
tet spell will typically squat to recover. Examination during the acute episode may
reveal decreased intensity of heart murmur. Though some episodes may resolve
spontaneously, prolonged spells can progress to loss of consciousness and
cardiac arrest. Prompt intervention is essential for the acute episode and infants,
and children presenting with hypercyanotic episodes should be referred for
surgical intervention to prevent potentially life-threatening recurrences. Acute
management of tet spells is discussed separately. (See "Management and
outcome of tetralogy of Fallot", section on 'Tet spells'.)

Physical examination — On inspection, individuals with TOF are usually

comfortable and in no distress. However, during hypercyanotic (tet) spells, they
will become hyperpneic, and infants will often become agitated. If cyanosis is
present, it is most easily seen in the nail beds and lips.

On palpation, one may appreciate a prominent right ventricular impulse and

occasionally a systolic thrill. Hepatomegaly is uncommon. Peripheral pulses are
usually normal, although the presence of prominent pulses may suggest the
existence of a significant patent ductus arteriosus or aorticopulmonary
collaterals.
Cardiac auscultation — On auscultation, the first heart sound is normal, and the
second heart sound is most commonly single because the pulmonic component is
rarely audible. Third and fourth heart sounds are uncommon. An early systolic
click along the left sternal border may be heard, which is thought to be due to flow
into the dilated ascending aorta. (See "Approach to the infant or child with a
cardiac murmur", section on 'Heart sounds'.)

Murmur — The murmur in TOF is due primarily to the right ventricular outflow

obstruction, not the VSD. The murmur is typically a systolic, crescendo-
decrescendo murmur with a harsh ejection quality; it is appreciated best along the
left mid to upper sternal border with radiation posteriorly. It can, however, have a
more regurgitant quality that can be easily mistaken for a VSD. (See "Approach to
the infant or child with a cardiac murmur".)

The murmur is due both to the degree of obstruction and to the amount of flow
across the obstruction. In TOF, unlike isolated valvar pulmonary stenosis, the
amount of flow across the RVOT will decrease as the obstruction increases, due to
the shunting of blood right-to-left across the VSD. Thus, as the obstruction
increases, the murmur will become softer. During severe hypercyanotic ("tet")
spells, the murmur may actually disappear due to the markedly diminished flow
across the obstruction. (See "Management and outcome of tetralogy of Fallot",
section on 'Tet spells'.)

DIAGNOSIS

The diagnosis of TOF is generally made by echocardiography. Other tests that are
often performed during the evaluation of TOF include electrocardiogram and chest
radiography. Findings from these studies are often suggestive but not conclusive
for the diagnosis of TOF. Cardiac catheterization is sometimes needed to further
delineate anatomy and hemodynamic changes.
Prenatal diagnosis — Improvements in prenatal screening and fetal
echocardiography have led to an increase in prenatal diagnosis of TOF [27-29].
Fetal diagnosis allows for advanced planning for delivery and perinatal
management, which is particularly important if there is evidence of severe right
ventricular outflow tract (RVOT) obstruction necessitating prostaglandin therapy to
maintain ductal patency. The approach to screening, evaluation, and pregnancy
management of suspected fetal cardiac abnormalities is discussed separately.
(See "Fetal cardiac abnormalities: Screening, evaluation, and pregnancy
management".)

Echocardiography — Two-dimensional echocardiography and Doppler examination

allow assessment of all essential features of TOF and have a crucial role in
diagnosis and preoperative evaluation. Complete echocardiographic evaluation
may obviate the need for other imaging or diagnostic studies before surgical
repair. Most of the information can be achieved with transthoracic
echocardiography, but occasionally transesophageal echocardiography may be
helpful for specific questions raised with transthoracic echocardiography. A
complete study must address:

● The location and number of VSDs

● The anatomy and severity of RVOT obstruction

● The coronary artery and aortic arch anatomy

● The presence of any associated anomalies

Ventricular septal defect — The characteristic large malaligned VSD must be

evaluated in multiple views. The degree of aortic override can be best assessed in
parasternal long axis and apical views (movie 1 and movie 2). The extension of the
defect from the membranous septum, beneath the tricuspid valve, and into the
infracristal outlet septum is well seen in the parasternal short axis view; extension
into the supracristal region, if present, can be seen in this view as well (movie 3).
Potential extension of the defect posteriorly toward the inlet septum, or apically
into the trabecular septum, can be examined in apical views; the transducer is
swept through serial imaging planes from the more caudal views of the inlet
septum to the anteriorly angulated views, showing the overriding aorta in
continuity with both the mitral and tricuspid valves.

The subcostal views are also helpful to delineate the bounds of the VSD, allowing
particularly good representation of the relationship between the defect and the
tricuspid and aortic valves. The subcostal right oblique view, obtained by rotating
the transducer counterclockwise from the coronal views, is also helpful in
identifying any potential extension of the defect into the supracristal region. In the
rare cases of restrictive VSD in this lesion, this view also defines abnormal
tricuspid valve attachments [30,31].

Right ventricular outflow obstruction — The multiple levels and severity of

obstruction in the RVOT can also be evaluated by echocardiography (image 4 and
movie 4). Parasternal short axis and subcostal coronal and sagittal views allow
the best examination of the infundibulum and pulmonary valve. These views
demonstrate the anterior deviation of the conal septum and the infundibular
muscle bundles that contribute to infundibular obstruction. The size of the usually
hypoplastic pulmonary annulus can be assessed and compared with normal
values for patient size and body surface area. This is important to establish the
potential need for a transannular patch. The pulmonary valve may appear
thickened and may dome in these views.

Pulmonary arteries — The size and anatomy of the main pulmonary artery, the
pulmonary arterial confluence, and the proximal branch pulmonary arteries can
also be assessed in parasternal short axis views. The proximal branch pulmonary
arteries should be assessed as far distally as possible in high parasternal views
and in suprasternal notch long and short axis views, directing the transducer into
the left and right chest (movie 5 and movie 6).
 Coronary arteries — The proximal coronary anatomy should be defined
echocardiographically in patients with TOF. In addition to examining the coronary
anatomy in the traditional short axis view, the examination should include
sweeping the transducer anterior to the pulmonary outflow tract in parasternal
long and short axis views (movie 7) [32-34]. This permits the identification of
variations in coronary anatomy, including the origin of the left anterior descending
from the right coronary artery or dual vessel supply to the anterior descending
distribution; in these situations, coronary branches crossing anteriorly complicate
the surgical approach to relief of RVOT obstruction.

Aortic arch — Aortic arch situs and the branching patterns of the

brachiocephalic arteries are defined in the suprasternal notch long and short axis
views. Complete evaluation of the arch in these views is also important in
delineating the presence of additional potential sources of pulmonary blood flow,
including aorticopulmonary collaterals and a patent ductus arteriosus. (See
"Clinical manifestations and diagnosis of patent ductus arteriosus in term infants,
children, and adults".)

Atrial and ventricular septa — The echocardiographic evaluation of patients

with TOF is completed by using both two dimensional imaging and color flow
mapping of the atrial septum and ventricular septum in multiple imaging planes.
This assessment defines additional atrial and ventricular septal defects and
evaluates potential abnormalities of pulmonary and systemic venous return and
the rare associated occurrence of left sided obstructive lesions.

Hemodynamic echocardiographic assessment — As previously discussed, the

large and generally unrestrictive defect in this lesion permits equalization of right
and left ventricular pressures. The direction and degree of shunting is determined
by the balance of resistance to flow into the systemic and pulmonary circulations
and, to a large degree, by the severity of RVOT obstruction. The modified Bernoulli
equation, applied to the peak flow velocity measured in the RVOT, can be used to
calculate the outflow tract gradient:

   ΔP = 4V2

Where ΔP = peak pressure gradient between the right ventricle and the pulmonary
artery (mmHg), V = velocity obtained by continuous wave Doppler interrogation of
the RVOT. The pulmonary artery pressure can be estimated by subtracting this
pressure gradient from the systemic blood pressure. (See "Principles of Doppler
echocardiography", section on 'Relationship between Doppler velocity and
pressure gradient'.)

While the modified Bernoulli equation is not valid in the setting of tunnel-like
and/or multiple levels of obstruction, values obtained with this method correlate
with those obtained in the cardiac catheterization laboratory [35]. In practice, the
contributions of the infundibulum value and branch pulmonary arteries cannot be
separated by Doppler interrogation.

In patients with minimal RVOT obstruction, the gradient across the RVOT will be
low; the estimated pulmonary arterial pressure will be elevated; and shunting
through the VSD, as assessed by pulsed Doppler and color flow mapping, will be
predominantly left-to-right through much of the cardiac cycle. (See "Isolated
ventricular septal defects in infants and children: Anatomy, clinical features, and
diagnosis".)

In patients with a large left-to-right shunt, left atrial and left ventricular dilation may
be apparent by two dimensional imaging. In patients with more severe RVOT
obstruction, the estimated pulmonary artery pressure is normal, and pulsed
Doppler and color flow mapping demonstrate increasing right-to-left shunting at
the ventricular septal defect during the cardiac cycle.

Electrocardiogram — The ECG in TOF typically shows right atrial enlargement and

right ventricular hypertrophy. Right axis deviation, prominent R waves anteriorly
and S waves posteriorly, an upright (waveform 1) T wave in V1 (after two days of
life), and a qR pattern in the right sided chest leads may also be seen (waveform
1). (See "ECG tutorial: Chamber enlargement and hypertrophy".)

Chest radiograph — The classic chest radiograph of a patient with TOF

demonstrates a "boot shaped" heart with an upturned apex and a concave main
pulmonary artery segment (image 5). The heart size is often normal, and
pulmonary flow will appear normal or decreased. A right aortic arch can be seen in
25 percent of patients.

Cardiac catheterization — Although echocardiography can reveal the anatomy in

many patients with TOF, cardiac catheterization may still be necessary to further
delineate the anatomy. It is particularly helpful for assessing levels of right
ventricular outflow obstruction, branch pulmonary artery stenosis or hypoplasia,
coronary artery anatomy, presence of aorticopulmonary collaterals, and presence
of accessory ventricular septal defects.

The hemodynamic findings at catheterization typically reveal normal or only mildly

elevated filling pressures. The left and right ventricular systolic pressures are
equal and systemic due to the presence of the large VSD. Pulmonary artery
pressures are normal or low. Saturations will indicate the degree of right-to-left
shunting.

Angiographic assessment should be geared toward the information that is needed;

biplane angiography is ideal. A right ventricular injection will often adequately
demonstrate the multiple levels of right ventricular obstruction as well as the
anatomy of the branch pulmonary arteries (image 2). This is typically done with
the AP camera angled in a cranial and left anterior oblique projection, which allows
better delineation of the branch pulmonary arteries. The lateral camera is kept in
straight lateral projection, which provides excellent visualization of the infundibular
and pulmonary valve anatomy (image 6).
An aortic root injection will usually provide adequate identification of the coronary
arteries, although selective injections may occasionally be needed. The coronary
arteries usually are seen well with the AP camera in a right anterior oblique (RAO)
projection and the lateral camera in a long axial oblique projection
(70LAO/20Cranial). The arch and descending aorta may also be seen in this view
and provide evidence of the presence of a patent ductus arteriosus or collateral
vessels. If collateral vessels are identified, selective injections are helpful to
assess the areas of the pulmonary bed that they supply and whether they are the
sole supply to these areas.

The ventricular septal defect is best seen from a left ventricular injection in a long
axial oblique projection (image 1). With the AP camera in an RAO projection, one
will often also see the infundibular obstruction from left to right flow across the
VSD (image 7).

Cardiac catheterization can also play a therapeutic role in some patients with TOF.
Balloon valvuloplasty of the pulmonary valve can improve pulmonary flow in many
children; there may also be an increase in pulmonary valve annulus size that may
decrease the need for transannular patch repair [36,37]. (See "Natural history and
treatment of pulmonic stenosis in adults".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain
language, at the 5th to 6th grade reading level, and they answer the four or five key
questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and
are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also locate
patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

● Basics topic (see "Patient education: Tetralogy of Fallot (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Tetralogy of Fallot (TOF) is a cyanotic congenital heart disorder that
encompasses four anatomic features: right ventricular hypertrophy,
ventricular septal defect (VSD), overriding aorta, and right ventricular (RV)
outflow obstruction (figure 1). (See 'Anatomy' above.)

● In the United States, the prevalence of TOF is approximately 4 per 10,000 live
births. TOF accounts for 7 to 10 percent of congenital heart disease. (See
'Epidemiology' above.)

● Although TOF typically occurs sporadically without other anomalies, it can be

present as part of a known syndrome or genetic disorder, such as Down
syndrome, Alagille syndrome, or DiGeorge (22q11 deletion) syndrome. Other
associated cardiac anomalies occur in approximately 40 percent of patients
with TOF. (See 'Genetic factors' above and 'Associated cardiac features'
above.)

● The pathophysiologic effects of TOF are largely dependent upon the degree of
RV outflow obstruction. The direction of blood flow across the VSD is
determined by the path of least resistance for blood flow and not by the size
of the VSD. If the resistance to the RV outflow is lower than systemic
 resistance, then there is a predominant left-to-right flow, and the patient is not
cyanotic. However, with significant RV obstruction, there will be a right-to-left
shunt across the VSD, resulting in cyanosis (figure 1). (See 'Pathophysiology'
above.)

● The clinical presentation is dependent on the degree of RV outflow

obstruction and determines whether there is a left-to-right (acyanotic) or right-
to-left shunt. In general, the earlier the onset of systemic hypoxemia, the more
likely it is that severe pulmonary outflow tract stenosis or atresia is present.
(See 'Clinical features' above.)

● Patients with TOF may intermittently experience hypercyanotic ("tet") spells in

which there can be transient near occlusion of the right ventricular outflow
tract with profound cyanosis. Tet spells typically arise when the infant
becomes agitated or upset. They are characterized by hyperpnea (rapid and
deep respirations), irritability, inconsolability, and progressively severe
cyanosis. Prolonged spells can lead to loss of consciousness and cardiac
arrest. Thus, prompt intervention is warranted. (See 'Tet spells' above and
"Management and outcome of tetralogy of Fallot", section on 'Tet spells'.)

● Typical findings on cardiac auscultation in patients with TOF include a

crescendo-decrescendo harsh systolic ejection murmur and a single second
heart sound. (See 'Cardiac auscultation' above.)

● The diagnosis of TOF is typically made by echocardiography, which can

usually delineate the location and number of VSDs, the anatomy and severity
of RV outflow tract obstruction, the coronary artery and aortic arch anatomy,
the presence of any associated anomalies, and the hemodynamic
abnormalities associated with the anatomical defects. (See
'Echocardiography' above.)
ACKNOWLEDGMENT

The editorial staff at UpToDate would like to acknowledge Thomas Graham Jr, MD,
who contributed to an earlier version of this topic review.

REFERENCES

1. Fallot E. Contribution a l'anatomie pathologique de la maladie bleu (cyanose

cardiaque). Mars Med 1888; 25:418.

2. Centers for Disease Control and Prevention (CDC). Improved national

prevalence estimates for 18 selected major birth defects--United States, 1999-
2001. MMWR Morb Mortal Wkly Rep 2006; 54:1301.

3. Reller MD, Strickland MJ, Riehle-Colarusso T, et al. Prevalence of congenital

heart defects in metropolitan Atlanta, 1998-2005. J Pediatr 2008; 153:807.

4. Report of the New England Regional Infant Cardiac Program. Pediatrics 1980;
65:375.

5. Perloff JK. The Clinical Recognition of Congenital Heart Disease, 4th, WB Sau
nders, Philadelphia 1994.

6. Breitbart, RE, Fyler, DC. Tetralogy of Fallot. In: Nadas' pediatric cardiology, 2nd
Ed, Keane JF, Lock JE, Fyler DC (Eds), Saunders, Philadelphia 2006. p.559.

7. Dabizzi RP, Caprioli G, Aiazzi L, et al. Distribution and anomalies of coronary

arteries in tetralogy of fallot. Circulation 1980; 61:95.

8. Goldmuntz E, Geiger E, Benson DW. NKX2.5 mutations in patients with

tetralogy of fallot. Circulation 2001; 104:2565.

9. Greenway SC, Pereira AC, Lin JC, et al. De novo copy number variants identify
new genes and loci in isolated sporadic tetralogy of Fallot. Nat Genet 2009;
 41:931.

10. Di Felice V, Zummo G. Tetralogy of fallot as a model to study cardiac

progenitor cell migration and differentiation during heart development. Trends
Cardiovasc Med 2009; 19:130.

11. Griffin HR, Töpf A, Glen E, et al. Systematic survey of variants in TBX1 in non-
syndromic tetralogy of Fallot identifies a novel 57 base pair deletion that
reduces transcriptional activity but finds no evidence for association with
common variants. Heart 2010; 96:1651.

12. Rauch R, Hofbeck M, Zweier C, et al. Comprehensive genotype-phenotype

analysis in 230 patients with tetralogy of Fallot. J Med Genet 2010; 47:321.

13. Marinho C, Alho I, Guerra A, et al. The methylenetetrahydrofolate reductase

gene variant (C677T) as a susceptibility gene for tetralogy of Fallot. Rev Port
Cardiol 2009; 28:809.

14. Kramer HH, Majewski F, Trampisch HJ, et al. Malformation patterns in

children with congenital heart disease. Am J Dis Child 1987; 141:789.

15. Freeman SB, Taft LF, Dooley KJ, et al. Population-based study of congenital
heart defects in Down syndrome. Am J Med Genet 1998; 80:213.

16. Krantz ID, Smith R, Colliton RP, et al. Jagged1 mutations in patients
ascertained with isolated congenital heart defects. Am J Med Genet 1999;
84:56.

17. Takahashi K, Kido S, Hoshino K, et al. Frequency of a 22q11 deletion in

patients with conotruncal cardiac malformations: a prospective study. Eur J
Pediatr 1995; 154:878.

18. Webber SA, Hatchwell E, Barber JC, et al. Importance of microdeletions of

chromosomal region 22q11 as a cause of selected malformations of the
 ventricular outflow tracts and aortic arch: a three-year prospective study. J
Pediatr 1996; 129:26.

19. Goldmuntz E, Clark BJ, Mitchell LE, et al. Frequency of 22q11 deletions in
patients with conotruncal defects. J Am Coll Cardiol 1998; 32:492.

20. Lammer EJ, Chak JS, Iovannisci DM, et al. Chromosomal abnormalities
among children born with conotruncal cardiac defects. Birth Defects Res A
Clin Mol Teratol 2009; 85:30.

21. Bauer RC, Laney AO, Smith R, et al. Jagged1 (JAG1) mutations in patients with
tetralogy of Fallot or pulmonic stenosis. Hum Mutat 2010; 31:594.

22. Kessler-Icekson G, Birk E, Weintraub AY, et al. Association of tetralogy of Fallot

with a distinct region of del22q11.2. Am J Med Genet 2002; 107:294.

23. Bristow JD, Bernstein HS. Counseling families with chromosome 22q11
deletions: the catch in CATCH-22. J Am Coll Cardiol 1998; 32:499.

24. van Engelen K, Topf A, Keavney BD, et al. 22q11.2 Deletion Syndrome is under-
recognised in adult patients with tetralogy of Fallot and pulmonary atresia.
Heart 2010; 96:621.

25. Kothari SS. Mechanism of cyanotic spells in tetralogy of Fallot--the missing

link? Int J Cardiol 1992; 37:1.

26. Duff DF, McNamara DG. History and physical examination of the cardiovascul
ar system. In: The science and practice of pediatric cardiology, Garson A Jr, Br
icker TM, Fisher DJ, Neish SR (Eds), Williams and Wilkins, Baltimore 1998. p.6
93.

27. Bhat AH, Kehl DW, Tacy TA, et al. Diagnosis of tetralogy of Fallot and its
variants in the late first and early second trimester: details of initial
assessment and comparison with later fetal diagnosis. Echocardiography
2013; 30:81.
28. Pepas LP, Savis A, Jones A, et al. An echocardiographic study of tetralogy of
Fallot in the fetus and infant. Cardiol Young 2003; 13:240.

29. Monaco M, Williams I. Tetralogy of Fallot: fetal diagnosis to surgical

correction. Minerva Pediatr 2012; 64:461.

30. Flanagan MF, Foran RB, Van Praagh R, et al. Tetralogy of Fallot with
obstruction of the ventricular septal defect: spectrum of echocardiographic
findings. J Am Coll Cardiol 1988; 11:386.

31. Musewe NN, Smallhorn JF, Moes CA, et al. Echocardiographic evaluation of
obstructive mechanism of tetralogy of Fallot with restrictive ventricular septal
defect. Am J Cardiol 1988; 61:664.

32. Berry JM Jr, Einzig S, Krabill KA, Bass JL. Evaluation of coronary artery
anatomy in patients with tetralogy of Fallot by two-dimensional
echocardiography. Circulation 1988; 78:149.

33. Caldwell RL, Ensing GJ. Coronary artery abnormalities in children. J Am Soc
Echocardiogr 1989; 2:259.

34. Jureidini SB, Appleton RS, Nouri S. Detection of coronary artery abnormalities
in tetralogy of Fallot by two-dimensional echocardiography. J Am Coll Cardiol
1989; 14:960.

35. Houston AB, Simpson IA, Sheldon CD, et al. Doppler ultrasound in the
estimation of the severity of pulmonary infundibular stenosis in infants and
children. Br Heart J 1986; 55:381.

36. Sreeram N, Saleem M, Jackson M, et al. Results of balloon pulmonary

valvuloplasty as a palliative procedure in tetralogy of Fallot. J Am Coll Cardiol
1991; 18:159.
37. Massoud I, Imam A, Mabrouk A, et al. Palliative balloon valvoplasty of the
pulmonary valve in tetralogy of Fallot. Cardiol Young 1999; 9:24.

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