Dextrocardia with Situs Inversus: A Complex Congenital Anomaly

Dextrocardia with situs inversus is an uncommon congenital anomaly that may not be diagnosed until later in life. It can be found in conjunction with other conditions, such as primary ciliary dyskinesis, but there are usually no associated severe cardiovascular anomalies. Other types of disturbances of symmetry, such as situs ambiguus, can result in severe anomalous development and varying degrees of cardiovascular compromise. Recent research has greatly expanded our understanding of the link between ciliary action and asymmetric expression of gene products in the development of cardiac asymmetry. Medical care is directed toward associated problems, such as respiratory infections with ciliary disorders and additional congenital anomalies.

Donna R. Coffman, MDStaff Physician

St. Louis, Mo

PRACTICE POINTS

• A patient with dextrocardia can still have normal cardiovascular functioning, therefore, diagnosis is often delayed.
• To avoid misleading electrocardiographic findings, the precordial leads and right and left arm leads should be reversed.

Illustrative Case

A 12-year-old boy presented to a walk-in clinic with a temperature of 101.6?F and a productive cough with purulent sputum. He had been ill with influenza and was recovering when the cough developed and his fever returned. He had pain with coughing and with deep breathing. He had no history of medical problems.

Physical examination revealed: blood pressure, 116/72 mm Hg; temperature, 99.8?F; pulse, 94 beats/min; respirations, 16/min; pulse oximetry measurement, 98%. He was in no acute distress and had no cyanosis or edema. Crackles were noted in the left lower posterior lung field. Heart sounds were louder on the right, but he had no murmur, gallop, or rub.

His chest x-ray showed an infiltrate in the lingular and lower left lobes. In addition, the cardiac shadow appeared on the right, with a right-sided aortic arch, and the liver shadow was on the left. After verifying positioning for the x-ray, it was determined that in addition to his pneumonia, the boy had a previously undiagnosed dextrocardia with situs inversus (Figure 1). He was treated for pneumonia and advised to follow up for further echocardiographic evaluation of his cardiac structures.

Diagnosis

Congenital heart abnormalities can be very complex. Diagnosis requires an evaluation of all cardiac structures in an organized manner. A segmental approach is commonly used for describing cardiac anatomy. Positioning is described as levocardia if the heart is on the left, dextrocardia if on the right, and mesocardia if in the center. Displacement of the heart to the right as a result of another condition, such as scoliosis or a hypoplastic lung, is called dextroposition.

Developmentally, the atria are a continuation of the pulmonary and systemic vasculature; thus, their position is almost always the same as that of the viscera. When the internal abdominal organs, atria, and lungs are positioned normally, it is called situs solitus. If the position of the viscera, lungs, and atria is reversed, it is called situs inversus. The term situs ambiguus is used to describe an indeterminate visceroatrial sidedness. Situs ambiguus is further divided according to its occurrence with asplenia or with polysplenia. In situs ambiguus with asplenia, there is usually a central liver, 2 right lungs, and no spleen. In situs ambiguus with polysplenia, there are 2 left lungs, multiple small spleens, and anomalous development of the intrahepatic vena cava.

These 2 variations are sometimes thought of as having bilateral left (polysplenia) or right (asplenia) sides. Multiple severe visceral and cardiac anomalies are common with both types of situs ambiguus (Table).

After identifying the position of the atria and viscera, the physician should determine the location of the ventricles. If the orientation of the right and left ventricles is normal, it is called a "D-loop," meaning that the right ventricular inflow tract is to the right of the left ventricle. If the position of the ventricles is reversed? and therefore the right ventricle is to the left of the left ventricle?the ventricles are described as "L-loop." In situs ambiguus, neither an L-loop nor Dloop can be identified, and it is referred to as an "Xloop." The loops can be further described as concordant if their position matches the visceroatrial situs and discordant if they do not.

Finally, the position of the great vessels is determined. The vessels are designated as normal if the pulmonary artery arises from the right ventricle and the aorta from the left ventricle. In levocardia, the position is referred to as solitus normal, or D-normal; in dextrocardia, it is inverted normal, or L-normal. The vessels are transposed if the aorta arises from the right ventricle and the pulmonary artery from the left ventricle. The vessels may also demonstrate double-outlet right ventricle, double-outlet left ventricle, truncus arteriosis, or other abnormal positioning, which has been referred to as malposition.

Our patient had dextrocardia with situs inversus that involved L-loop ventricles and L-normal (inverted normal) great vessels. This complete reversal of all segments allows normal cardiovascular function, which is probably why the boy's condition was not identified until he was 12 years old. In the largest study to date, which included 125 patients with dextrocardia, the most common cardiac anomaly was situs inversus (39%), followed by situs solitus (34%), and situs ambiguus (26%).¹

Incidence

Situs inversus and situs ambiguus are uncommon cardiac anomalies. In the Baltimore-Washington Infant Study, conducted between 1981 and 1989, the records of 906,646 live births were reviewed to identify infants with congenital heart disease.² A total of 47 cases of corrected transposition and 92 cases of situs ambiguus were found. Of these, 3 infants had Kartagener's syndrome, which amounts to an estimated incidence of cardiac looping defects of 1.53 per 10,000 live births. The incidence of dextrocardia with situs inversus is estimated at 2 per 10,000 in the general population; 20% of such individuals have Kartagener's syndrome.³

Embryonic Development

Sidedness is one of the earliest changes noted in normal embryologic development. Two symmetrical groups of cells known as precardiac cells migrate toward the central node (an infolding along the primitive streak) and join to form the primitive heart tube. The embryo is symmetric until just after the heart tube is formed. Shortly thereafter, the heart tube begins to bend to the right. The primitive heart tube folds and remodels during weeks 4 through 7, gradually becoming the 4-chambered heart and great vessels. It typically rotates toward the right at the 22nd to 23rd day of development, and the apex moves to the left (Figure 2).

Genetic Contributors to Asymmetry

Many studies have investigated what causes and directs genetically inherited asymmetry noted in animals and humans and have attempted to determine what goes wrong when the polarity is disturbed.

Primary ciliary dyskinesis is a genetic abnormality that results in immotile cilia. Affected individuals have chronic sinusitis, otitis media, respiratory infections, and infertility resulting from the lack of motile cilia. Various forms of ciliary defects can occur. Genetically, these can be the result of a spontaneous mutation or be inherited as an autosomal dominant or recessive trait. Of note, half of the affected individuals also have situs inversus. The clinical grouping of ciliary dysfunction with the resultant chronic respiratory tract infections and situs inversus is called Kartagener's syndrome.

Research has shown that genetic defects in mice that interfere with ciliary function also result in random determination of sidedness. One study demonstrated that normal monocilia in the ventral node region of the mouse produce a leftward flow in the extraembryonal fluid.⁴ If a rapid rightward flow is produced by a peristaltic pump in the culture media during the presomite stage of embryonic development, left-right symmetry is reversed. Another study found monocilia in chick, xenopus, and zebra fish embryos, suggesting that the same mechanisms may account for asymmetry in other species as well.⁵

Asymmetric gene expression is also involved. Sonic hedgehog (Shh) is a gene product initially found throughout the Hensen's node, but when chicken activin receptor IIa expression begins on the right side of the node, Shh becomes restricted to the left side. The presence of Shh directly affects situs, possibly by inducing left-sided chicken nodal-related (cNR)-1, which acts locally as a growth factor.⁶ The role of numerous gene products in asymmetric development is currently under investigation. Of the 3 excellent review articles on the subject,^7-9 one includes a summary of mouse gene products known to affect right-left polarity.⁹

Since many of the asymmetric early mechanisms seem to vary in timing in different species, it is not yet clear whether the same mechanisms that explain the development of asymmetry in animals also apply to humans. But some discoveries in human genetics have opened new avenues for investigation. Mutations in the connexin43 gap-junction gene appear to be one cause of heterotaxy in humans.¹⁰ Disruption in cell-to-cell communication, which interferes with cell grouping, may disturb left-right boundary formation, allowing polarity to develop randomly.¹⁰

ACVR2B

LEFTYA

DNAH5

Because of the variable patterns observed in genetic inheritance, there are probably many genetic defects that lead to disturbed asymmetry in humans. One report described a family that was known to have X-linked patterns of inheritance for heterotaxy.¹¹ The investigators were able to map the genetic defect to chromosome Xq24-q27.1. Mutations at and have also been found in some patients with situs defects.¹² And a familial inheritance pattern of primary ciliary dyskinesis has been described that demonstrated X-linked or dominant inheritance of ciliary abnormalities, but investigators were unable to locate the chromosomal defect.¹³ Other researchers who studied a family with an autosomal recessive pattern of inheritance of primary ciliary dyskinesis were able to localize the defect to mutations in on chromosome 5p.¹⁴

Studies have also yielded some insights into possible predisposing factors for heterotaxy. A review of the data from the Baltimore-Washington Infant Study showed that maternal diabetes, family history of malformations, cocaine use during the 2 months before conception and through the first trimester, or being a conjoined twin increased the risk of heterotaxy.¹⁵

One group of investigators reviewed data from 167 pairs of human conjoined twins and found that in almost half of the twin pairs who were joined at the chest or abdomen, 1 twin had a heart situs reversal.¹⁶ These "laterality defects" occurred in the twin on the right side in 86% of dicephalus twins and 71% of thoracopagus twins. The investigators thought that the cause of such defects might be explained in part by using the example of gene expression in twin chick embryos. They noted that Shh and nodal (a growth regulator produced by the node that is related to cNR-1) were normally expressed on the left side of the left embryo of twin chick embryos, whereas neither occurred on either side of the right embryo. In twin chicks who arise from 2 parallel primitive streaks, activin (which inhibits the expression of Shh) from the right side of the left embryo could repress the expression of Shh in the left side of the right embryo, resulting in a normal left embryo and a right embryo with random heart situs, because it had no expression of Shh in the node and hence no expression of nodal. Similarly, Shh on the left side of the right embryo could stimulate the induction of nodal on the right side of the left embryo, leaving the right embryo normal but the left embryo with a lateralization defect because of the doublesided nodal expression. The authors postulated that a similar mechanism may explain the findings observed in human conjoined twins.¹⁶

Long-term Sequelae

Long-term prognosis depends on associated congenital defects and the presence of cardiovascular compromise. Most patients with dextrocardia with situs inversus do not have any significant cardiac defects, and their life expectancy is normal. Those who have ciliary defects require frequent treatment for chronic pulmonary infections and complications.

Situs ambiguus is almost always associated with severe cardiovascular impairment; often, congenital anomalies occur in other organ systems as well. Patients with asplenia have the additional problem of recurrent, severe infections that contribute to their higher mortality rate.

Electrocardiographic (ECG) differences can be minimized by reversing the precordial leads and the right and left arm leads. The P waves, QRS complex, and T waves are all inverted in lead I.¹⁷ Comparing changes between an old and new ECG may sometimes be helpful, but in all cases, a consultation with a cardiologist who is experienced in reading these types of ECGs is advised. Patients with heterotaxy who need cardiac evaluation should undergo echocardiography and/or cardiac catheterization when possible because of their high incidence of cardiac anomalies.

Conclusion

Disturbances of asymmetric development in humans can be as benign as dextrocardia with situs inversus or result in severe cardiac malformations and cardiovascular compromise. Recent research into the molecular processes contributing to the development of asymmetry has led to a better understanding of embryologic development and the identification of specific genetic defects in humans. Since some of these developmental disturbances are inheritable, we may one day have the ability to identify carriers of defective genes. For now, most of the molecular embryonic development process remains unknown, and researchers continue to discover more pieces of the puzzle, gradually adding to our understanding of the mysteries of the generation of life.

SELF-ASSESSMENT TEST

1. Which of the following best describes dextrocardia?

• Heart on the right
• Solitus normal great vessels

2. Which of these steps best describes the segmental approach for evaluating cardiac anatomy in the patient with a congenital heart abnormality?

• Determine the position of the great vessels, atria, right and left ventricles, and viscera
• Determine the position of the atria, viscera, right and left ventricles, and great vessels

3. Which of these features is associated with dextrocardia with situs inversus?

• Normal symmetry of viscera
• Multiple small spleens

4. What is most characteristic of Kartagener's syndrome?

• Dextrocardia and respiratory tract infections
• Absence of a spleen and respiratory tract infections

5. Which of the following conditions is associated with the best prognosis?

• Situs ambiguus with polysplenia syndrome
• Dextrocardia with situs solitus

(Answers at end of reference list)

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Answers:

1. B; 2. D; 3. A; 4. B; 5. C