SITUS INVERSUS AND CARDIAC DEFECTS

SITUS INVERSUS A N D CARDIAC DEFECTS A Study of 111 Cases of Reversed Asymmetry Robert J. Merklin,

Ph.D.*

and

Nicholas R. Varano, M.D.,**

Philadelphia,

Pa.

S

of form is a fairly constant attribute of living organisms and, to a certain extent, a feature of numerous nonliving objects. In man, symmetry is typified by a bilateral arrangement of organs, systems, and appendages which, if we may pass over minor asymmetries of face, limb, and trunk, is broken normally only by deviations of the cardiovascular and gastrointestinal systems. Conditions of symmetry and asymmetry pose some important questions for the investigator and clinician. The most fundamental question is one of the forces involved in the production of symmetry and asymmetry. Current information on this subject is very fragmentary, mainly because little attention is being given to the problem. On the other hand, the clinical aspects of situs inversus are receiving considerable attention and becoming the subject of numerous reports in the literature. The attention given this problem will be viewed with mixed feeling and, indeed, a proper perspective regarding the problem is difficult to achieve. The condition of situs inversus is certainly of minor importance from the standpoint of its occurrence which is, perhaps, once in 6,000 persons. Its clinical importance, however, assumes major proportions when it is realized that many of these individuals have defects incompatible with normal existence. Bronchiectasis, for example, was found in 25 per cent of an extensive series of cases of situs inversus studied by Torgersen 1 ; and cardiac defects were present in a similar percentage of cases of dextrocardia and in 8 per cent of the cases of situs inversus totalis reported by Schmutzer and Linde 2 in 1958. Our purpose in this communication is to point out that the incidence of cardiac defects in individuals with situs inversus is even higher than previously reported and to analyze these defects and relate them to the degree of visceral transposition. A review of the literature will not be attempted here. The interested reader is referred to Varano and Merklin 3 for a literature review, analysis of causal relations, and a discussion of clinically important defects. YMMETRY

Pa.

From The Daniel Baugh Institute of Anatomy, Jefferson Medical College, Philadelphia, Supported by U. S. Public Health Service Grant H-5787. Received for publication April 3, 1962. •Assistant Professor of Anatomy. *'Assistant Professor of Urology. 334

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SITUS INVEKSUS AND CARDIAC DEFECTS

MATERIAL

The data upon which this study is based were compiled from a study of hospital case histories. To the best of our knowledge none of these cases have been reported before, with the exception of 3 cases previously described by us. 3 Twenty-one hospitals kindly consented to the use of data from their record files. We are most grateful to the directors of these hospitals for this privilege and for their courtesy and interest in our study. TABLE I. SUMMARY OP M A J O R DEFECTS IN VARIOUS T Y P E S OP SITUS

TOTALS

5D* 614 Tetralogy of Fallot Cor biloculare 5D 2L 2D Cor triloculare Interventricular septal 4D 11L defects Interatrial septal defects 2D 3L Transposition of the 2D great vessels Truncus arteriosus ID Venous anomalies IL Cyanosis 9L Other heart defects ID 2L Kartagener's triad 4L Atelectasis 2L Abdominal visceral 2D defects 2L 3D Multiple birth defects 27D 42L Totals *D—Dead. fL—Alive.

COMPLETE SITUS INVERSUS

2D ID 2D

2L

2D

3L IL

DETROCARDIA

ID ID

IL IL

ID

8D

IL 4L

13L

DEXTROPOSITION

3D

3L IL

ID 2L IL 4L

PARTIAL SITUS INVERSUS

IL IL

INVERSUS

ID

LEVOCARDIA

IL

3D

2L IL

3L

ID ID

IL

5D

4L

ID ID 2L IL

IL

2L 2D 5D

13L

2D ID 8D

2L 7L

ID

5L

RESULTS

Including cases of dextroposition of the heart, we have compiled 111 cases of situs inversus viscerum. The distribution of cases among the various categories of situs inversus is as follows: 1. Complete situs inversus—the thoracic and abdominal viscera reversed (49 cases). 2. Dextrocardia—the heart displaced to the right and the chambers reversed with the abdominal viscera in the normal position (25 cases). 3. Partial situs inversus—dextrocardia with some degree of abdominal visceral inversion or the heart in normal position and inversion of all or part of the abdominal viscera (18 cases). 4. Dextroposition of the heart—the heart displaced to the right but the chambers not reversed (10 cases). 5. Levocardia—the heart displaced to the left with its chambers and all abdominal viscera reversed (9 cases). Sixty-nine of these individuals had defects of the cardiovascular or gastrointestinal system. The principal defect in each case is listed in Table I, and correlated with the type of situs inversus suffered by the individual. In addition

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to these listed defects there were numerous additional defects, many of which were of a critical nature. In tetralogy of Fallot there was no predominant, additional defect, however, 2 of these cases were actually pentalogy of Fallot since there were additional interatrial septal defects. One of these individuals lived to 59 years of age, having, in addition, a corrected transposition of the

TABLE

STATUS

II.

COMPLETE S I T U S I N V E R S U S : 21 OP 49 CASES W I T H GASTROINTESTINAL D E F E C T S

AGE

MAJOR CARDIAC OR GI DEFECT

CARDIOVASCULAR OR

OTHER DEFECTS

1. Dead

Newborn

Cor biloculare

Persistent pleuroperitoneal canal; atelectasis; bifid aortic valve; double superior vena cava

2. Dead

2 da.

Cor triloculare

Hydrocephalus; diaphragmatic hernia; spine anomalies; right kidney and ear agenesis; lung lobe defects; other heart defects

3. Dead

4 da.

Tetralogy of Fallot

Pulmonary stenosis; malrotation duodenal atresia

4. Dead

16 da.

Interventricular tal defect

sep

Tricuspid atresia; aortic stenosis; large interatrial septal defect; dilated bicuspid valve; stenotic tricuspid valve

5. Dead

8 mo.

Interventricular tal defect

sep

Pulmonary and tricuspid valve atresia; lung lobe defects; atelectasis; cardiomegaly

0. Dead

13 mo.

Tetralogy of Fallot

Cyanosis

7. Dead

15 mo.

Cor triloculare

Pulmonary atresia; tricuspid atresia; interatrial septal defect; lung lobe defects; ductus arteriosus to subclavian artery

8. Dead

4 yr.

Truncus arteriosus

Aneurysm of interventricular septum, muscular and membranous parts

9. Alive

2 mo.

Cyanosis

Ventricular hypertrophy

10. Alive

6 mo.

Interventricular tal defect

11. Alive

4 yr.

Cyanosis

sep

of

gut;

Pulmonary hypertension Pulmonary hypertension; biventricular hypertrophy

12. Alive

5 yr.

Tetralogy of Fallot

Cyanosis; right-to-left shunt

13. Alive

7 yr.

Interatrial septal de feet

Left superior vena cava into right atrium; cyanosis

14. Alive

8 yr8 yr.

Kartagener's triad

None

Interventricular tal defect

Pulmonary artery stenosis; cyanosis

15. Alive

sep

10. Alive

9 yr.

Tetralogy of Fallot

Retroesophageal subclavian artery

17. Alive

12 yr.

Interventricular tal defect

Cyanosis

18. Alive

15 yr-

Kartagener's triad

Chronic pneumonia

19. Alive

17 yr.

Endocarditis

Not recorded

20. Alive

50 yr.

Kartagener's triad

None

21. Alive

51 yr.

Kartagener's triad

Poorly developed paranasal sinuses

sep

SITUS INVERSUS AND CARDIAC DEFECTS

.Vol. 45, No. 3 March, 1963

337

great vessels and pulmonary stenosis. The added defects, in this individual, may cast some doubt on the diagnosis of tetralogy of Pallot. However, the other patient with pentalogy of Fallot also displayed pulmonary stenosis, as did 2 additional individuals with tetralogy of Fallot. There was one case of duodenal atresia in this group and one instance of a retropharyngeal (sic) subclavian artery. In 4 of the 5 fatal cases of cor biloculare, there was agenesis of the spleen. In the fifth case, the spleen was present and had entered the thorax through a persistent pleuroperitoneal canal. No mention of asplenia is made in the other 2 patients diagnosed as having cor biloculare; these individuals were 3 and 12 years of age at the time of the report. Interventricular septal defects15 were the most common defect, particularly when cases of tetralogy of Fallot, cor biloculare, cor triloeulare, and one case of truncus arteriosus are added, giving a total of 36 individuals with this defect. Four of them who had interventricular septal defect had defects of the pulmonic system, such as pulmonary stenosis

TABLE

STATUS

III.

DEXTROCARDIA : 18 OF 25 CASES W I T H CARDIOVASCULAR OR GASTROINTESTINAL DEFECTS

AGE

M A J O R CARDIAC OR 01 DEFECT

sep-

OTHER DEFECTS

1. Dead

1 wk.

Interventricular tal defect

Corrected transposition great vessels; cyanosis; pulmonary valve atresia; lung lobe defects; accessory splenic tissue

2. Dead

8 wk

Transposition of great vessels

Interventricular and interatrial septal defects; atelectasis; spleen agenesis

3. Dead

5 mo.

Multiple birth defects

Microcephalia; atresia of gall bladder and bile ducts; accessory splenic tissue

4. Dead

11 mo.

Cor biloculare

Heart block; cyanosis; spleen agenesis

5. Dead

3 y-

Multiple birtli defects

Hydrocephalus; spina bifida; club foot

Tetralogy of Fallot

Not recorded

6. Alive

Newborn

7. Alive

Newborn

Cyanosis

Not recorded

8. Alive

Newborn

Atelectasis

Not recorded

9. Alive

10 da.

10. Alive

1 mo.

11. Alive

Cyanosis

Atelectasis

Atelectasis

Not recorded

2 mo.

Venous anomaly

Inferior vena cava drained into azygos vein

12. Alive

3 mo.

Interatrial septal defect

Tricuspid atresia; accessory splenic tissue

13. Alive

6 mo.

Interventricular tal defect

Left ventricular hypertrophy

14. Alive

2 yr.

Interventricular septal defect

15. Alive

2 yr.

Cyanosis

16. Alive

9 yr.

Interventricular tal defect

17. Alive

12 yr-

Cor biloculare

Cyanosis, exertional dyspnea

54 yr.

Cyanosis

Chronic respiratory distress; pitting edema

18. Alive

sep-

Pneumonia Not recorded

sep-

Possible valvular defects

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and pulmonary valve atresia; and a fifth case might also have been classed as an Eisenmenger's complex. In 3 of the 5 cases of interatrial septal defect there were additional defects of the major arteries or veins; and with the inclusion of the cases of cor biloculare and other cases in which this defect occurred there were 16 additional clear examples of atrial septal defects (instances of patent foramen ovale were excluded from this count). Transposition of the great vessels is listed twice in Table I, however, there were 2 additional cases (both of interventricular septal defects). Including the case of pentalogy of Pallot previously mentioned, there were 3 cases of corrected transposition of the great vessels. Venous anomalies occurred in a total of 6 cases, the pulmonary veins being involved in 3 of these. TABLE

STATUS

IV.

PARTIAL S I T U S I N V E R S U S : 15 OF 18 CASES W I T H GASTROINTESTINAL D E F E C T S

1. Dead

Newborn

2. Dead

MAJOR CARDIAC OR Gl DEFECT

CARDIOVASCULAR OR

OTHER DEFECTS

Transposition of great vessels

No post mortem; dextrocardia

3 da.

Abdominal visceral defects

Atresia of small bowel; accessory splenic tissue; lung lobe defects

3. Dead

3 da.

Multiple birth defects

Hydrocephalus; bilateral club feet; spine and rib defects; myelomeningocele; lung lobe defects; atelectasis

4. Dead

2 wk.

Abdominal visceral defects

Duodenal atresia; atelectasis; accessory splenic tissue; lung lobe defects

5. Dead

5 wk.

Cor biloculare

Pulmonary artery and valve atresia, cyanosis; dextrocardia; spleen agenesis; atelectasis; lung lobe defects

6. Dead

6 wk.

Truncus arteriosus

Hypoplasia of left heart; atelectasis, cyanosis, pulmonary veins to portal vein; spleen agenesis; lung lobe defects; dextrocardia; transposition of great vessels

7. Dead

4 mo.

Cor biloculare

Cyanosis, atelectasis; pulmonary valve atresia; spleen agenesis; dextrocardia

8. Dead

8 mo.

Cor biloculare

Cyanosis; pulmonary artery and valve atresia; partial fusion of mitral and tricuspid valves; pulmonary veins to portal vein; spleen agenesis; lung lobe defects; dextrocardia

9. Alive

17 da.

Murmur

Noncyanotie

10. Alive

6 mo.

Cyanosis

Eight ventricular hypertrophy

11. Alive

9 mo.

Interventricular tal defect

12. Alive

2 yr.

Cyanosis

Pulmonary stenosis; right ventricular hypertrophy

13. Alive

4 yr.

Abdominal visceral defects

Transposed colon

14. Alive

6 yr.

Abdominal visceral defects

Rotated stomach: duodenal constriction

15. Alive

27 yr.

Interatrial septal de feet

Cyanosis, venous anomalies; lower cervical spine anomaly; condition deteriorating

sep

Dextrocardia

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In addition to the 4 cases of spleen agenesis mentioned above there were 2 additional instances of this defect, one in the case of truncus arteriosus and one in a case of transposition of the great vessels. Accessory splenic tissue was found in 5 cases. Anomalous lung lobation was observed in 11 cases and had no apparent correlation with the presence of other defects. Finally, it should be mentioned that in 12 cases there was a diagnosis of atelectasis, only 5 of these were associated with interventricular septal defects. The principal defects found in the 69 cases of situs inversus in which the individual had cardiovascular or gastrointestinal defects are summarized in Tables II-VI.

TABLE -V.

STATUS

DEXTROPOSITION : 6 OF 10

AGE

CASES W I T H DEFECTS

CARDIOVASCULAR

M A J O R CARDIAC OR GI DEFECT

No post mortem

4 da.

Interventricular tal defect

Not recorded

Newborn

2. Alive

sep-

GASTROINTESTINAL

OTHER DEFECTS

Interatrial septal defect

1. Dead

OR

3. Alive

7 wk.

Cyanosis

Not recorded

4. Alive

8 yr.

Tetralogy of Fallot

Not recorded

5. Alive

22 yr.

Interventricular tal defect

sep-

Cyanosis; possible transposition of vessels

6. Alive

24 yr.

Interventricular tal defect

sep-

Cyanosis; overriding aorta

TABLE VI.

STATUS

1LEVOCARDIA : 9 OF 9 CASES W I T H CARDIOVASCULAR

AGE

M A J O R CARDIAC OR GI DEFECT

OR GASTROINTESTINAL

great

DEFECTS

OTHER DEFECTS

1. Dead

Newborn

Tetralogy of Fallot

Anomalous pulmonary veins; cyanosis; lung lobe defects

2. Dead

6 wk.

Interatrial septal defect

Coarctation of a o r t a ; cyanosis; anomalous venous drainage

3. Dead

5 mo.

Interventricular tal defect

Cyanosis

4. Dead

5 yr.

Tetralogy of Fallot

Retarded development

sep-

5. Dead

9 yr.

Tetralogy of Fallot

Interatrial septal defect; atelectasis, corrected transposition of great vessels; pulmonary stenosis

6. Alive

4 mo.

Interventricular

Corrected transposition of great vessels; possible interatrial septal defect

7. Alive 8. Alive 9. Alive

sep-

tal defect

Cyanosis; partial heart block

3 yr.

Cor biloculare

3 yr.

Tetralogy of Fallot

Cyanosis; pulmonary stenosis; mental retardation; interatrial septal defect; cervical rib

4 yr.

Tetralogy of Fallot

Cyanosis; pulmonary stenosis

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DISCUSSION

Interest in situs inversus should properly stem from several important considerations. Of immediate importance is the frequent occurrence (69 of 111 cases) of critical defects which may make surgical intervention imperative if the patient is to live and enjoy a normal life. Second, the association of cardiac defects with situs inversus provides a unique opportunity to study the etiology of congenital cardiac defects. The knowledge derived from such studies will be of value in understanding the forces which determine body symmetry and asymmetry and will equip the surgeon with information which will improve the treatment of all patients with cardiac defects. The first fact which warrants comment is the high occurrence of defects among individuals with situs inversus who become hospital patients. In particular, it should be noted that a high number of patients with situs inversus totalis (20 of 49) are afflicted with cardiac defects. Previous to this report it was believed that these individuals, with the exception of those with Kartagener's triad, are relatively free of defects. An inspection of Table I I I will show that many of these patients need surgical attention early in life and, more important, many succumb to these defects at an early age. The seriousness of cardiac defects in situs inversus totalis is further emphasized by the low incidence of Kartagener's triad in this series (4 of 49 cases), whereas its incidence has been estimated at 25 per cent in two earlier studies. 1 - 2 The youth of the individuals in this series does not account for this discrepancy. Bergstrom and his associates4 have emphasized that the syndrome is a pediatric problem and support this contention with 13 cases from the literature in which it was recognized before the age of 2, and 10 more cases in which children under 14 years of age were affected. We must conclude, reluctantly, that Kartagener's syndrome is unrecognized in many cases or that the syndrome and cardiac defects are often mutually exclusive. The absence of bronchiectasis and sinusitis from cases of dextrocardia is also unusual since Dickey5 has described this as a valid form of Kartagener's syndrome with a 10 to 20 per cent occurrence. The prevalence of cardiac defects in dextrocardia and partial situs inversus has been noted before 2 ' 6 ' 7 and estimated to occur in a quarter of such cases. The present study indicates that in a hospital population this rate is much higher. Fourteen of 25 patients with dextrocardia had defects, 3 of these died while the majority of the living patients with defects were extremely young and in serious cardiac distress (Table I V ) . In partial situs inversus, 10 of 18 individuals had heart defects; 5 of these succumbed to the defects. It should be noted that while multiple birth defects and gastrointestinal defects are in the minority they are almost exclusively associated with dextrocardia and partial situs inversus. The small number of instances of multiple birth defects in this series seems to indicate that this is not a major factor in the etiology of situs inversus. It suggests, instead, that genetic factors are largely responsible for the production of this defect. We have distinguished between dextrocardia and partial situs inversus in this study and defined each in the first paragraph of Results. It should be

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°^±

pointed out, therefore, that dextrocardia was present in 5 cases of partial situs inversus and that all these individuals suffered heart defects and succumbed to these defects. Pour, and possibly all 5, of these cases were examples of the spleen agenesis syndrome which will be discussed later. The last two classes of situs inversus, dextroposition and levocardia, are small in numbers but are very important from the standpoint of accompanying defects. Without exception these are cardiac defects and their incidence is high. In 6 of 10 cases of dextroposition and all 9 cases of levocardia there were cardiac defects. These two types of transposition would seem to be similar and to stem from related causes, since both are shifts in heart position contrary to .body asymmetry. Apparently this is not true since the nature of the defects in each type is strikingly different. The defects in cases of dextroposition are usually simple, and survival is high, whereas defects associated with levocardia are complex and fatalities are high. This suggests that the normal asymmetry of the cardiovascular and gastrointestinal systems has a very definite, although unknown, purpose. Table VI summarizes the defects accompanying levocardia. Whereas all of the patients had serious defects, it should be noted that 5 of the 9 cases were of tetralogy of Fallot. Only one patient with situs inversus totalis had a gastrointestinal defect, and examination of the other types of cases brings the total of gastrointestinal defects to 12. In 6 cases these defects were serious, 4 being small bowel atresia, one biliary system atresia, and one a malrotation of the intestines. The condition of asplenia in 6 cases cannot be considered a critical defect by itself, but the condition does warrant concern since it is invariably associated with serious heart defects. This fact, known for many years, has gained recognition as a distinct syndrome in which the spleen is absent, the heart has a common atrioventricular canal, or is two-chambered, and the lungs are trilobed; some degree of situs inversus invariably accompanies this syndrome. Perhaps the first comprehensive review of this complex was made by Putschar 8 who reported 22 cases of asplenia, 20 patients of whom had additional defects of heart, lungs, and reversed asymmetry. Putschar, in collaboration with Manion,9 reported additional cases of asplenia in 1956. Notable studies have been made by Polhemus and Schafer 10 ' " who recognized the syndrome as such, and by Ivemark 12 who, in an extensive monograph, thoroughly reviewed asplenia and its relation to heart defects. Ivemark's study indicates that heart defects accompanied by asplenia result from fairly early developmental arrest and that these infants, because of asplenia, are susceptible to meningitis. Ivemark noted that where multiple spleens are found the cardiac defects are of less rudimentary types, and a later developmental arrest must be considered. From our study we might add that multiple splenic tissue was present only in cases of dextrocardia (3 cases) and partial situs inversus (2 cases). SUMMARY

1. Cardiovascular or gastrointestinal defects were found in over half of the patients with situs inversus whose records were reviewed.

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2. Cardiovascular defects were six times more frequent than gastrointestinal defects. 3. The defects associated with situs inversus become manifest early in life and present formidable surgical problems. 4. Patients with situs inversus totalis, in this series, had a high rate of cardiac defects and a surprisingly low incidence of Kartagener's syndrome. 5. Partial situs inversus, which takes several forms, is characterized by a very high rate of defects. These defects are frequently severe, complex, and fatal. 6. Multiple birth defects were rarely seen in this series of cases. This suggests that these defects and the transposition of viscera have unrelated causes. REFERENCES 1. Torgersen, J . : Genie Factors in Visceral Asymmetry and in the Development and Pathologic Changes of Lungs, Heart and Abdominal Organs, Arch. Path. Chir. 47: 566-593, 1949. 2. Schmutzer, K. J., and Linde, L. M.: Situs Inversus Totalis Associated With Complex Cardiovascular Anomalies, Am. Heart J . 56: 761-768, 1958. 3. Varano, N. E., and Merklin, R. J . : Situs Inversus; Review of the Literature, Eeport of Four Cases and Analysis of the Clinical Implications, J. Internat. Coll. Surgeons 33: 131-148, 1960. 4. Bergstrom, W. H., Cork, C. C , Scannell, J . G., and Berenberg, W . : Situs Inversus, Bronchiectasis and Sinusitis; Eeport of a Family With Two Cases of Kartagener's Triad and Two Cases of Bronchiectasis Among Six Siblings, Pediatrics 6: 573-580, 1950. 5. Dickey, L. B . : Kartagener's Syndrome in Children, Dis. Chest 2 3 : 657-666, 1953. 6. Johnson, J . E.: Situs Inversus With Associated Abnormalities; Review of the Literature and Report of Four Cases, Arch. Surg. 58: 149-162, 1949. 7. McKeown, T., MacMahon, B., and Parsons, C. G.: The Familial Incidence of Congenital Malformations of the Heart, Brit. Heart J . 15: 273-277, 1953. 8. Putschar, W.: The Entwicklungstorungen der Milz in Die Morphologie der Missbildungen des Menschen und der Tiere, edited by G. B. Gruber, Jena, 1934, Gustar Fish, Publisher. 9. Putschar, W., and Manion, W. C.: Congenital Absence of the Spleen and Associated Anomalies, Am. J . Clin. Path. 26: 427-470, 1956. 10. Polhemus, D. W., and Schafer, W. B . : Congenital Absence of the Spleen; Syndrome With Atrioventricularis (Communis) and Situs Inversus; Case Beports and Eeview of Literature, Pediatrics 9: 696-706, 1952. 11. Polhemus, D. W., and Schafer, W. B . : Absent Spleen Syndrome; Hematologic Findings as an Aid to Diagnosis, Pediatrics 24: 254-257, 1959. 12. Ivemark, B . I . : Implications of Agenesis of the Spleen on the Pathogenesis of ConoTruncus Anomalies in Childhood, Aeta Paediat. 44: Suppl. 104, 1-110, 1955.