cardiac malformations in trisomy-18: a study of 41 postmortem … · trisomy-18, all karyotype...

1586 JACC Vol. 13, No. 7 June 1989:158&97

Cardiac Malformations in Trisomy-18: A Study of 41 Postmortem Cases

STELLA VAN PRAAGH, MD,* TIMOTHY TRUMAN, MD,* ADOLF0 FIRPO, MD,t ANTONIO BANO-RODRIGO, MD,* RUTHELLEN FRIED, MD,* BRUCE McMANUS, MD,+ MARY ALLEN ENGLE, MD, FACC,t RICHARD VAN PRAAGH, MD, FACC” Boston, Massachusetts

The cardiac malformations in 41 karyotyped and autopsy cases of trisomy-18 are presented in detail. The salient findings were a ventricular septal defect in all cases; tricuspid valve anomalies in 33 cases (80%); pulmonary valve anomalies in 30 (70%); aortic valve malformations in 28 (68%); mitral valve anomalies in 27 (66%); polyvalvular disease (that is, malformations of more than one valve) in 38 (93%); a subpulmonary infundibulum (conus) in 40 (98%); a bilateral conus with a short subaortic infundibulum in 1 case with double outlet right ventricle (this being the only documented case of bilateral infundibulum in trisomy-18); double outlet right ventricle in 4 cases (lo%), three having a subpulmonary infundibulum only and all 4 having mitral atresia; tetralogy of Fallot in 6 cases (15%), 2 having pulmonary atresia; and a striking absence of transposition of the great arteries and inversion at any level

(visceral or cardiac), findings that appear to be characteristic of all trisomies.

These data suggest that excessive chromosomal material (as in trisomies) may result in situs solitus at all levels. The malformations of the atrioventricular and semilunar valves were characterized by redundant or thick myxomatous leaflets, long chordae tendineae and hypoplastic or absent papillary muscles. The ventricular septal defect was associated with anterosuperior conal septal malalignment in 25 cases (61%). On the basis of the characteristic valvular lesions, the type of ventricular septal defect and the absence of transposition or inversions, two-dimensional echocardio- graphic diagnosis of trisomy-18 in the fetus may become possible.

(J Am Co11 Cardiol1989;13:1586-97)

Infants with trisomy-18 have severe mental retardation with anomalies of the nervous, cardiovascular, gastrointestinal, genitourinary and musculoskeletal systems (l-36), and survival beyond 1 year of age is rare (21). Even if their heart defects were successfully repaired, the prognosis would not be greatly altered.

Hence, this study of the congenital heart defects of trisomy-18 was undertaken not for therapeutic reasons, but rather in the hope of improving understanding of these cardiac anomalies. Such improved understanding may facil-

itate the noninvasive prenatal and postnatal diagnosis of trisomy-18 by two-dimensional echocardiography and nu- clear magnetic resonance imaging. Moreover, we questioned the nature of the relation between trisomy-18 and the kinds of congenital heart disease that these patients have and do not have. For example, it has been observed that individuals with Down’s syndrome (trisomy-21) do not have transposition of the great arteries (37-42) or visceral or cardiac inversions (42). Do patients with trisomy-18 also lack these conditions? If so, what does this absence of transposition and inversion in trisomies signify?

From the *Departments of Cardiology and Pathology, The Children’s Hospital, Boston, Massachusetts; tDepartments of Pediatric Cardiology and Pathology, Cornell University Medical Center, New York, New York and *Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska. This study was supported in part by a grant from the Riley Fund, Boston. It was presented in part at the Second World Congress of Pediatric Cardiology, New York, New York, June 2 to 6, 1985.

Manuscript received October 5, 1988: revised manuscript received De- cember 7, 1988, accepted December 15, 1988.

Address for renrints: Stella Van Praagh, MD, Department of Cardiology, The Children’s Hospital, Boston, Massachusetts 02115.

Methods Autopsy cases. This study is based on 41 autopsy cases of

trisomy-18, all karyotype proven-the largest study of this condition reported to date. Of these 41 cases, 31 were from the Cardiac Registry of The Children’s Hospital, Boston and 10 were from the Department of Pathology of the New York

01989 by the American College of Cardiology 0735.1097189/$3.50

JACC Vol. 13. No. 7 VAN PRAAGH ET AL. 1587 June 1989: 158697 CARDIAC MALFORMATIONS IN TRISOMY-I8

Figun an ex: conus infuna forms of the

below

: 1. The heart of this 26 h old female infant (Case 7, Table 2) is imple of double outlet right ventricle with only subpulmonary and with mitral atresia (MAt). A, Right ventricular view. The

libular septum (IS) is slightly underdeveloped. malaligned and a long arch over the septal band (SB), ending on the free wall right ventricle (RV). The ventricular septal defect (VSD) is

ed by the infundibular septum (IS) above and the septal band The aortic outflow (Ao out) and the aortic valve (Ao) are

above the right ventricle (that is, double outlet right ventric present). The tricuspid valve (TV) has very redundant leaflets, few interchordal spaces and very small papillary muscles. superior commissure (SC) of the tricuspid valve is unusl cephalad. The pulmonary valve (PV) is bicuspid and stenotic. F right atrium. B, Left atrial view. The mitral valve orifice is at (MAt). The pulmonary veins (PV) drain normally into the atrium (LA).

:le is very The

ually :A =

left

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Hospital, Cornell University Medical Center. Of the latter 10 cases, 4 were previously reported (30).

All heart specimens were examined by us, particular attention being focused on the anatomic types of ventricular septal defect, the anomalies of the atrioventricular (AV) and semilunar valves and the anatomic variations of the infundibulum (conus). In 25 of the 41 cases, the pulmonary vascular bed was studied by the methods of Wagenvoort et al. (43) and Rabinovitch and Reid (44).

Gender. There were 23 female and 17 male infants (ratio 1.4:1).

Age at death. The median age was 2 days (range stillborn to 2.5 years).

Results Heart position. Levocardia (left-sided heart) was present

in 37 cases (90%). Mesocardia (midline heart), but with the ventricular apex formed by the left ventricle and pointing leftward, was present in four cases (10%). Dextrocardia (right-sided heart) was found in none.

Visceroatrial situs solitus. This was present in all cases. The spleen was left-sided and normally formed in all. One small accessory spleen was present in the infant with double outlet right ventricle and bilateral conus.

Systemic and pulmonary veins. These were normally connected in all.

Ventricular situs. A situs solitus or d-loop ventricle was present in all cases (that is, right-sided and noninverted right ventricular inflow and left-sided and noninverted left ventricle).

Infundibulum. Solitus muscular subpulmonary infundibulum was present in 40 cases (98%), with aortic-mitral fibrous continuity in 40 (98%). Bilateral infundibulum (subaortic and subpulmonary) was found in one case (2%) with double outlet right ventricle and mitral atresia; this is the only known documented case of a bilateral infundibulum in association with trisomy- 18.

Atrioventricular alignments. These were concordant in all.

Ventriculoarterial alignments. These were concordant, with solitus normally related great arteries in 37 cases (90%). There was a double outlet right ventricle in four cases (10%). In three of the four latter cases, only a subpulmonary conus was present (that is, normal solitus conal development) and the aortic valve was in direct fibrous continuity with the tricuspid valve. The mitral valve was atretic and the left ventricle very hypoplastic in all these three cases (Fig. 1). The position of the aorta above the right ventricle was apparently due not to an abnormal conotruncus, but to underdevelopment of the left ventricle and mitral valve atresia. In only one case of double outlet right ventricle was a bilateral conus present (Fig. 2). The subaortic component of the bilateral conus was very poorly developed (2 to 3 mm

long). The mitral valve was also atretic and the left ventricle very small in this case. Typical transposition of the great arteries with subaortic infundibulum and pulmonary-mitral fibrous continuity did not occur in this series.

Atria1 septum. The septum primum (that is, the valve of the foramen ovale) was redundant in 21 cases (51%) (Table 1). Single or multiple atria1 septal defects of the secundum type were found in nine (22%).

Ventricular septum. A ventricular septal defect was present in all cases. Several different anatomic types of ventricular septal defect were found (Table 1).

1. A membranous ventricular septal defect was observed in nine cases (22%). The diagnosis of membranous ventricular septal defect indicates that only the membranous septum is deficient (Fig. 3). A membranous defect typically is small (that in Fig. 3A is 3 x 4 mm). The designation membranous ventricular septal defect connotes that the infundibular septum is normally formed, being neither hypoplastic nor malaligned. This diagnosis also implies that the aortic valve is not dextroposed because dextroposition of the aortic valve is associated with infundibular septal malalignment, as in tetralogy of Fallot. In Figure 3A, the infundibular septum is normally developed and joins the ventricular septum and septal band in a normal fashion. From the left ventricular view (Fig. 3B), the mitral valve is in direct fibrous continuity with the left coronary and noncoronary cusps (that is, normal).

The membranous ventricular septal defect extended somewhat posteriorly-behind the septal leaflet of the tricuspid valve-in an additional six cases (15%) (Table 1). The presence of a posterior extension resulted in a large membranous ventricular septal defect in these cases. Hence, membranous ventricular septal defect, with and without posterior extension, was present in 15 cases (37%).

2. Infundibular septal malalignment without infundibular hypoplasia (that is, the Eisenmenger complex) was present in 16 cases (39%) (Table 1). An infundibuloventricular type of defect denotes that the ventricular septal defect lies between the infundibular septum above and the ventricular septum and septal band below. This malalignment type of ventricular septal defect is large, as the left ventricular view makes clear (compare Fig. 3B and 4).

The infundibuloventricular type of ventricular septal defect also occurred with anterior infundibular septal malalignment and infundibular septal hypoplasia, but without pulmonary outflow tract stenosis (Fig. 5A). The anterior and leftward position of the infundibular septum is associated with dextroposition of the aortic valve (Fig. 4 and 5B). The mitral valve is in direct continuity only with the left coronary cusp, instead of with half of the noncoronary and half of the left coronary cusp, which is the normal aortic to mitral fibrous continuity.

3. A ventricular septal defect with hypoplasia and malalignment of the infundibular septum as well as the free wall

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VAN PRAAGH ET AL. 1589 CARDIAC MALFORMATIONS IN TRISOMY-18

Figure 2. The heart of this 30 min old female infant is the very rare case of double outlet right ventricle with bilateral but underdeveloped infundibulum. It has a left aortic arch and bilateral patent ductus arteriosus. A, Right ventricular view. The papillary muscles of the tricuspid valve (TV) are very hypoplastic and the leaflets are redundant. The aortic valve (AoV) is anterior to the pulmonary vein (PV). The infundibular septum (IS) is very underdeveloped and malpositioned above the right ventricle (RV). The aortic isthmus (AoI) is hypoplastic. The left patent ductus arteriosus (LPDA) is large with wrinkled intima, equal in circumfer- ence to the descending aorta (DAo). The right patent ductus arteriosus (RPDA) is much smaller and connects the right subclavian artery (RX) with the right pulmonary artery (RPA) (that is, isolation of the right subclavian artery is present). LCC and RCC = left and right coronary cusps of the aortic valve, respectively: LL = left lung; LSC = left subclavian artery; LPA = left pulmonary artery; RL = right lung; VSD = ventricular septal defect. B, Left atria1 and left ventricular view. A secundum type of atria1 septal defect (ASD) is present. The pulmonary veins (PVs) enter the left atrium (LA). The mitral valve is atretic (MAt). The left ventricle (LV) is very underdeveloped. A ventricular septal defect divided by a muscular bridge extends over the en- tire width of the ventricular portion of the atrioventricular canal septum. The left atria1 appendage (LAA) is seen.

of the infundibulum, resulting in subpulmonary stenosis or artery was unusually well developed. In two cases, the pulmonary atresia, was present in six cases of tetralogy of pulmonary valve was very stenotic; in another two, it was Fallot and three cases of double outlet right ventricle. atretic. The pulmonary atresia was at the valvular rather Hence, an infundibuloventricular septal defect associated than at the infundibular level, and the infundibular septum with malalignment of the conal septum was present in a total was not fused with the infundibular free wall, as it usually is of 25 cases (61%) (Table 1). in nontrisomic patients (Fig. 6). All three cases of double

In all cases of tetralogy of Fallot, the main pulmonary outlet right ventricle with an infundibuloventricular septal

1590 VAN PRAAGH ET AL. CARDIAC MALFORMATIONS IN TRISOMY-18

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Table 1. Cardiac Malformations in 41 Postmortem Cases of Trisomv-18

Cardiac Region

Atria1 septum

Ventricular septum

Malformation

Redundant septum primum Single or multiple secundum atrial septal defects Membranous septal defect, small Membranous with posterior extension, large lnfundibuloventricular septal defect with IS malalignment, but without infundibular hypoplasia or PS Infundibuloventricular septal defect with IS and infundibular free wall hypoplasia and sub

PS (tetralogy of Fallot and DORV)

n %

21 51 9 22 9 22 6 IS

I6

> 61

9

Tricuspid valve Mitral valve

Pulmonary valve

Aortic valve

AV canal type subdivided by muscular bridge Additional mid-muscular, very small Redundant leaflets, long chordae and small papillary muscles Redundant leaflets, decreased interchordal spaces, hypoplastic or absent papillary muscles Cleft anterior leaflet Atretic Total Bicommissural Bicommissural and redundant Bicommissural and stenotic Tricommissural and redundant Atretic Total Bicommissural Bicommissural and redundant (two with prolapsed RCC) Tricommissural and redundant (one with prolapsed RCC) Unequal cusp size Unicommissural and redundant Total

Coronary arteries High left coronary orifice Single CO in LCC; the right CA coursed in front of the MPA before reaching the right AV groove Left circumflex from RCO Total

Aortic arch and isthmus

Valvular involvement

Coarctation of Ao or isthmic hypoplasia with PDA Common brachiocephalic trunk Bilateral PDA and isolation of right subclavian Two valves Three valves Four valves Total

I 2

33 21 2 4

27 IO 9 6 3 2

30 I5 8 3

1 28 4 2

1 17 11 21 4 10 I 2

13 32 11 27 14 34 38 93

2 5

80

66

73

68

AO = aorta; AV = atrioventricular; CA = coronary artery; CO = coronary orifice; DORV = double outlet right ventricle; IS = infundibular septum; LCC = left cornary cusp; MPA = main pulmonary artery; PDA = patent ductus arteriosus; PS = pulmonary stenosis; RCC = right coronary cusp; RCO = right coronary orifice.

defect and malalignment of the infundibular septum had a bicuspid and, in one case a stenotic, pulmonary valve (Fig. 1A).

4. Ventricular septal defect in the area of the AV canal septum occurred in the very rare case of double outlet right ventricle and bilateral conus. This defect was subdivided by a muscular bridge (Fig. 2). The vascular malformations of this rare case are described in the legend to Figure 2.

Valvular anomalies (Table 1). The tricuspid valve was the most frequently abnormal valve (38 cases [80%]). Its leaflets were usually long and redundant (Fig. 1A and 6) or very thick and myxomatous (Fig. SA). The chordae tendineae were longer than normal (Fig. 6) and contrasted with the papillary muscles, which were very hypoplastic (Fig. 5A and

6). The deformities of the tricuspid valve were often compatible with tricuspid regurgitation. There were no deformities indicative of tricuspid stenosis, and we never encountered a case of tricuspid atresia.

The pulmonary valve was the second most frequently malformed valve (30 cases [73%]01). It was bicommissural in 25 cases (61%), with redundant or thickened leaflets resulting in pulmonary stenosis (Fig. IA). In two cases of tetralogy of Fallot, pulmonary valve atresia was present (Fig. 6).

The aortic valve was the third most frequently malformed valve (28 cases [68%]). Bicuspid (that is, bicommissural) aortic valve was the most common aortic valve abnormality (Fig. 3B). Often, it was bicommissural and redundant or tricommissural and redundant (Fig. 4). In three cases, there

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Figure 3. The heart of this 1 day old male infant exemplifies a small membranous ventricular septal defect. A, Right ventricular view. The tricuspid valve (TV) has redundant leaflets, long chordae tendineae and very hypoplastic papillary muscles. The infundibular septum (IS) is normally developed and joins the septal band (SB) in a normal fashion. The pulmonary valve (PV) is bicuspid and slightly redundant. Arrow is through a small (3 x 4 mm) membranous ventricular septal defect (VSD). B, Left ventricular view. The right coronary (RC) and noncoronary (NC) cusps of the aortic valve are in common because of a very underdeveloped right coronary to noncoronary commissure. The mitral valve (MV) is in direct fibrous continuity with the left coronary and noncoronary cusps. The membranous ventricular septal defect (VSD) is partly obliterated by the tricuspid valve.



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Figure 4. The heart of this 26 day old male infant (Case 6, Table 2) repre- sents an example of an infundibuloventricular ventricular septal defect (VSD) with infundibular septum malalignment, but not hypoplasia and without pulmonary stenosis. On the left ventricular view, the mitral valve (MV) has only one hypoplastic papillary muscle (PM), the posteromedial. Be- cause the anterolateral is absent, the mitral valve inserts directly into the free wall of the left ventricle (LV). The leaflets are poorly separated and redundant, with a lacelike appearance. The aortic valve (Ao) is bicuspid. The noncoronary (NC) to right coronary cusp commissure is extremely underdeveloped. The left coronary (LC) cusp only is continuous with the mitral valve. The tricuspid valve (TV) is continuous with the right and noncoronary cusps and with the mitral valve by means of the ventricular septal defect. Note the deficiency of fine trabecula- tion in the free wall and lower septal surface of the left ventricle.

was a prolapsing right coronary cusp compatible with aortic regurgitation. We did not encounter any case with evidence of aortic valve stenosis. Yet in two of the three cases of double outlet right ventricle with only subpulmonary conus and in the rare case with a bilateral conus (Fig. 2A), there appeared to be some subaortic obstruction due to the position of the aortic valve between the infundibular septum and the tricuspid valve (Fig. 1A) or to the poorly expanded subaortic infundibulum (Fig. 2A).

The mitral valve showed the lowest frequency of malformations (27 cases [66%]). The abnormalities involved the leaflets, which were redundant and lacy in appearance, the interchordal spaces, which were often decreased, or the papillary muscles, which were very underdeveloped or absent (Fig. 4 and SB). In only two cases was a cleft mitral valve encountered (Table 1). In contrast to the malformations of the tricuspid valve, which were compatible with tricuspid regurgitation, the malformations of the mitral valve often resulted in mitral stenosis (Fig. 4 and 5B). Also, although there was not a single case of tricuspid atresia, there were four cases of mitral atresia, all associated with a double outlet right ventricle.

Polyvalvular disease. In 38 cases (93%), two or more valves were abnormal, and in 14 cases (34%), all four valves were malformed (Table 1).

Other associated malformations (Table 1). These included coarctation of the aorta, large patent ductus arteriosus, a common brachiocephalic trunk and minor abnormalities of the position of the coronary ostia.

Pulmonary vascular obstructive disease (Table 2). Signifi- cant hypertrophy of the media and intimal proliferation were observed in 8 (32%) of the 25 cases in which lung histology was studied. Five of these cases had an infundibuloventricular type of ventricular septal defect with anterosuperior malalignment of the infundibular septum, but without pulmonary outflow obstruction. One case had a large membranous ventricular septal defect with posterior extension and a ductus arteriosus patent at the age of 7 months. One infant with a double outlet right ventricle had subpulmonary and pulmonary valve stenosis; despite the presence of pulmonary outflow tract obstruction, pulmonary hypertension was probably present as a result of the coexistence of mitral atresia.

Six of these eight infants were under the age of 2 months and none was older than 7 months. Hence, these cases with the Eisenmenger type of ventricular septal defect (anterosuperior deviation of the infundibular septum, but without pulmonary outflow tract stenosis) were associated with unusually early development of pulmonary vascular obstructive disease. It is also possible that patients with trisomy-18 may be predisposed to develop pulmonary vascular obstructive changes earlier than are eukaryotypic infants with ventricular septal defect (45).

Discussion Previous studies. After the almost simultaneous discov-

ery of the trisomy-18 syndrome by Edwards (1) and Patau (2)

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Figure 5. The heart of this 4 month old female infant (Case 2, Table 2) is an example of an infundibuloventricular ventricular septal defect with infundibular septum malalignment and hypoplasia, but without pulmonary stenosis. A, Right ventricular view. The tricuspid valve (TV) has redundant leaflets with thickened edges and hypoplastic papillary muscles. The infundibular septum (IS) is very short, malaligned and joins the superior limb- instead of the bifurcation-of the septal band (SB). There is normal development of the free wall of the subpulmonary infundibulum and a large main pulmonary artery (MPA). The large ventricular septal defect (VSD) is outlined by the infundibular septum supe- riorly, the septal band inferiorly and the tricuspid valve posteriorly. The coronary sinus (CoS) orifice is seen above the tricuspid valve. B, Left ventricular view. The mitral valve (MV) has very abnormal myxomatous leaflets. The papillary muscles are very hypoplastic. The anterior leaflet at- taches directly on the septum in a fashion similar to the one observed in common atrioventricular canal defects. The mitral valve is directly continuous only with the left coronary (LC) cusp. The right coronary to noncoronary (RC to NC) commissure is very underdeveloped, and the two cusps form a large leaflet. The noncoronary cusp is in continuity with the tricuspid valve (TV). The tricuspid valve fills the area of the ventricular septal defect (VSD) and is continuous with the mitral valve. Coarc = coarctation; LV = left ventricle; PA = pulmonary artery.

and their coworkers in 1960, a multitude of articles (3-36) aortic overriding (6). The severe and extensive noncardiac presented new cases and emphasized the high incidence of malformations dominated the earlier reports. ventricular septal defect (34) and polyvalvular disease In a few case reports, malformations of the membranous (46,47). Yet the type of ventricular septal defect was seldom septum (48), tricuspid valve (49) and mitral valve (50) were described or presented photographically. It was occasionally reported in detail and documented photographically. Slowly, referred to as “high” (6,22), membranous (23) or large with articles about the cardiac malformations began to appear


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Figure 6. The heart of this 36 h old male infant shows a malaligned and hypoplastic infundibular septum (IS) and atresia of the pulmonary valve (PAt), (that is, tetralogy of Fallot with pulmonary atresia [PAt]). The hypoplastic infundibular septum is not fused with the infundibular free wall. The main pulmonary artery (MPA) is relatively large. The ventricular septal defect (VSD) is outlined by the infundibular septum above and the septal band (SB) below. The tricuspid valve (TV) has redundant leaflets, long chordae tendineae and hypoplastic papillary muscles. Other abbreviations as before.

(30,51) and the striking polyvalvular involvement was emphasized (46,47).

Conclusions from the present series. The 41 heart specimens in this series (personally examined and described in detail) provide the material basis for the following conclusions.

1. The most frequent type of ventricular septal defect (25 cases [61%]) was located between the infundibular (conal) septum above and the septal band and ventricular septum below (conoventricular or infundibuloventricular) and was associated with superoanterior displacement (malalignment) of the infundibular septum. Underdevelopment of the free wall of the infundibulum and the pulmonary valve resulted in pulmonary outflow stenosis in the six cases of tetralogy of Fallot (two with pulmonary atresia) and in the three cases of double outlet right ventricle with only a subpulmonary conus.

2. Two or more ofthe valves ofthe heart were malformed in 38 cases (93%) in this series.

3. Malformations of the AV valves were more extensive and more pronounced than were those of the semilunar valves. The leaflets and chordae tendineae tended to be redundant and longer than normal, while the papillary muscles were hypoplastic or absent. Because the development of the AV valves is intimately related to that of the ventricular myocardium (52), one may infer that the normal process of differentiation of the mitral and tricuspid valves and their tensor apparatus from the AV endocardial cushions and the ventricular myocardium is interfered with in trisomy-18. It has been shown histologically that the AV valves of patients with trisomy-18 are similar to those of the fetus (47). Hence, the abnormal appearance of the valves has been thought to be due to an arrest of the process of leaflet maturation (47).

However, the pathologic features of the AV valves we encountered in this series (Fig. 1 to 6) appear to reflect more than leaflet immaturity. Human fetal AV valves may differ histologically from normal neonatal valves, but their general gross configuration is very similar to that of normal neonatal

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VAN PRAAGH ET AL. 1595 CARDIAC MALFORMATIONS IN TRISOMY-I8

Table 2. Abnormal Pulmonary Histologic Findings in Eight Cases of Trisomy- 18 Pulmonary Findings

Other Cardiac Heath-Edwards Reid-Rabinovitch Case No. Age Type and Size of VSD Malformations Grade* Gradet

I I mo Membranous with post ext. 5 x 9 mm PDA 3 III B 2 4 mo IV with IS ma1 and hypoplasia without Sub PS 2 x 8 mm PDA 3 II B

Coarctation of Ao MS. severe

3 5 days IV with IS ma1 without Sub PS 5 x 7 mm PDA, small I II B Coarctation of Ao

4 1.5 mo IV with IS mal without PS 5 x 4 mm MS, severe I II B PDA, small

5 3 days Membranous 3 x 4 mm PDA. small 2 II B 6 26 day\ IV with IS mal without Sub PS 6 x 8 mm PDA, large 2 II B

Hemorrhages 7 26 h IV with IS mal with Sub PS and PVS DORV, MAt l-2 II A 8 7 week\ IV with IS mal without Sub PS 5 x 6 mm Mild mitral 2 II N

stenosis

*Graded by RVP; tgraded by RF. Ao = aorta; ext = extension; IS = infundibular septum; IV = infundibuloventricular; ma1 = malalignment; MAt = mitral atresia; MS = mitral stenosis: post = posterior; PS = pulmonary stenosis: PVS = pulmonary valve stenosis: VSD = ventricular septal defect; other abbreviations as in Table 1.

valves. What was very abnormal in the AV valves of the patients with trisomy-18, in addition to the consistency of their leaflets, was the relative dimensions of the leaflets, chordae tendineae and papillary muscles. There was an increase in the size of the leaflets and sometimes of the chordae tendineae, and a decrease in the size of the papillary muscles. The anterolateral papillary muscle of the mitral valve appeared to be the one most severely affected, in many cases being very small or completely absent (Fig. 4 and 5).

4. Mitral atresia, which occurred in four cases (lo%), was never associated with premature closure of the foramen ovale or endocardial fibroelastosis of the left atrium or left ventricle. In one case, the papillary muscles of the mitral valve could be distinguished on the free wall of the small left ventricle. In the other three cases, the leaflets and the tensor apparatus of the mitral valve were absent (Fig. 2B). It appeared that the process of differentiation of the mitral valve was either incomplete or had never occurred.

5. The association of double outlet right ventricle with all the cases of mitral atresia is noteworthy. In three of the four cases, there was a normal conotruncus, with only a subpulmonary conus and the aortic valve posterior, inferior and to the right of the pulmonary valve. Normal absorption of the subaortic conus allowed direct fibrous continuity between the aortic and tricuspid valves. It appeared that the double outlet right ventricle relation was the consequence of the mitral atresia and left ventricular underdevelopment, rather than resulting from a malformation of the infundibulum and the great arteries.

Only one case had a bilateral conus and, although the subaortic conus was very underdeveloped, the aortic valve was anterior and superior to the pulmonary valve (Fig. 2A).

To our knowledge, this case is the first and only documented case of trisomy-18 (or, in fact, of any trisomy) with a double outlet right ventricle and bilateral conus.

6. Visceral heterotaxy or any kind of visceral or cardiac inversion was not encountered in our series or found in reported cases (l-39,42-51). The same was true for transposition of the great arteries. Among the 2,829 cases in the Cardiac Registry of The Children’s Hospital in Boston, there is not a single case of trisomy-13, -18 or -21 associated with transposition of the great arteries or inversion of any of the viscera or cardiac segments.

Absence of transposition of the great arteries in trisomy-18. Transposition of the great arteries may be viewed as isolated “inversion” or reversal of the growth and resorption pattern of the conal region of the embryonic heart. Normally, the left side of the conus, which is subpulmonary in a d-loop, grows and moves anteriorly, while the right side of the conus (which is subaortic in d-loop hearts) undergoes “resorption” and the aortic valve moves posteriorly and inferiorly to the pulmonary valve and becomes connected to the mitral valve.

If this pattern of growth and resorption is “inverted,” then the right-sided (subaortic) part of the conus will grow and the left (subpulmonary) part will resorb. The aortic valve will be anterior and superior to the pulmonary valve and will be connected with the right ventricle, whereas the pulmonary valve will be inferior and posterior to the aortic valve and will be connected to the mitral valve and left ventricle. Typical complete transposition of the great arteries will be the resulting ventriculoarterial alignment (53). Because trisomy cases do not exhibit any kind of visceral or cardiac inversion, it should not be surprising that they also do not have transposition of the great arteries. The frequently


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quoted case of trisomy-18 with transposition of the great arteries (9) “did not show all the clinical signs of trisomy-18” and did not have a clear-cut karyotype of trisomy-18. The authors themselves had reservations about including this case in their series, and the cardiac malformations were not documented photographically.

In 1954, Hambach (54) described six cases of “mongolism with transposition of the great arteries.” Karel Khun, the successor of the deceased Hambach, found the clinical diagnosis of mongolism in only one of the reported cases. He thought that “the diagnosis of transposition of the great arteries according to the classification of Pernkopf and Wirtinger was correct,” but he could not confirm it by detailed descriptions or illustrations, and the heart specimens are no longer available for reexamination (personal communication). Hambach mentions the classification of Pernkopf and Wirtinger in the footnote of his table (54), but he does not give a reference. It should be pointed out that in earlier published reports, the dextroposed aorta of tetralogy of Fallot was considered to be a transposed aorta (55).

Other reports (56,57) included patients who did not have karyotype-proven trisomy. Tandon et al. (58,59) reported a case of isolated ventricular inversion in a patient with Down’s syndrome. Correspondence with one of the coau- thors (J.E.E.) disclosed a lack of karyotype documentation. Furthermore, reexamination of the heart specimen did not support the diagnosis /of ventricular inversion. Despite a careful search of the/published studies, we have not been able to find a documented case of transposition of the great arteries in a trisomic patient since the introduction of cyto- genie studies (60). The same is true for visceral or cardiac inversion.

Genetic factors in trisomy-18. After the study of 128 iv/iv mice embryos, Layton and Manasek (61) postulated that the high incidence of situs inversus, visceral heterotaxy and heart malformations may be due to the loss or absence of the genetic factor responsible for the development of the normal asymmetry between various asymmetric organs and even within an asymmetric organ such as the heart. Torgersen (55) noted a high incidence of twinning in patients with visceral heterotaxy and the presence of heterotaxy in only one of the monozygotic or conjoined twins.

In our ongoing study of visceral heterotaxy, we found 5 cases (9%) of twinning among the 53 cases of asplenia. Two twins were monozygotic, one was a conjoined twin, one twin was nonidentical and, in one, the type of twinning was not known. In all five cases, one twin had visceral heterotaxy with asplenia and the other twin was completely normal.

Could one postulate that the factor responsible for situs solitus was “taken” by the normal twin during the very first division of the fertilized egg? Could the lack of a consistent situs solitus in heterotaxic patients and the iv/iv mice represent the result of “genetic underdosage,” while the complete absence of heterotaxy or any inversion in trisomic patients is

the consequence of “genetic overdosage”? Current ad- vances in molecular genetics may find the answers to these questions.

Conclusion. The detailed analysis of the cardiac malformations of trisomy-18 presented in this report should facili- tate the diagnosis of this syndrome by two-dimensional echocardiography during fetal life and assist in the decision for elective abortion. Polyvalvular disease of a specific type in combination with a ventricular septal defect (usually large and associated with conal septal malalignment), complete situs solitus and absence of transposition of the great arteries represent very strong if not absolute criteria for the diagnosis of the trisomy-18 syndrome.

We thank Gloria Gaskill for typing, Michael Mantone for photography and Emily Flynn-McIntosh for artwork.

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