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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 (visceral or cardiac), findings that appear to be character-
cases of trisomy-18 are presented in detail. The salient istic of all trisomies.
findings were a ventricular septal defect in all cases; These data suggest that excessive chromosomal material
tricuspid valve anomalies in 33 cases (80%); pulmonary (as in trisomies) may result in situs solitus at all levels. The
valve anomalies in 30 (70%); aortic valve malformations in malformations of the atrioventricular and semilunar valves
28 (68%); mitral valve anomalies in 27 (66%); polyvalvular were characterized by redundant or thick myxomatous
disease (that is, malformations of more than one valve) in leaflets, long chordae tendineae and hypoplastic or absent
38 (93%); a subpulmonary infundibulum (conus) in 40 papillary muscles. The ventricular septal defect was asso-
(98%); a bilateral conus with a short subaortic infundibu- ciated with anterosuperior conal septal malalignment in 25
lum in 1 case with double outlet right ventricle (this being cases (61%). On the basis of the characteristic valvular
the only documented case of bilateral infundibulum in lesions, the type of ventricular septal defect and the absence
trisomy-18); double outlet right ventricle in 4 cases (lo%), of transposition or inversions, two-dimensional echocardio-
three having a subpulmonary infundibulum only and all 4 graphic diagnosis of trisomy-18 in the fetus may become
having mitral atresia; tetralogy of Fallot in 6 cases(15%), possible.
2 having pulmonary atresia; and a striking absence of (J Am Co11Cardiol1989;13:1586-97)
transposition of the great arteries and inversion at any level

Infants with trisomy-18 have severe mental retardation with itate the noninvasive prenatal and postnatal diagnosis of
anomalies of the nervous, cardiovascular, gastrointestinal, trisomy-18 by two-dimensional echocardiography and nu-
genitourinary and musculoskeletal systems (l-36), and sur- clear magnetic resonance imaging. Moreover, we questioned
vival beyond 1 year of age is rare (21). Even if their heart the nature of the relation between trisomy-18 and the kinds
defects were successfully repaired, the prognosis would not of congenital heart disease that these patients have and do
be greatly altered. not have. For example, it has been observed that individuals
Hence, this study of the congenital heart defects of with Downs syndrome (trisomy-21) do not have transposi-
trisomy-18 was undertaken not for therapeutic reasons, but tion of the great arteries (37-42) or visceral or cardiac
rather in the hope of improving understanding of these inversions (42). Do patients with trisomy-18 also lack these
cardiac anomalies. Such improved understanding may facil- conditions? If so, what does this absence of transposition
and inversion in trisomies signify?

From the *Departments of Cardiology and Pathology, The Childrens


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, Methods
Nebraska. This study was supported in part by a grant from the Riley Fund,
Autopsy cases. This study is based on 41 autopsy cases of
Boston. It was presented in part at the Second World Congress of Pediatric
Cardiology, New York, New York, June 2 to 6, 1985. trisomy-18, all karyotype proven-the largest study of this
Manuscript received October 5, 1988:revised manuscript received De- condition reported to date. Of these 41 cases, 31 were from
cember 7, 1988,accepted December 15, 1988.
Address for renrints: Stella Van Praagh, MD, Department of Cardiology, the Cardiac Registry of The Childrens Hospital, Boston and
The Childrens Hospital, Boston, Massachusetts 02115. 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 : 1. The heart of this 26 h old female infant (Case 7, Table 2) is above the right ventricle (that is, double outlet right ventric:le is
an ex:imple of double outlet right ventricle with only subpulmonary present). The tricuspid valve (TV) has very redundant leaflets, very
conus and with mitral atresia (MAt). A, Right ventricular view. The few interchordal spaces and very small papillary muscles. The
infuna libular septum (IS) is slightly underdeveloped. malaligned and superior commissure (SC) of the tricuspid valve is unuslually
forms a long arch over the septal band (SB), ending on the free wall cephalad. The pulmonary valve (PV) is bicuspid and stenotic. F:A =
of the right ventricle (RV). The ventricular septal defect (VSD) is right atrium. B, Left atrial view. The mitral valve orifice is at
ed by the infundibular septum (IS) above and the septal band (MAt). The pulmonary veins (PV) drain normally into the left
below The aortic outflow (Ao out) and the aortic valve (Ao) are atrium (LA).
1588 VAN PRAAGH ET AL. JACC Vol. 13, No. 7
CARDIAC MALFORMATIONS IN TRISOMY-18 June 1989: 158697

Hospital, Cornell University Medical Center. Of the latter 10 long). The mitral valve was also atretic and the left ventricle
cases, 4 were previously reported (30). very small in this case. Typical transposition of the great
All heart specimens were examined by us, particular arteries with subaortic infundibulum and pulmonary-mitral
attention being focused on the anatomic types of ventricular fibrous continuity did not occur in this series.
septal defect, the anomalies of the atrioventricular (AV) and Atria1septum. The septum primum (that is, the valve of
semilunar valves and the anatomic variations of the infun- the foramen ovale) was redundant in 21 cases (51%) (Table
dibulum (conus). In 25 of the 41 cases, the pulmonary 1). Single or multiple atria1 septal defects of the secundum
vascular bed was studied by the methods of Wagenvoort et type were found in nine (22%).
al. (43) and Rabinovitch and Reid (44). Ventricular septum. A ventricular septal defect was
Gender. There were 23 female and 17 male infants (ratio present in all cases. Several different anatomic types of
1.4:1). ventricular septal defect were found (Table 1).
Age at death. The median age was 2 days (range stillborn 1. A membranous ventricular septal defect was observed
to 2.5 years). in nine cases (22%). The diagnosis of membranous ventric-
ular septal defect indicates that only the membranous sep-
tum is deficient (Fig. 3). A membranous defect typically is
Results small (that in Fig. 3A is 3 x 4 mm). The designation
Heart position. Levocardia (left-sided heart) was present membranous ventricular septal defect connotes that the
in 37 cases (90%). Mesocardia (midline heart), but with the infundibular septum is normally formed, being neither hypo-
ventricular apex formed by the left ventricle and pointing plastic nor malaligned. This diagnosis also implies that the
leftward, was present in four cases (10%). Dextrocardia aortic valve is not dextroposed because dextroposition of the
(right-sided heart) was found in none. aortic valve is associated with infundibular septal malalign-
Visceroatrialsitus solitus. This was present in all cases. ment, as in tetralogy of Fallot. In Figure 3A, the infundibular
The spleen was left-sided and normally formed in all. One septum is normally developed and joins the ventricular
small accessory spleen was present in the infant with double septum and septal band in a normal fashion. From the left
outlet right ventricle and bilateral conus. ventricular view (Fig. 3B), the mitral valve is in direct
Systemicand pulmonaryveins. These were normally con- fibrous continuity with the left coronary and noncoronary
nected in all. cusps (that is, normal).
Ventricularsitus. A situs solitus or d-loop ventricle was The membranous ventricular septal defect extended
present in all cases (that is, right-sided and noninverted right somewhat posteriorly-behind the septal leaflet of the tri-
ventricular inflow and left-sided and noninverted left ventri- cuspid valve-in an additional six cases (15%) (Table 1). The
cle). presence of a posterior extension resulted in a large mem-
Infundibulum. Solitus muscular subpulmonary infundib- branous ventricular septal defect in these cases. Hence,
ulum was present in 40 cases (98%), with aortic-mitral membranous ventricular septal defect, with and without
fibrous continuity in 40 (98%). Bilateral infundibulum (sub- posterior extension, was present in 15 cases (37%).
aortic and subpulmonary) was found in one case (2%) with 2. Infundibular septal malalignment without infundibular
double outlet right ventricle and mitral atresia; this is the hypoplasia (that is, the Eisenmenger complex) was present
only known documented case of a bilateral infundibulum in in 16 cases (39%) (Table 1). An infundibuloventricular type
association with trisomy- 18. of defect denotes that the ventricular septal defect lies
Atrioventricular alignments. These were concordant in between the infundibular septum above and the ventricular
all. septum and septal band below. This malalignment type of
Ventriculoarterial alignments. These were concordant, ventricular septal defect is large, as the left ventricular view
with solitus normally related great arteries in 37 cases (90%). makes clear (compare Fig. 3B and 4).
There was a double outlet right ventricle in four cases (10%). The infundibuloventricular type of ventricular septal de-
In three of the four latter cases, only a subpulmonary conus fect also occurred with anterior infundibular septal malalign-
was present (that is, normal solitus conal development) and ment and infundibular septal hypoplasia, but without pul-
the aortic valve was in direct fibrous continuity with the monary outflow tract stenosis (Fig. 5A). The anterior and
tricuspid valve. The mitral valve was atretic and the left leftward position of the infundibular septum is associated
ventricle very hypoplastic in all these three cases (Fig. 1). with dextroposition of the aortic valve (Fig. 4 and 5B). The
The position of the aorta above the right ventricle was mitral valve is in direct continuity only with the left coronary
apparently due not to an abnormal conotruncus, but to cusp, instead of with half of the noncoronary and half of the
underdevelopment of the left ventricle and mitral valve left coronary cusp, which is the normal aortic to mitral
atresia. In only one case of double outlet right ventricle was fibrous continuity.
a bilateral conus present (Fig. 2). The subaortic component 3. A ventricular septal defect with hypoplasia and mal-
of the bilateral conus was very poorly developed (2 to 3 mm alignment of the infundibular septum as well as the free wall
JACC Vol. 13, No. 7 VAN PRAAGH ET AL. 1589
June 1989: 1586-97 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 bilat-
eral but underdeveloped infundibulum.
It has a left aortic arch and bilateral
patent ductus arteriosus. A, Right ven-
tricular view. The papillary muscles of
the tricuspid valve (TV) are very hypo-
plastic and the leaflets are redundant.
The aortic valve (AoV) is anterior to
the pulmonary vein (PV). The infundib-
ular septum (IS) is very underdevel-
oped 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 ar-
tery 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
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CARDIAC MALFORMATIONS IN TRISOMY-18 June 1989: 1586-97

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


Cardiac Region Malformation n %
Atria1septum Redundant septum primum 21 51
Single or multiple secundum atrial septal defects 9 22
Ventricular septum Membranous septal defect, small 9 22
Membranous with posterior extension, large 6 IS
lnfundibuloventricular septal defect with IS malalignment, but without infundibular hypoplasia or PS I6
Infundibuloventricular septal defect with IS and infundibular free wall hypoplasia and sub 61
PS (tetralogy of Fallot and DORV) 9>
AV canal type subdivided by muscular bridge I 2
Additional mid-muscular, very small 2 5
Tricuspid valve Redundant leaflets, long chordae and small papillary muscles 33 80
Mitral valve Redundant leaflets, decreased interchordal spaces, hypoplastic or absent papillary muscles 21
Cleft anterior leaflet 2
Atretic 4
Total 27 66
Pulmonary valve Bicommissural IO
Bicommissural and redundant 9
Bicommissural and stenotic 6
Tricommissural and redundant 3
Atretic 2
Total 30 73
Aortic valve Bicommissural I5
Bicommissural and redundant (two with prolapsed RCC) 8
Tricommissural and redundant (one with prolapsed RCC) 3
Unequal cusp size
Unicommissural and redundant 1
Total 28 68
Coronary arteries High left coronary orifice 4
Single CO in LCC; the right CA coursed in front of the MPA before reaching the right AV groove 2
Left circumflex from RCO
Total 1 17
Aortic arch and isthmus Coarctation of Ao or isthmic hypoplasia with PDA 11 21
Common brachiocephalic trunk 4 10
Bilateral PDA and isolation of right subclavian I 2
Valvular involvement Two valves 13 32
Three valves 11 27
Four valves 14 34
Total 38 93

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 6). The deformities of the tricuspid valve were often com-
bicuspid and, in one case a stenotic, pulmonary valve (Fig. patible with tricuspid regurgitation. There were no deformi-
1A). ties indicative of tricuspid stenosis, and we never encoun-
4. Ventricular septal defect in the area of the AV canal tered a case of tricuspid atresia.
septum occurred in the very rare case of double outlet right The pulmonary valve was the second most frequently
ventricle and bilateral conus. This defect was subdivided by malformed valve (30 cases [73%]01).It was bicommissural in
a muscular bridge (Fig. 2). The vascular malformations of 25 cases (61%), with redundant or thickened leaflets result-
this rare case are described in the legend to Figure 2. ing in pulmonary stenosis (Fig. IA). In two cases of tetralogy
Valvular anomalies (Table 1). The tricuspid valve was the of Fallot, pulmonary valve atresia was present (Fig. 6).
most frequently abnormal valve (38 cases [80%]). Its leaflets The aortic valve was the third most frequently malformed
were usually long and redundant (Fig. 1A and 6) or very valve (28 cases [68%]). Bicuspid (that is, bicommissural)
thick and myxomatous (Fig. SA). The chordae tendineae aortic valve was the most common aortic valve abnormality
were longer than normal (Fig. 6) and contrasted with the (Fig. 3B). Often, it was bicommissural and redundant or
papillary muscles, which were very hypoplastic (Fig. 5A and tricommissural and redundant (Fig. 4). In three cases, there
JACC Vol. 13, No. i VAN PRAAGH ET AL. 1591
June 1989: 1586-97 CARDIAC MALFORMATIONS IN TRISOMY-18

Figure 3. The heart of this 1 day old


male infant exemplifies a small mem-
branous ventricular septal defect. A,
Right ventricular view. The tricuspid
valve (TV) has redundant leaflets,
long chordae tendineae and very hy-
poplastic papillary muscles. The in-
fundibular septum (IS) is normally
developed and joins the septal band
(SB) in a normal fashion. The pulmo-
nary 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 cor-
onary (RC) and noncoronary (NC)
cusps of the aortic valve are in com-
mon because of a very underdevel-
oped 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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CARDIAC MALFORMATIONS IN TRISOMY-18 June 1989:1586-97

Figure 4. The heart of this 26 day old


male infant (Case 6, Table 2) repre-
sents an example of an infundibuloven-
tricular ventricular septal defect (VSD)
with infundibular septum malalign-
ment, but not hypoplasia and without
pulmonary stenosis. On the left ven-
tricular 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 re-
dundant, with a lacelike appearance.
The aortic valve (Ao) is bicuspid. The
noncoronary (NC) to right coronary
cusp commissure is extremely under-
developed. The left coronary (LC)
cusp only is continuous with the mitral
valve. The tricuspid valve (TV) is con-
tinuous 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 Pulmonary vascular obstructive disease (Table 2). Signifi-
regurgitation. We did not encounter any case with evidence cant hypertrophy of the media and intimal proliferation were
of aortic valve stenosis. Yet in two of the three cases of observed in 8 (32%) of the 25 cases in which lung histology
double outlet right ventricle with only subpulmonary conus was studied. Five of these cases had an infundibuloventri-
and in the rare case with a bilateral conus (Fig. 2A), there cular type of ventricular septal defect with anterosuperior
appeared to be some subaortic obstruction due to the posi- malalignment of the infundibular septum, but without pul-
tion of the aortic valve between the infundibular septum and monary outflow obstruction. One case had a large membra-
the tricuspid valve (Fig. 1A) or to the poorly expanded nous ventricular septal defect with posterior extension and a
subaortic infundibulum (Fig. 2A). ductus arteriosus patent at the age of 7 months. One infant
The mitral valve showed the lowest frequency of malfor- with a double outlet right ventricle had subpulmonary and
mations (27 cases [66%]). The abnormalities involved the pulmonary valve stenosis; despite the presence of pulmo-
leaflets, which were redundant and lacy in appearance, the nary outflow tract obstruction, pulmonary hypertension was
interchordal spaces, which were often decreased, or the probably present as a result of the coexistence of mitral
papillary muscles, which were very underdeveloped or ab- atresia.
sent (Fig. 4 and SB). In only two cases was a cleft mitral Six of these eight infants were under the age of 2 months
valve encountered (Table 1). In contrast to the malforma- and none was older than 7 months. Hence, these cases with
tions of the tricuspid valve, which were compatible with the Eisenmenger type of ventricular septal defect (anterosu-
tricuspid regurgitation, the malformations of the mitral valve perior deviation of the infundibular septum, but without
often resulted in mitral stenosis (Fig. 4 and 5B). Also, pulmonary outflow tract stenosis) were associated with
although there was not a single case of tricuspid atresia, unusually early development of pulmonary vascular obstruc-
there were four cases of mitral atresia, all associated with a tive disease. It is also possible that patients with trisomy-18
double outlet right ventricle. may be predisposed to develop pulmonary vascular obstruc-
Polyvalvular disease. In 38 cases (93%), two or more tive changes earlier than are eukaryotypic infants with
valves were abnormal, and in 14 cases (34%), all four valves ventricular septal defect (45).
were malformed (Table 1).
Other associated malformations (Table 1). These included
coarctation of the aorta, large patent ductus arteriosus, a Discussion
common brachiocephalic trunk and minor abnormalities of Previous studies. After the almost simultaneous discov-
the position of the coronary ostia. ery of the trisomy-18 syndrome by Edwards (1) and Patau (2)
JACC Vol. 13, No. 7 VAN PRAAGH ET AL. 1593
June 1989: 1586-97 CARDIAC MALFORMATIONS IN TRISOMY-18

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 infundib-
ular septum malalignment and hypo-
plasia, but without pulmonary steno-
sis. A, Right ventricular view. The
tricuspid valve (TV) has redundant
leaflets with thickened edges and hypo-
plastic papillary muscles. The infundib-
ular septum (IS) is very short, mala-
ligned and joins the superior limb-
instead of the bifurcation-of the sep-
tal band (SB). There is normal devel-
opment of the free wall of the subpul-
monary infundibulum and a large main
pulmonary artery (MPA). The large
ventricular septal defect (VSD)is out-
lined by the infundibularseptum supe-
riorly, the septal band inferiorly and
the tricuspid valve posteriorly. The
coronary sinus (CoS) orifice is seen
above the tricuspid valve. B, Left ven-
tricular view. The mitral valve (MV)
has very abnormal myxomatous leaf-
lets. The papillary muscles are very
hypoplastic. The anterior leaflet at-
taches directly on the septum in a fash-
ion similar to the one observed in com-
mon 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 underdevel-
oped, 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 ventri-
cle; 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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CARDIAC MALFORMATIONS IN TRISOMY-18 June 1989: 1586-97

Figure 6. The heart of this 36 h old male infant


shows a malaligned and hypoplastic infundibu-
lar septum (IS) and atresia of the pulmonary
valve (PAt), (that is, tetralogy of Fallot with
pulmonary atresia [PAt]). The hypoplastic in-
fundibular septum is not fused with the infun-
dibular 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 papil-
lary muscles. Other abbreviations as before.

(30,51) and the striking polyvalvular involvement was em- 3. Malformations of the AV valves were more extensive
phasized (46,47). and more pronounced than were those of the semilunar
Conclusions from the present series. The 41 heart speci- valves. The leaflets and chordae tendineae tended to be
mens in this series (personally examined and described in redundant and longer than normal, while the papillary mus-
detail) provide the material basis for the following conclu- cles were hypoplastic or absent. Because the development of
sions. the AV valves is intimately related to that of the ventricular
1. The most frequent type of ventricular septal defect (25 myocardium (52), one may infer that the normal process of
cases [61%]) was located between the infundibular (conal) differentiation of the mitral and tricuspid valves and their
septum above and the septal band and ventricular septum tensor apparatus from the AV endocardial cushions and the
below (conoventricular or infundibuloventricular) and was ventricular myocardium is interfered with in trisomy-18. It
associated with superoanterior displacement (malalignment) has been shown histologically that the AV valves of patients
of the infundibular septum. Underdevelopment of the free with trisomy-18 are similar to those of the fetus (47). Hence,
wall of the infundibulum and the pulmonary valve resulted in the abnormal appearance of the valves has been thought to
pulmonary outflow stenosis in the six cases of tetralogy of be due to an arrest of the process of leaflet maturation (47).
Fallot (two with pulmonary atresia) and in the three cases of However, the pathologic features of the AV valves we
double outlet right ventricle with only a subpulmonary encountered in this series (Fig. 1 to 6) appear to reflect more
conus. than leaflet immaturity. Human fetal AV valves may differ
2. Two or more ofthe valves ofthe heart were malformed histologically from normal neonatal valves, but their general
in 38 cases (93%) in this series. gross configuration is very similar to that of normal neonatal
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Table2. AbnormalPulmonaryHistologicFindingsin 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 ma1and hypoplasia without Sub PS 2 x 8 mm PDA 3 II B
Coarctation of Ao
MS. severe
3 5 days IV with IS ma1without 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 abbrevi-
ations as in Table 1.

valves. What was very abnormal in the AV valves of the To our knowledge, this case is the first and only documented
patients with trisomy-18, in addition to the consistency of case of trisomy-18 (or, in fact, of any trisomy) with a double
their leaflets, was the relative dimensions of the leaflets, outlet right ventricle and bilateral conus.
chordae tendineae and papillary muscles. There was an 6. Visceral heterotaxy or any kind of visceral or cardiac
increase in the size of the leaflets and sometimes of the inversion was not encountered in our series or found in
chordae tendineae, and a decrease in the size of the papillary reported cases (l-39,42-51). The same was true for transpo-
muscles. The anterolateral papillary muscle of the mitral sition of the great arteries. Among the 2,829 cases in the
valve appeared to be the one most severely affected, in many Cardiac Registry of The Childrens Hospital in Boston, there
cases being very small or completely absent (Fig. 4 and 5). is not a single case of trisomy-13, -18 or -21 associated with
4. Mitral atresia, which occurred in four cases (lo%), was transposition of the great arteries or inversion of any of the
never associated with premature closure of the foramen viscera or cardiac segments.
ovale or endocardial fibroelastosis of the left atrium or left Absenceof transpositionof the great arteriesin trisomy-18.
ventricle. In one case, the papillary muscles of the mitral Transposition of the great arteries may be viewed as isolated
valve could be distinguished on the free wall of the small left inversion or reversal of the growth and resorption pattern
ventricle. In the other three cases, the leaflets and the tensor of the conal region of the embryonic heart. Normally, the left
apparatus of the mitral valve were absent (Fig. 2B). It side of the conus, which is subpulmonary in a d-loop, grows
appeared that the process of differentiation of the mitral and moves anteriorly, while the right side of the conus
valve was either incomplete or had never occurred. (which is subaortic in d-loop hearts) undergoes resorption
5. The association of double outlet right ventricle with all and the aortic valve moves posteriorly and inferiorly to the
the cases of mitral atresia is noteworthy. In three of the four pulmonary valve and becomes connected to the mitral valve.
cases, there was a normal conotruncus, with only a subpul- If this pattern of growth and resorption is inverted,
monary conus and the aortic valve posterior, inferior and to then the right-sided (subaortic) part of the conus will grow
the right of the pulmonary valve. Normal absorption of the and the left (subpulmonary) part will resorb. The aortic valve
subaortic conus allowed direct fibrous continuity between will be anterior and superior to the pulmonary valve and will
the aortic and tricuspid valves. It appeared that the double be connected with the right ventricle, whereas the pulmo-
outlet right ventricle relation was the consequence of the nary valve will be inferior and posterior to the aortic valve
mitral atresia and left ventricular underdevelopment, rather and will be connected to the mitral valve and left ventricle.
than resulting from a malformation of the infundibulum and Typical complete transposition of the great arteries will be
the great arteries. the resulting ventriculoarterial alignment (53). Because tri-
Only one case had a bilateral conus and, although the somy cases do not exhibit any kind of visceral or cardiac
subaortic conus was very underdeveloped, the aortic valve inversion, it should not be surprising that they also do not
was anterior and superior to the pulmonary valve (Fig. 2A). have transposition of the great arteries. The frequently
1596 VAN PRAAGH ET AL. JACC Vol. 13, No. 7
CARDIAC MALFORMATIONS IN TRISOMY-18 June 1989:158&97

quoted case of trisomy-18 with transposition of the great the consequence of genetic overdosage? Current ad-
arteries (9) did not show all the clinical signs of trisomy-18 vances in molecular genetics may find the answers to these
and did not have a clear-cut karyotype of trisomy-18. The questions.
authors themselves had reservations about including this Conclusion. The detailed analysis of the cardiac malfor-
case in their series, and the cardiac malformations were not mations of trisomy-18 presented in this report should facili-
documented photographically. tate the diagnosis of this syndrome by two-dimensional
In 1954, Hambach (54) described six cases of mongolism echocardiography during fetal life and assist in the decision
with transposition of the great arteries. Karel Khun, the for elective abortion. Polyvalvular disease of a specific type
successor of the deceased Hambach, found the clinical in combination with a ventricular septal defect (usually large
diagnosis of mongolism in only one of the reported cases. He and associated with conal septal malalignment), complete
thought that the diagnosis of transposition of the great situs solitus and absence of transposition of the great arteries
arteries according to the classification of Pernkopf and represent very strong if not absolute criteria for the diagnosis
Wirtinger was correct, but he could not confirm it by of the trisomy-18 syndrome.
detailed descriptions or illustrations, and the heart speci-
mens are no longer available for reexamination (personal We thank Gloria Gaskill for typing, Michael Mantone for photography and
communication). Hambach mentions the classification of Emily Flynn-McIntosh for artwork.
Pernkopf and Wirtinger in the footnote of his table (54), but
he does not give a reference. It should be pointed out that in 1. Edwards JH, Hamden DG, Cameron AH, Crosse MV, Wolff OH. A new
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