FIG 26.19 Production of isomeric atrial appendages by genetic manipulation of developing mice The top panel, which shows unequivocally right atrial appendages bilaterally as revealed by scanning electron microscopy, was produced by knocking out the Pitx2 gene The bottom panel shows a frontal histologic section from a mouse in which Lefty-1 was knocked out, producing isomeric left atrial appendages and a common atrioventricular (AV) junction (Bottom panel, Courtesy Professor C Meno, Kyushu University, Japan.) Isomerism and Conjoined Twinning There is a fascinating association between conjoined twins and disruption of normal left-right asymmetry Complex cardiac malformations and absence of the spleen in one of the twins have been well described.27,30–32 The most complex cardiac anomalies are usually, but not always, observed in the right-hand twin (see Chapter 48) Features of left isomerism, in contrast, are rarely observed Morphogenesis Most early studies of the development of the “splenic syndromes” concentrated their attention upon the spleen.3,9 While of undoubted value in terms of knowledge of splenic development, this approach did little to clarify the grossly abnormal cardiac development associated with isomerism Here, as with the analysis of the heart itself, the significant feature is the isomeric nature of the atrial appendages The significant point from the stance of development is that the apical parts of the ventricles, which confer morphologic rightness or leftness, balloon in series from the inlet and outlet parts of the ventricular component of the primary heart tube, while the atrial appendages balloon in parallel from the atrial component (see Chapter 3) Therefore it is not surprising that the isomeric malformation should produce duplication of the atrial appendages without producing symmetry of the ventricles The venous malformations are equally well explained With bilateral morphologically right atrial appendages, there will be no focus for incorporation of the pulmonary venous component In normal development, this occurs by lumenization of the pulmonary vein in the developing dorsal mesocardial connection between the heart tube and the body (see Chapter 3) These connections are grossly abnormal when both appendages develop with right morphology Therefore the intrapulmonary venous plexuses developing in the mediastinum will join up with suitable systemic channels to form totally anomalous connections, or else will connect directly but anomalously to the roof of the atrial chambers Persistence of the initial bilateral symmetry of the systemic venous tributaries accounts for the usual finding of bilateral superior caval veins and absence of the coronary sinus The bilateral formation of the terminal crests accounts for the development of bilateral sinus nodes Since the inferior caval vein is able to drain in normal fashion to the atrial chamber, the hepatic veins will also develop normally When both the atrial appendages develop morphologically left characteristics, the pulmonary venous channels can be incorporated into either side of the atrium, accounting for the common finding of bilateral pulmonary venous connections Because the terminal crest develops from the morphologically right side, the superior caval venous channels will never drain in normal fashion in hearts with left isomerism, and there will be no potential for formation of a normal sinus node Since the ventricles develop in series, they can form in any fashion as occurs in malformations without isomerism This is reflected in the