Imaging Considerations Because of the vast number of anatomic anomalies that may be present in the setting of isomerism, imaging becomes of great importance Those involved with imaging patients with isomerism must be aware of the various manifestations of isomerism and should be thorough in their interpretation of any acquired images Terminology must be selected carefully, and terms such as “situs ambiguous” should be avoided, with findings explicitly described.48,85,114–116 Fetal magnetic resonance imaging is able to demonstrate many of these anomalies While this is not routinely indicated, those who undergo fetal imaging should have these images reviewed with attention paid to all organ systems to find associated anomalies.85,117,118 Cardiac imaging is of obvious importance Echocardiography is the cornerstone of such imaging, but may be limited in some regard, particularly in imaging the atrial appendages The rest of the cardiac anatomy is well demonstrated by echocardiography Computed tomography and magnetic resonance imaging may also be used and can be helpful in delineating the morphology of the atrial appendages, particularly the venous anatomy.119 In the event that the atrial appendages cannot be imaged well, an aggregate of anatomic anomalies can help segregate isomerism into its subsets The presence of an interrupted aortic arch, biventricular circulation, and the presence of a coronary sinus are more frequent in left isomerism, whereas supracardiac or infracardiac total anomalous pulmonary venous connection, functionally univentricular circulation, and pulmonary outflow tract obstruction are more frequent in right isomerism.120 Ciliary Dysfunction Cilia are hair-like organelles, sensory or motile, that are present on nearly every cell in the human body, with at least a single sensory cilium being presented on each cell These sensory cilia are important in cell-cell signaling Motile cilia are found in the epithelial cell lining of the respiratory tract and the reproductive system Motile cilia are responsible for moving fluids and particles in the body Cilia have been found to be involved in lateralization of organs, vision, hearing, taste, production and clearance of cerebrospinal fluid, movement of particles, and immune response Abnormalities in cilia, or ciliary dysfunction, can thus have a variety of consequences Ciliary dysfunction has been noted in up to 40% of those with isomerism, with those with ciliary dysfunction having increased sinopulmonary disease Those with mutations in known ciliary genes seem to have worse clinical phenotypes.121–123 Investigations into ciliary function in those with isomerism are still in their infancy, but it appears that ciliary dysfunction may be a mechanism of increased morbidity and mortality in those with isomerism Studies in animal models of ciliary dysfunction with normal ciliary ultrastructure have demonstrated that function can be restored to some extent in these patients Ciliary dysfunction in those with isomerism, nonetheless, is not synonymous with what is seen in those with primary ciliary dyskinesia The ultrastructure of the cilia, as demonstrated by electron microscopy, is often normal in those with isomerism Rather, the density of cilia, the beat frequency of the cilia, and the beat synchronization are abnormal Thus simple electron microscopy does not rule out ciliary dysfunction in those with isomerism Video microscopy on nasal epithelium obtained via nasal swab can allow for quantification of ciliary function Exhaled nitric oxide may also be a surrogate marker of ciliary function, with those who have ciliary dysfunction having lower exhaled nitric oxide levels.121 The importance of cilia in those with isomerism goes beyond just postnatal life Ciliary dysfunction likely has mechanistic implications in isomerism Cilia are responsible for producing a leftward flow of extraembryonic fluid that impacts organ lateralization by distribution of growth factors and proteins In addition, sensory aberration, particularly secondary to abnormal calcium signaling, may also provide another mechanism to how nodal cilia underpin isomerism.124–127 Much has now been learned concerning the genetic pathways producing these changes, with experiments confirming the reality of isomerism of the atrial appendages Thus it is known that cilia in the primitive node create a wave that drives molecules in one specific direction across the cells of the developing embryo, with expression of the gene Nodal mostly confined to the left side The wave of molecular material produced from the node, which influences development of lateralized features, is stopped from crossing the midline of the embryo by a process known to be under the influence of the gene Sonic hedgehog Because of this midline barrier, other genes, such as Lefty, and Pitx2, along with the gene Cited2, also known to be part of the genetic cascade, have their expression confined to the left side of the body, thus producing the morphologically left characteristic This is why knocking out genes such as Pitx2 or Cited2 in mice produces animals with unequivocal right isomerism (Fig 26.19, top), while knocking out Lefty-1 permits the left-forming genes to occupy the right side of the body, thus producing left isomerism (see Fig 26.19B, right).9,128