Extracardiac Anomalies Isomerism is a multiorgan issue As such, anatomic and functional anomalies may be found in nearly any organ system The number of organ systems, and the extent to which each system is impacted, is highly variable from patient to patient Central Nervous System A necroscopy study demonstrated anatomic central nervous system anomalies in nearly half of those with right isomerism, albeit none of the patients in this particular series with left isomerism had central nervous system anomalies.48 Studies in mice have also demonstrated that those with right isomerism show an isomeric arrangement of the synapses in the hippocampus Whereas in the normal situation synaptic arrangement differs in the two hemispheres of the hippocampus, these mice demonstrated right-sided synaptic arrangement in both hemispheres.71 Central nervous system anomalies that may be present include neural tube defects, corpus callosum abnormalities, various cranial deformities, and aqueductal stenosis.31,72–77 Hydrocephalus may also be noted in those with isomerism.78 The precise functional impacts of isomerism on the central nervous system have yet to be delineated While it is understood that those with congenital heart disease are at higher risk for developmental delay and behavioral issues, decreased executive functioning, and deficits in attention, whether there is an additive effect due to isomerism has yet to be determined.79,80 Pulmonary System From an anatomic standpoint, the pulmonary system is nearly always affected The most common anatomic anomaly in the pulmonary system in those with isomerism is isomeric arrangement of the bronchi and the lungs themselves As described earlier in this chapter, those with right isomerism will have short, eparterial bronchi bilaterally, while those with left isomerism will have long, hyparterial bronchi bilaterally Additionally, the tracheobronchial angle in those with left isomerism will generally be less than 135 degrees bilaterally while in those with right isomerism it will generally be greater than 135 degrees.68–70 There have also been three instances of a more unusual bronchial arrangement described in the literature In these cases there have been a total of four bronchi arising from the trachea directly In all these cases the trachea first gave rise to a pair of bronchi (one to the left and other to the right lung) that were isomeric in appearance but the trachea continued inferiorly to once again give rise to a pair of bronchi (one to the left and other to the right lung) that were also isomeric in appearance.48 The lungs themselves will also demonstrate isomerism in a majority of patients with isomerism Those with left isomerism will tend to have bilobed lungs bilaterally while those with right isomerism will tend to have trilobed lungs bilaterally.48,70 Functional issues have also been noted in the pulmonary system of those with isomerism While both those with right and left isomerism tend to have increased sinopulmonary issues compared to those without isomerism, those with left isomerism are more likely to have recurrent upper respiratory infections, require chronic pulmonology follow-up, and require home oxygen.81 Anecdotally, those with isomerism also appear to be more likely to have greater chest tube drainage and require longer periods of postoperative mechanical ventilation Cardiopulmonary exercise testing demonstrates the presence of both restrictive and obstructive lung disease in those with isomerism While the etiology of the restrictive component is likely repeat sternotomies, the etiology of the obstructive component has yet to be delineated Cardiopulmonary exercise testing also demonstrates that children and adolescents with isomerism do not tend to have impaired exercise tolerance although this may be due to a survival and selection bias as some “sicker” isomerism patients will die in infancy In addition, those with isomerism who do survive to an age appropriate for cardiopulmonary exercise testing may be deemed too ill to be evaluated by cardiopulmonary exercise testing.82 Those with isomerism are also more prone to pulmonary vascular disease and pulmonary hypertension than those without isomerism While objective data have not been published to document this in children, such data have been documented in adults with isomerism Isomerism in adults independently increased the odds of pulmonary vascular disease or pulmonary hypertension by 80% As the mechanism of this increase is not clear at this point, it is also not possible to comment on specific therapeutic interventions in this specific patient population.83,84 Gastrointestinal System As discussed previously in this chapter, abnormal lateralization of the abdominal organs is commonly noted in isomerism While this is most readily apparent in the position of the stomach and liver, it must be kept in mind that the gallbladder, pancreas, and spleen are also frequently affected.48 When describing the laterality of the abdominal organs, the term “situs ambiguous” is not a helpful term There is, in fact, nothing ambiguous about the location of the organs The sidedness of each organ should be described explicitly Other gastrointestinal anomalies that may occur in the setting of isomerism include tracheoesophageal fistula, congenital diaphragmatic hernia, omphalocele, biliary atresia, duodenal atresia, pancreatic agenesis, anal atresia, and Abernethy malformation.48,85–87 Each one of those anomalies is noted in less than 10% of isomerism patients when studied individually In the setting of isomerism, the intestines are also often abnormally lateralized What is unique to the intestine compared to the other abdominal organs is that the intestines will remain present in both halves of the abdomen, but the rotation will be abnormal Indeed, a form of intestinal malrotation may be the entire absence of rotation to begin with In this effect, there is a spectrum of intestinal malrotation that may be present in the children with and without isomerism Some form of intestinal malrotation is present in a majority of patients, with studies demonstrating a frequency of 33% to 90% depending on the specific evaluation done.88,89 What is unique to those with isomerism, however, is the greater frequency of rotational anomalies without a particularly increased risk of volvulus Those with isomerism and intestinal malrotation have approximately a 1% frequency of volvulus.89–92 Those with the duodenojejunal junction on the contralateral side as the stomach, resulting in a narrow mesentery, are more likely to experience volvulus Many centers will evaluate all isomerism patients for intestinal malrotation via upper gastrointestinal studies In some of these centers, those found to have any anomaly of intestinal rotation will undergo a prophylactic Ladd procedure Upper gastrointestinal studies will require some critically ill infants to be transported to radiology suites, tasks that can be labor intensive and high risk In addition, these procedures are associated with an additional cost Furthermore, asymptomatic patients who are found to have intestinal malrotation may undergo a prophylactic Ladd procedure, incurring more cost and risk This raises the question of whether all infants with isomerism should be