history of malformations and maternal cocaine use, suggesting both genetic and environmental factors play a role. Several genes in the TGF-beta pathway, which controls left-right patterning of visceral organs across the body axis, have been indicated in sporadic and familial cases of atrial isomerism. There is also overlap between genes associated with situs ambiguus and primary ciliary dyskinesia, likely due to the important role of cilia in establishing left-right asymmetry. The planar cell polarity has an important role in positioning these cilia, and thus genes within this pathway are increasingly associated with situs ambiguus. Disrupted mitochondria function has also been recently linked to heterotaxy. Pathophysiology Molecular and cellular mechanism Several genes have been identified in normal development of the right-left axis. These genes have been extensively researched. Gene mutations that lead to atrial isomerism is a growing area of research. Mutations in genes that encode proteins in the TGF-beta pathway, including NODAL, NKX2-5, and ZIC3, have been linked to tetralogy of Fallot and hypoplastic left heart syndrome. Mutations in the ZIC3 gene, which encodes a zinc finger family transcription factor, is linked to a 50% risk of atrial isomerism in families. It is also an X-linked disorder, so testing for ZIC3 mutations is highly encouraged in male births. The most prevalent and best characterized genetic associations of heterotaxy include: Classical pathology Cardiac looping malformations: Fallot's tetralogy transposition of the great vessels Ventricular and atrial septal defects. Deranged abdominal organ asymmetry: The stomach and spleen are prone to isolated reversal The stomach, liver, and a single adrenal gland are occasionally found in the midline. Organ malformations: asplenia and polysplenia often lead to sepsis More rarely, the head of the pancreas fails to form Horseshoe kidneys develop, which can lead to cancer, kidney stones, and/or infection. Malrotation errors cause volvulus and/or faulty peritoneal attachments, which completely obstruct the bowel. Vascular abnormalities: Interrupted inferior vena cava, Bilateral superior or inferior venae cavae Intrahepatic interruption of the inferior vena cava with connection to the azygos or hemiazygos veins Aberrant portal veins. Bronchial tree and lungs Pathophysiology in the bronchial tree can be observed by radiography. Under normal development, the bronchial tree consists of two main bronchi that are anatomically different: Hyparterial bronchus (below the pulmonary artery): supplies blood to the bi-lobed left lung Eparterial bronchus (adjacent to the artery): supplies blood to the tri-lobed right lung In situs ambiguus, there is a duplication of