Situs ambiguus

There are a variety of clinical manifestations of situs ambiguus. Acute symptoms can be due to both cardiac and non-cardiac defects. Cyanosis or blue skin coloration, primarily affecting the lips and fingernails, can indicate a systemic or circulatory issue. Poor feeding, failure to thrive, and rapid shallow breathing may also be observed due to poor circulation. Upon examination, arrhythmia and heart murmur may raise further suspicion of a cardiac abnormality. Non-cardiac symptoms include impairments of the liver and gastrointestinal tract. Biliary atresia, or inflammation and destruction of the bile ducts, may lead to jaundice. Vomiting and swelling of the abdominal region are features that suggest improper positioning of the intestines. Poor positioning of the intestine also makes it more prone to blockage, which can result in numerous chronic health issues. Asplenia and polysplenia are also possible features of heterotaxy. Due to abnormal cardiac development, patients with situs ambiguus usually develop right atrial isomerism consisting of two bilaterally paired right atria, or left atrial isomerism consisting of two bilaterally paired left atria. Clinical features and symptoms can vary dependent upon assignment of left versus right atrial isomerism. In either instance, the apex of the heart will be poorly positioned, which should alert a clinician of the likelihood of atrial isomerism. It is estimated that 5–10% of isomeric patients have mesocardia, in which the heart is positioned at the center of the thorax, 25–50% have dextrocardia, in which the apex of the heart is pointed toward the right side of the thorax, and 50–70% have levocardia, in which the apex of the heart is pointed toward the left side of the thorax. Pulmonary valve stenosis results in issues of blood flow to the lungs. Abdominal organs Abdominal organs, including the liver, stomach, intestinal tract, and spleen may be randomly arranged throughout the left-right axis of the body. Distribution of these organs largely dictates treatment, clinical outcomes, and further evaluation. The liver is typically symmetrical across the left-right axis in patients with situs ambiguus, which is abnormal. A majority of left atrial isomeric patients have defects throughout the biliary tree, which is responsible for bile production, even when the gall bladder is functional and morphologically normal. This biliary atresia can lead to acute problems such as nutrient malabsorption, pale stools, dark urine, and abdominal swelling. If this condition continues without proper treatment, cirrhosis and liver failure become a major concern. Biliary atresia is not usually observed in patients with right atrial isomerism. Isomeric patients often experience disruptions to splenic development during embryogenesis, resulting in an overall lack of a spleen (asplenia) or development of many spleens (polysplenia). Asplenia is most often observed in patients with right atrial isomerism. Polysplenia results in 90% of patients with left atrial isomerism. Although they have many spleens, each is usually ineffective resulting in functional asplenia. Rarely, left atrial isomeric patients have a single, normal, functional spleen. Patients lacking a functional spleen are in danger of sepsis and must be monitored. == Causes ==

Situs ambiguus has been linked to family 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: Mechanisms leading to bronchial duplication are not thoroughly understood. In pulmonary valve stenosis, there is a reduction in blood flow to the lungs due to an obstruction of the heart at the pulmonic valve. This contributes to cyanosis and pulmonary hypertension. ==Diagnosis==

For proper diagnosis of situs ambiguus, cardiac and non-cardiac features must be evaluated. Diagnostic criteria for atrial isomerism includes observation of symmetry of thoracic visceral organs upon echocardiogram, arrhythmia upon electrocardiogram, and chest x-ray for confirmation of the heart's location across the left-right axis. Additional radiographic and cross-sectional imaging may be obtained to evaluate both cardiac and non-cardiac manifestations of situs ambiguus. In addition, a series of gastrointestinal tests can be conducted for observation of intestinal malrotation, as well as a scan of the liver and spleen for biliary function. Diagnostic techniques for cardiac causes • Echocardiography • Electrocardiography • Computed tomography • Magnetic resonance imaging • Cardiac catheterization and angiography • Chest x-ray Diagnostic techniques for non-cardiac causes • Computed tomography • Magnetic resonance imaging • Splenic function analysis • Evaluation of biliary anatomy and cholangiogram • Evaluation of intestinal malrotation • Pulse oximeter Other diagnostic features • Assessment of family history • Genetic testing == Management ==

Each of the symptoms of situs ambiguus must be managed with appropriate treatment dependent upon the organ system involved. Intestinal malrotation is treated surgically using the Ladd procedure. This procedure widens a fold in the peritoneum so that the intestines can be placed in non-rotated formation. It is not possible to return the bowel to a normal morphology However, 89% of patients that undergo the Ladd surgery experience a complete resolution of symptoms. Following cholangiogram, a Kasai procedure is usually performed in cases of biliary atresia. In this surgery, a Y-shaped shunt is used to passage bile from the liver directly to the intestine. If this is unsuccessful, liver transplantation can be considered based on the overall health of the patient. The Kasai procedure is successful in approximately 80% of patients. Following the operation, patients are advised to take fat-soluble vitamins, choleretics, and anti-inflammatory medications. Functionally asplenic patients have an elevated lifetime risk of sepsis, as they have no functional spleen for fighting infection. For this reason, asplenic patients are under constant observation for any signs of fever or infection. In the case of infection, patients are placed on controlled empiric antibiotic therapy to avoid development of antibiotic resistance. This therapy battles infection by both gram-positive and gram-negative bacteria. Right-atrial and left-atrial isomerism and associated pulmonary issues are treated in a series of steps based on the severity of symptoms. Isomeric patients are first treated by inserting a shunt that will move incoming blood through the pulmonary circuit. The Fontan procedure routes blood through the patient's single ventricle, to the lungs, and into systemic circulation. This process is favorable in patients aged 2 to 5 years old. About 20–30% of patients will require a heart transplant. Left-atrial isomeric patients have less severe complications, as they typically have 2 functional ventricles. In this case, they can undergo biventricular repair to form 2 separate ventricles and functional associated valves. ==Prognosis==

Prognosis for patients with situs ambiguus is quite varied, owed to the spectrum of clinical manifestations. Infants who experience severe cyanosis at birth may die within hours of delivery if medical intervention is not immediate. Alternatively, longevity of neonates with mild cardiac lesions is unaffected. Ten percent of patients born with right atrial isomerism die by the age of 5 without intervention. Improvements in therapies has increased the 5-year survival to 30–74% for right atrial isomeric patients and 65–84% for left atrial isomeric patients based on the cause of their disease. == Research ==

There have been vast amounts of research on the clinical features, racial disparities, and physiological mechanisms of heterotaxy syndrome dating back to 1973. Mishra et al. published a review in November 2015 describing current knowledge of cardiac and non-cardiac abnormalities associated with situs ambiguus. The author stresses the importance of genetic testing prior to deciding a prognosis for affected patients. She also proposes prenatal screening and evaluation in cases at risk for development of situs ambiguus. Recent studies have shown higher rates of heterotaxy syndrome among Hispanic infants of Mexican descent, as well as female infants of non-Hispanic black and white mothers. Additional studies must be done to clarify the mechanisms behind racial disparities in heterotaxy syndrome. Individuals of Asian descent show a higher prevalence of heterotaxy syndrome in general than members of the Western world. The National Birth Defects Prevention study (October 2014) attempted to link clinical presentations of situs ambiguus to demographics in an epidemiological study. This proved a difficult task due to the vast differences in presentation of this disorder. However, the authors are hopeful that finding a link can help inform clinical decision-making, predictive analyses, and future outcomes. == See also ==