Introduction
Background
Although symmetry is a characteristic of the external mammalian phenotype and of some internal organs, notably the genitourinary system, much of our internal anatomy, notably the cardiovascular, pulmonary, and gastrointestinal systems, is asymmetrical.1,2,3,4 The asymmetry is specific and originates in the genetic and molecular identity of the embryonic midline developmental field complex.5,6,7 This normal asymmetrical arrangement is called situs solitus, a descriptive term derived from the Latin situs, which means position, and solitus, which means customary. Thus, situs solitus signifies the customary, or normal, asymmetrical arrangement of the viscerovascular anatomy.8,9
Computed tomography scan obtained in the excretory phase during the intravenous administration of contrast material in a patient with polysplenia. This image demonstrates multiple splenules in the right upper quadrant, along the greater curvature of the right-sided stomach. Note that the liver extends over the splenic mass.
Interruption of the inferior vena cava. Coronal T1-weighted magnetic resonance image of the abdomen in a patient with polysplenia. This image demonstrates the enlarged azygous vein, which is parallel to the aorta and to its right. A partial volume-averaging artifact is present in the azygous vein and arch.
Situs inversus is the mirror image of situs solitus in toto. Although this condition is embryologically related to other situs anomalies, situs inversus must be strictly differentiated, because it has significantly different pathophysiologic and clinical implications. All other conditions occur in a spectrum called situs ambiguus, which is commonly changed to the Anglican situs ambiguous.
The concept of situs or laterality of the viscerovascular anatomy is important to the understanding, imaging, and interpretation of congenital visceral and vascular malformations. Assignment of laterality can be inherently difficult and affected by specific clinical biases. For example, to the cardiologist applying the concept of segmental classification of cardiac anomalies, situs refers to atrial morphology.10 The pulmonologist is likely to assess lung lobation and bronchovascular anatomy. The gastroenterologist may focus on the presence or absence of the spleen.11
Patients with situs ambiguus tend to be grouped with those in whom right- or left-sided structures predominate. Generalizations may be made in these groups. Patients with right-sided symmetry typically lack a spleen, whereas patients with left-sided symmetry typically have a segmented spleen or multiple splenules.12
These common characteristics have led to the somewhat arbitrary classification of asplenia and polysplenia. However, heterotaxia, or situs ambiguus, occurs in a continuum; this is acknowledged in the classification of polyasplenia syndrome. This term recognizes the fact that left- and right- sided tendencies are on a continuum of heterotaxy or midline derangement. Radiologists and other clinicians must be cognizant of the viscerovascular arrangements that are possible in infants with these conditions, and they must describe the specific viscerovascular anomalies in the patient. Many infants with situs ambiguus present with severe congenital cardiac anomalies. In these patients, knowing the presence of an associated interruption of the inferior vena cava is helpful before performing cardiac catheterization.13
Situs ambiguus, or heterotaxia, is associated with other conditions of major clinical relevance, such as intestinal malrotation, biliary atresia, splenic abnormalities and consequent immunologic derangements, faulty gastric suspension mechanisms, displacement of abdominal viscera, and aberrant vascular structures and vascular connections. Each of these abnormalities is derived from an embryologic inability to determine laterality and establish the complex solitus asymmetry, whereas symmetrical structures remain unaffected.14
In a retrospective review (1994-2008) of heterotaxy patients by Anagnostopoulos et al, the authors sought to determine whether current management has improved patient outcomes. They found that surgical outcomes have improved with current procedures. They also determined that patients with left atrial isomerism (LIA) had a higher incidence of sinus node dysfunction than patients with right atrial isomerism (RIA). Risk of operative mortality and attrition was found to be highest during first- and second-stage palliation. In RAI, significant atrioventricular valve regurgitation and obstructed total anomalous pulmonary venous return (TAPVR) were found to be risk factors.15
Pathophysiology
The control of normal human somatic asymmetry is not yet known.
A mouse animal model exists in which a spontaneous mutation called the iv locus is localized to the 12th chromosome.16,17 Homozygous animals have a random phenotype: approximately 30% have situs solitus; 30%, situs inversus; and 40%, situs ambiguus. A second murine genetic mutation has been identified in the inv gene.18,19 Homozygous individuals have shown reversed embryonic turning, the earliest manifestation of laterality in mouse embryos. Asymmetrical expressions of genes have been identified in other animal models, notably Xenopus species and chick embryos.20
In humans, familial situs ambiguus has been related to both autosomal and X-linked inheritance patterns, although most cases arise sporadically.2,21,22,23,24 Situs inversus and situs ambiguus have been described within the same family trees; this finding indicates a phenotypic arrangement similar to that in the iv/iv mice. ZIC 3 is an X-linked gene identified in both sporadic and familial cases; affected males typically have the situs ambiguus phenotype, and females have either situs solitus or situs inversus. This particular genetic code is also associated with midline anomalies, particularly neural tube defects.
A submicroscopic deletion in Xq26 and a deletion at 18p have been associated with familial situs ambiguus.25,26 Further, balanced and unbalanced autosomal translocations have also been described in sporadic cases of situs ambiguus.27 Finally, environmental factors, including exposure to retinoic acid and maternal diabetes, have been implicated in laterality defects among the offspring of affected parents.28,29
Asymmetrical or unilateral organs are derived from embryologic midline structures. Disruption of embryonic laterality leads to faulty development of asymmetrical organs. Importantly, in the absence of solitus control, the viscerovascular arrangement becomes largely random, within broad generalizations regarding right- or left-sided tendencies. However, the affected organs or systems are predictable and characterized by complex asymmetry.
The heart is most often affected, and it is the organ that most frequently leads to clinically detectable abnormalities. The liver and spleen have a variety of patterns, ranging from malformation to malpositioning, to an absence of the spleen or biliary structures. The gastrointestinal tract has a variety of malrotation anomalies. As a result of selective resorption of embryonic paired structures, vascular structures typically demonstrate a variety of abnormalities related to malpositioning or segmental absence.30,31
Frequency
United States
The true incidence of situs abnormalities is not known. Some estimates suggest that situs inversus totalis occurs in approximately 1 per 8,000-25,000 live births, and approximately 20-25% of these are associated with immotile cilia, or Kartagener syndrome.
In situs ambiguus, there are estimates that 1.44 infants per 10,000 are affected. This number is based on patients with congenital heart disease and is likely to be an underestimation, although it may include most of these patients. Others estimate the incidence as 1 case per 5000 births, with the affected cases evenly divided between situs inversus and situs ambiguus.
Mortality/Morbidity
The major causes of mortality and morbidity in the heterotaxy syndromes are undoubtedly the cardiac malformations that typically occur in these conditions. These are based on the inability of the complex asymmetrical connections to develop correctly, and they predictably consist of an ambiguus and single atrium, a single ventricle, and conotruncal anomalies such as truncus arteriosus and transposition of the great vessels.32,33,15
Vascular malconnections that are associated with high mortality and morbidity rates include total anomalous pulmonary venous connections (TAPVCs).34 Visceral abnormalities with clinically notable adverse consequences include biliary atresia and the absence of the spleen. Malrotation may become clinically evident if obstruction develops secondary to the presence of Ladd bands or if a midgut volvulus supervenes.35 Intrinsic duodenal obstruction, such as that secondary to duodenal diaphragm, may also occur.
Sex
Although most cases of heterotaxia are sporadic, many cases are familial, and some are X linked. Thus, the abnormality is more common in males than in females.
Age
Situs is congenital; therefore, situs abnormalities are always present in affected neonates. However, clinical manifestations depend on the individual's specific anatomic derangements. Severe and complex cardiac abnormalities are likely to be apparent at birth or soon afterward. Individuals without congenital heart disease may present later with conditions such as biliary atresia or volvulus. In persons without clinically morbid abnormalities, these conditions may be discovered during an evaluation for an unrelated problem or complaint when they are adults.36,37
Anatomy
Anatomic pathologic findings in patients with heterotaxy syndrome are described in this section within the broad categories of right- and left-sided tendencies. Some of the more notable exceptions to these general groupings are also discussed.38,39,40
Splenic anomalies
Patients with asplenia lack a spleen, and they typically have a right-sided tendency. In these patients, Howell-Jolly bodies may be present, and diminished immunologic defenses may result in overwhelming sepsis.
Polysplenia. Ultrasonogram of the left upper quadrant reveals multiple, widely spaced splenules above the left kidney (same patient in Images 1 and 3 in Multimedia). Reproduced with permission.
Polysplenia. Ultrasonogram of the left upper quadrant reveals few, closely spaced splenules above the left kidney. The adrenal gland lies medial and immediately adjacent to the splenules. Reproduced with permission.
T1-weighted magnetic resonance image obtained in a patient with polysplenia (same patient in Images 1 and 3 in Multimedia). Multiple widely spaced splenules are obvious along the greater curvature of the left-sided stomach. Reproduced with permission from Hernanz-Schulman M et al. AJR Am J Roentgenol. 1990;154(4):797-802.
Computed tomography scan obtained in the excretory phase during the intravenous administration of contrast material in a patient with polysplenia. This image demonstrates multiple splenules in the right upper quadrant, along the greater curvature of the right-sided stomach. Note that the liver extends over the splenic mass.
Patients with polysplenia have large variations in the configurations of the splenic tissue. Splenules develop along both sides of the dorsal mesogastrium (rather than just on the left side, as in solitus asymmetry). The resultant splenic tissue is always found along the greater curvature of the stomach. It may consist of multiple small splenules or a single splenic mass with 1 or more septae (see Images 1-4).
Gastrointestinal and hepatic anomalies
Patients in both the asplenia and polysplenia subgroups have a variety of gastrointestinal abnormalities. The stomach may be located on the right, on the left, or in the midline. Faulty mesenteric attachments of the stomach may result in gastric volvulus. Malrotation anomalies encompass a wide spectrum that ranges from nonrotation to reversed rotation and faulty peritoneal attachments. Duodenal atresia or stenosis may also be present (see Images 3-6).
Abnormalities of rotation. Upper gastrointestinal image demonstrates inverted nonrotation and a right-sided stomach in a patient with polysplenia (same patient in Images 5-6 in Multimedia).
Abnormalities of rotation. Image obtained during a barium enema examination in a patient with polysplenia (same patient in Images 5-6 in Multimedia). This radiograph demonstrates inverted nonrotation.
The liver may lie in the midline or in the right or left side of the abdomen. In patients with polysplenia, biliary atresia may be present.36,41,42,43,44 In fact, 10% of all patients with biliary atresia also have polysplenia. This co-diagnosis is important to establish, because it has the potential for anomalous caval and portal venous connections and because it is relevant to eventual surgical planning. The gallbladder may lie in the midline or be lateralized with the bulk of the hepatic mass. The hepatic venous drainage is variable.
Some patients with heterotaxy, notably those with polysplenia, may also have a congenitally short pancreas, which is the result of maldevelopment or agenesis of the dorsal pancreas (which develops in the dorsal mesogastrium).12 A midline adrenal gland or a horseshoe adrenal gland may be seen in other patients, notably those with asplenia. Approximately 1% of patients may also have renal anomalies, such as a multicystic dysplastic kidney.
Central nervous system anomalies
A small subset of individuals with situs ambiguus also has a variety of midline defects, including central nervous system (CNS) anomalies (eg, holoprosencephaly, neural tube defects) and caudal regression syndrome. This association underscores the derangement of the midline developmental complex, which is implicated in the early genesis of situs derangements.
Vascular anomalies
Interruption of the inferior vena cava is most common in patients with polysplenia. This occurs in approximately 50-60% of patients with this condition. In patients with an interrupted inferior vena cava, venous return occurs via the right- or left-sided azygous systems (see Images 7-9). This condition is rare in patients with asplenia, but it has been reported in several patients. This finding underscores both the heterogeneity and underlying similarities among all patients with situs ambiguus. As a generalization, in a patient with heterotaxy, interruption of the inferior vena cava suggests polysplenia, with very few exceptions, as discussed.
Interruption of the inferior vena cava. Transverse ultrasonogram of the abdomen in a patient with polysplenia (same patient in Images 7-8 in Multimedia). This image demonstrates a large retrocrural vessel, which is similar in size and adjacent to the right side of the aorta, a finding that indicates azygous continuation and caval interruption.
Interruption of the inferior vena cava. Axial T1-weighted magnetic resonance image of the abdomen (same patient in Images 7-8 in Multimedia). This image demonstrates a large retrocrural vessel, which is similar in size and adjacent to the right side of the aorta, a finding that indicates azygous continuation and caval interruption.
Interruption of the inferior vena cava. Coronal T1-weighted magnetic resonance image of the abdomen in a patient with polysplenia. This image demonstrates the enlarged azygous vein, which is parallel to the aorta and to its right. A partial volume-averaging artifact is present in the azygous vein and arch.
In patients with an intact vena cava, both the vena cava and the aorta may be to one side of the midline; this condition was once considered characteristic of asplenia. Alternatively, the vena cava and aorta may lie on opposite sides of the midline. When the vena cava lies to the right, situs solitus is simulated. When the vena cava lies to the side opposite its atrial connection, it crosses over the aorta in piggyback fashion to reach its destination. This condition has also been reported to be characteristic of asplenia, but it can occur in any patient with heterotaxy and an intact vena cava. When the inferior cava is present, any of these anatomic arrangements may occur, regardless of a right- or left-sided tendency (see Image 10-13).
Intact inferior vena cava. Transverse ultrasonogram of the abdomen in patient with polysplenia (same patient in Images 10-11 in Multimedia). This image demonstrates an antecrural vessel, a finding that indicates an intact inferior vena cava, which is in the process of crossing over anterior to the aorta to enter the atrium.
Intact inferior cava. Sagittal ultrasonogram of the abdomen in a patient with polysplenia (same patient in Images 10-11 in Multimedia). This image demonstrates an antecrural vessel, a finding that indicates an intact inferior cava, which is in the process of crossing over anterior to the aorta to enter the atrium. Compare this ultrasonogram with the transverse ultrasonogram in Image 10.
Intact inferior cava. Sagittal ultrasonogram of the abdomen in a patient with polysplenia. This image demonstrates an intact intrahepatic cava with a normal appearance. Because the abdominal caval laterality was congruent with that of the atria in this patient, crossing over did not occur. Reproduced with permission.
Intact inferior vena cava. Transverse ultrasonogram in a patient with asplenia. This image demonstrates the aorta and vena cava on either side of the midline, an appearance that simulates solitus anatomy. Reproduced with permission.
In TAPVC, the common pulmonary vein fails to become incorporated into the left atrium; instead, it drains anomalously. Return may be supracardiac (via a vertical vein or directly into the superior cava or azygous vein), intracardiac (typically into the coronary sinus), or infracardiac and infradiaphragmatic. Venous obstruction can occur in any of these situations, but it is the rule in infradiaphragmatic connections (see Images 14-16, Images 22-24).
Total anomalous pulmonary venous connection (TAPVC). Sagittal abdominal ultrasonogram in a patient with asplenia and TAPVC below the diaphragm (same patient in Images 14-16 and 22-23 in Multimedia). This image shows that the anomalous vessel bypasses the portal vein and connects to a hepatic vein. Note the abrupt caliber change in the draining pulmonary vein in this patient with severe pulmonary venous outflow obstruction. Reproduced with permission.
Total anomalous pulmonary venous connection (TAPVC). Axial T1-weighted magnetic resonance image in a patient with asplenia and TAPVC below the diaphragm (same patient in Images 14-16 and 22-23 in Multimedia). This image shows the anomalous vessel anterior to the gastroesophageal junction (high-intensity focus). The hepatic draining vein is the smaller-caliber vessel immediately anterior to the anomalous vessel. The caliber difference indicates the presence of an obstruction. The intrahepatic vena cava is seen to the right, and the aorta is anterior to the spine to the left of the midline.
Total anomalous pulmonary venous connection (TAPVC). Coronal T1-weighted magnetic resonance image obtained in a patient with asplenia and TAPVC below the diaphragm (same patient in Images 14-15, 22-23 in Multimedia). The anomalous vessel receives the pulmonary veins in the chest and courses below the diaphragm. Reproduced with permission.
TAPVC is most common in patients with asplenia, although abnormal pulmonary venous connections can occur in both asplenia and polysplenia groups; more often, the abnormal pulmonary venous connection is partial in the polysplenia group. TAPVC is one of the lesions that is associated with the overall higher mortality rate of the group of patients with asplenia.
Conotruncal anomalies and total anomalous pulmonary venous connection (TAPVC). Axial T1-weighted magnetic resonance image in a patient with asplenia (same patient in Images 14-16 and 22-23 in Multimedia). This image demonstrates truncus arteriosus type II, with pulmonary arteries arising from the arterial trunk. A single right-sided superior vena cava is noted to the right of the truncus (see also Image 23 in Multimedia).
Conotruncal anomalies and total anomalous pulmonary venous connection (TAPVC). Axial T1-weighted magnetic resonance image in a patient with asplenia (same patient in Images 14-16 and 22-23 in Multimedia). This image demonstrates the common pulmonary vein is dorsal to the ambiguus atrium and receives pulmonary venous return. The signal intensity of the lung fields is relatively high; this finding indicates increased water content in the edematous lung, which is due to obstruction of pulmonary venous return. Note the single-atrium, single-ventricle anatomy. The descending aorta lies to the left of the spine. The cardiac apex is to the right.
Chest and abdominal radiograph in a neonate with asplenia. This image demonstrates a midline liver, mesocardia, and a right-sided stomach. Severe pulmonary edema is present, with a normal heart size; this finding is strongly suggestive of total anomalous pulmonary venous connection (TAPVC) with obstruction, which most likely drains subdiaphragmatically. Note the extension of the liver into both upper quadrants.
The typical differences in atrial venous connections can be conceptualized within the context of atrial isomerism. In patients with polysplenia, the common atrium has left-sided characteristics, and the inferior vena cava fails to connect to a morphologic left atrium. In patients with asplenia, the common atrium has right-sided characteristics, and the pulmonary veins in turn fail to make the appropriate connections to a morphologic right atrium.
Bilateral superior vena cavae are common in both asplenia and polysplenia (see Image 17).
Bilateral superior cavae. Coronal T1-weighted magnetic resonance image in a patient with polysplenia. This image demonstrates bilateral superior cavae, a large atrial septal defect, and a single-ventricle anatomy. Portions of a transverse aortic arch and pulmonary outflow tract are also visible.
Preduodenal portal vein. Transverse ultrasonogram obtained just caudal to the pancreas in an infant with polysplenia (same patient in Images 18-20 in Multimedia). This image demonstrates the superior mesenteric vein just ventral to and to the left of the superior mesenteric artery (denoted by the characteristic hyperechoic halo) (see Image 19 in Multimedia). The relationship of the artery and vein is abnormal; the vein is to the left and anterior to the artery, rather than to the right and in the same plane as the artery in the normal relationship. Reproduced with permission.
Preduodenal portal vein. Transverse ultrasonogram obtained at the level of the pancreas in an infant with polysplenia (same patient in Images 18-20 in Multimedia). This image demonstrates that the superior mesenteric vein lies ventral to the pancreas and is separated from the superior mesenteric artery (denoted by the characteristic hyperechoic halo) by the pancreas. Reproduced with permission.
Preduodenal portal vein. Sagittal ultrasonogram obtained in an infant with polysplenia (same patient in Images 18-20 in Multimedia). This image demonstrates the superior mesenteric vein, which courses ventral to the pancreas, in a staircase configuration. Reproduced with permission.
Preduodenal portal vein. Sagittal ultrasonogram in an infant with asplenia. This image demonstrates the characteristic staircase configuration of the ventral course of the superior mesenteric–portal junction anterior to the pancreas and duodenum. The hyperechoic triangular structure indicates gas within the duodenal cap.
Vitelline anatomy is also skewed in situs ambiguus. The normal retroduodenal course of the portal vein is a result of specific resorption of segments of the paired vitelline veins. When the larger portion of the left vitelline vein is resorbed, the resultant anatomic relationship of the portal vein is preduodenal. This anatomy is most often noted in patients with polysplenia, although it also occurs in the asplenia group (see Images 18-21).
Cardiac anomalies
Patients with asplenia and those with polysplenia often have biventricular hearts, in which large atrioventricular defects result in a single-atrium, single-ventricle configuration. However, in general, patients with asplenia tend to have complex cardiac lesions more frequently than those with polysplenia. Patients with polysplenia may have only a ventricular septal defect or no cardiac anomalies at all. (Interestingly, this is the subset of patients who most often have biliary atresia.)
When the patients with cardiac abnormalities are examined, a description of the lesions based on the cardiac segmental anatomy is helpful. Atrial morphology is described in terms of the situs condition, as follows: solitus (S), inversus (I), or ambiguus (A). Ventricular morphology is described in terms of cardiac looping, either to the right or dextroposed (D), which results in the normal position of the left ventricle on the left side and the right ventricle on the right side, or to the left or levoposed (L), which results in an inverted ventricular configuration. The great arteries are described in terms of the position of the aorta relative to the pulmonary artery, either normal (ie, to the right [D]) or abnormal (ie, to the left [L]).
In normal hearts, solitus atria is present, with a morphologic right atrium. This contains nodal tissue, a coronary sinus, and a wide-based atrial appendage; it receives the systemic veins; and it is located on the right.45 Also present is a morphologic left atrium, which has a narrow-based atrial appendage, receives the pulmonary veins, and is located on the left. Patients with situs ambiguus typically have atrial isomerism. In patients with asplenia, a single atrium that morphologically resembles a right atrium tends to be present, whereas in patients with polysplenia, the atrium morphologically resembles a left atrium.
Abnormal ventricular looping is also present in patients with an ambiguus situs. The incidence of L-loop ventricles occurs in approximately 38% of patients with asplenia and in 30% of those with polysplenia. A normal heart, with solitus atria, a D loop, and a right-sided aortic valve with respect to the pulmonary valve, is designated SDD. Patients with congenital heart disease and situs ambiguus tend to have discordant cardiac segmental anatomic features.
In patients with asplenia, conotruncal abnormalities are common. They include truncus arteriosus, conal hypoplasia with pulmonary outflow obstruction or pulmonary atresia, and anomalous pulmonary venous connections (see Images 14-16, Images 21-23). These patients tend to have diminished pulmonary blood flow and cyanosis. In patients with polysplenia, atrioventricular septal defects are common (see Image 17). Pulmonary stenosis is not common, and these patients tend to have increased pulmonary blood flow.
Presentation
See the Anatomy section, above.
Preferred Examination
No single examination is best for the evaluation of heterotaxy. What may be best, however, is an ambiguous and subjective term that can be defined as the fastest and easiest study (eg, plain radiography), the least invasive study (in terms of radiation exposure or the need for sedation), the least expensive study, or the most sensitive or specific study. Knowledge of the various anatomic derangements that occur in these patients enables the informed radiologist to make the appropriate observations on most cross-sectional images.
Often, the initial examination performed in these patients is plain chest radiography, which is often performed in patients with suspected congenital heart disease, for which the patients may seek clinical attention in the first place.46,47,48 Patients with an abdominal catastrophe, such as midgut or gastric volvulus, also undergo plain radiography as part of their initial diagnostic imaging examination.49 On the other hand, patients with biliary atresia do not undergo plain radiography as part of their initial workup.
Historically, the diagnosis often depends on the angiographic findings in the cardiac and abdominal structures or on the results of abdominal examination via an iatrogenic pneumoperitoneum. However, ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) are all useful in assessing the various viscerovascular abnormalities in patients with heterotaxy.37,48,50,51,52,53,54,55 MRI is particularly useful because it can also delineate cardiac defects.
Limitations of Techniques
Plain radiographs can be helpful in delineating an abnormal visceroatrial situs. A midline heart and liver, with a midline or right-sided stomach, and symmetrical bronchial branching are diagnostic findings. However, many patients with situs ambiguus do not have any of these findings, and plain radiographic findings may erroneously suggest situs solitus or situs inversus totalis.
Ultrasonography is extremely useful, but it is operator dependent, and findings may be unrevealing in cases in which the operator fails to understand the complex anatomic relationships that result from derangement of the normal laterality.
CT scanning may be limited in young infants because they have little body fat, especially if the contrast agent bolus is suboptimal.
MRI is limited by patient motion and its relatively long imaging times, which require optimal sedation.
Differential Diagnoses
Other Problems to Be Considered
Isolated dextrocardia
Isolated interruption of the inferior vena cava
Isolated preduodenal portal vein
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References
Izpisúa Belmonte JC. How the body tells left from right. Sci Am. Jun 1999;280(6):46-51. [Medline].
Casey B. Two rights make a wrong: human left-right malformations. Hum Mol Genet. 1998;7(10):1565-71. [Medline]. [Full Text].
Fujinaga M. Development of sidedness of asymmetric body structures in vertebrates. Int J Dev Biol. Apr 1997;41(2):153-86. [Medline]. [Full Text].
Srivastava D. Left, right ... which way to turn?. Nat Genet. Nov 1997;17(3):252-4. [Medline].
Martínez-Frías ML. Primary midline developmental field. I. Clinical and epidemiological characteristics. Am J Med Genet. May 8 1995;56(4):374-81. [Medline].
Martínez-Frías ML, Urioste M, Bermejo E, et al. Primary midline developmental field. II. Clinical/epidemiological analysis of alteration of laterality (normal body symmetry and asymmetry). Am J Med Genet. May 8 1995;56(4):382-8. [Medline].
Opitz JM, Gilbert EF. CNS anomalies and the midline as a "developmental field". Am J Med Genet. Aug 1982;12(4):443-55. [Medline].
Maldjian PD, Saric M. Approach to dextrocardia in adults: review. AJR Am J Roentgenol. Jun 2007;188(6 suppl):S39-49; quiz S35-8. [Medline].
Cohen MS, Anderson RH, Cohen MI, Atz AM, Fogel M, Gruber PJ, et al. Controversies, genetics, diagnostic assessment, and outcomes relating to the heterotaxy syndrome. Cardiol Young. Sep 2007;17 Suppl 2:29-43. [Medline].
Jacobs JP, Anderson RH, Weinberg PM, et al. The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. Cardiol Young. Sep 2007;17 (suppl 2):1-28. [Medline].
Uemura H, Ho SY, Devine WA, Anderson RH. Analysis of visceral heterotaxy according to splenic status, appendage morphology, or both. Am J Cardiol. Oct 15 1995;76(11):846-9. [Medline].
Herman TE, Siegel MJ. Polysplenia syndrome with congenital short pancreas. AJR Am J Roentgenol. Apr 1991;156(4):799-800. [Medline]. [Full Text].
Ruscazio M, Van Praagh S, Marrass AR, et al. Interrupted inferior vena cava in asplenia syndrome and a review of the hereditary patterns of visceral situs abnormalities. Am J Cardiol. Jan 1 1998;81(1):111-6. [Medline].
Horwich A, Brueckner M. Left, right and without a cue. Nat Genet. Dec 1993;5(4):321-2. [Medline].
Anagnostopoulos PV, Pearl JM, Octave C, Cohen M, Gruessner A, Wintering E, et al. Improved current era outcomes in patients with heterotaxy syndromes. Eur J Cardiothorac Surg. May 2009;35(5):871-7; discussion 877-8. [Medline].
Iida A, Emi M, Matsuoka R, et al. Identification of a gene disrupted by inv(11)(q13.5;q25) in a patient with left-right axis malformation. Hum Genet. Mar 2000;106(3):277-87. [Medline].
Layton WM, Layton MW, Binder M, et al. Expression of the IV (reversed and/or heterotaxic) phenotype in SWV mice. Teratology. Jun 1993;47(6):595-602. [Medline].
Mazziotti MV, Willis LK, Heuckeroth RO, et al. Anomalous development of the hepatobiliary system in the Inv mouse. Hepatology. Aug 1999;30(2):372-8. [Medline].
Morishima M, Yasui H, Nakazawa M, et al. Situs variation and cardiovascular anomalies in the transgenic mouse insertional mutation, inv. Teratology. Jun 1998;57(6):302-9. [Medline].
Levin M. Left-right asymmetry in vertebrate embryogenesis. Bioessays. Apr 1997;19(4):287-96. [Medline].
Casey B, Cuneo BF, Vitali C, et al. Autosomal dominant transmission of familial laterality defects. Am J Med Genet. Feb 2 1996;61(4):325-8. [Medline].
Alonso S, Pierpont ME, Radtke W, et al. Heterotaxia syndrome and autosomal dominant inheritance. Am J Med Genet. Mar 13 1995;56(1):12-5. [Medline].
Lindor NM, Smithson WA, Ahumada CA, Michels VV, Opitz JM. Asplenia in two father-son pairs. Am J Med Genet. Mar 13 1995;56(1):10-1. [Medline].
Fishman LN, Lavine JE. What's wrong when it isn't right: situs inversus and genetic control of organ position. Hepatology. Jan 1994;19(1):257-8. [Medline].
Digilio MC, Marino B, Giannotti A, Di Donato R, Dallapiccola B. Heterotaxy with left atrial isomerism in a patient with deletion 18p. Am J Med Genet. Sep 18 2000;94(3):198-200. [Medline].
Ferrero GB, Gebbia M, Pilia G, et al. A submicroscopic deletion in Xq26 associated with familial situs ambiguus. Am J Hum Genet. Aug 1997;61(2):395-401. [Medline]. [Full Text].
Freeman SB, Muralidharan K, Pettay D, Blackston RD, May KM. Asplenia syndrome in a child with a balanced reciprocal translocation of chromosomes 11 and 20 [46,XX,t(11;20)(q13.1;q13.13)]. Am J Med Genet. Feb 2 1996;61(4):340-4. [Medline].
Kim SH, Son CS, Lee JW, Tockgo YC, Chun YH. Visceral heterotaxy syndrome induced by retinoids in mouse embryo. J Korean Med Sci. Aug 1995;10(4):250-7. [Medline]. [Full Text].
Morishima M, Yasui H, Ando M, Nakazawa M, Takao A. Influence of genetic and maternal diabetes in the pathogenesis of visceroatrial heterotaxy in mice. Teratology. Oct 1996;54(4):183-90. [Medline].
Zhang Z, Alpert D, Francis R, Chatterjee B, Yu Q, Tansey T, et al. Massively parallel sequencing identifies the gene Megf8 with ENU-induced mutation causing heterotaxy. Proc Natl Acad Sci U S A. Mar 3 2009;106(9):3219-24. [Medline].
Mohapatra B, Casey B, Li H, Ho-Dawson T, Smith L, Fernbach SD, et al. Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations. Hum Mol Genet. Mar 1 2009;18(5):861-71. [Medline].
Takeuchi K, Murakami A, Hirata Y, et al. Surgical outcome of heterotaxy syndrome in a single institution. Asian Cardiovasc Thorac Ann. Dec 2006;14(6):489-94. [Medline].
Yu DC, Thiagarajan RR, Laussen PC, Laussen JP, Jaksic T, Weldon CB. Outcomes after the Ladd procedure in patients with heterotaxy syndrome, congenital heart disease, and intestinal malrotation. J Pediatr Surg. Jun 2009;44(6):1089-95; discussion 1095. [Medline].
Foerster SR, Gauvreau K, McElhinney DB, Geva T. Importance of totally anomalous pulmonary venous connection and postoperative pulmonary vein stenosis in outcomes of heterotaxy syndrome. Pediatr Cardiol. Nov 15 2007;epub ahead of print. [Medline].
Oh SK, Han BK, Levin TL, et al. Gastric volvulus in children: the twists and turns of an unusual entity. Pediatr Radiol. Mar 2008;38(3):297-304. [Medline].
Puche P, Jacquet E, Godlewski G, et al. [Polysplenia syndrome: two cases in adults revealed by biliary and pancreatic malformations] [French]. Gastroenterol Clin Biol. Oct 2007;31(10):863-8. [Medline].
Gayer G, Apter S, Jonas T, et al. Polysplenia syndrome detected in adulthood: report of eight cases and review of the literature. Abdom Imaging. Mar-Apr 1999;24(2):178-84. [Medline].
Jacobs JP, Anderson RH, Weinberg PM, Walters HL 3rd, Tchervenkov CI, Del Duca D, et al. The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. Cardiol Young. Sep 2007;17 Suppl 2:1-28. [Medline].
Seo HI, Jeon TY, Sim MS, Kim S. Polysplenia syndrome with preduodenal portal vein detected in adults. World J Gastroenterol. Nov 7 2008;14(41):6418-20. [Medline].
Ferdman B, States L, Gaynor JW, Hedrick HL, Rychik J. Abnormalities of intestinal rotation in patients with congenital heart disease and the heterotaxy syndrome. Congenit Heart Dis. Jan 2007;2(1):12-8. [Medline].
Herman TE. Special imaging casebook. Left-isomerism (polysplenia) with congenital atrioventricular block and biliary atresia. J Perinatol. Mar 1999;19(2):155-7. [Medline].
Varela-Fascinetto G, Castaldo P, Fox IJ, et al. Biliary atresia-polysplenia syndrome: surgical and clinical relevance in liver transplantation. Ann Surg. Apr 1998;227(4):583-9. [Medline]. [Full Text].
Vazquez J, López Gutierrez JC, Gámez M, et al. Biliary atresia and the polysplenia syndrome: its impact on final outcome. J Pediatr Surg. Mar 1995;30(3):485-7. [Medline].
Davenport M, Howard ER. Biliary atresia and the polysplenia syndrome. J Pediatr Surg. Apr 1992;27(4):539-40. [Medline].
Uemura H, Ho SY, Devine WA, Kilpatrick LL, Anderson RH. Atrial appendages and venoatrial connections in hearts from patients with visceral heterotaxy. Ann Thorac Surg. Sep 1995;60(3):561-9. [Medline].
Danias PG, Manning WJ. Is this right? (...or is it left?). Circulation. Jul 13 1999;100(2):209-10. [Medline]. [Full Text].
Applegate KE, Goske MJ, Pierce G, Murphy D. Situs revisited: imaging of the heterotaxy syndrome. Radiographics. Jul-Aug 1999;19(4):837-52; discussion 853-4. [Medline]. [Full Text].
Hernanz-Schulman M, Ambrosino MM, Genieser NB, et al. Pictorial essay. Current evaluation of the patient with abnormal visceroatrial situs. AJR Am J Roentgenol. Apr 1990;154(4):797-802. [Medline]. [Full Text].
Ditchfield MR, Hutson JM. Intestinal rotational abnormalities in polysplenia and asplenia syndromes. Pediatr Radiol. May 1998;28(5):303-6. [Medline].
Görg C. The forgotten organ: contrast enhanced sonography of the spleen. Eur J Radiol. Nov 2007;64(2):189-201. [Medline].
Gayer G, Zissin R, Apter S, et al. CT findings in congenital anomalies of the spleen. Br J Radiol. Aug 2001;74(884):767-72. [Medline].
Wang JK, Li YW, Chiu IS, et al. Usefulness of magnetic resonance imaging in the assessment of venoatrial connections, atrial morphology, bronchial situs, and other anomalies in right atrial isomerism. Am J Cardiol. Oct 1 1994;74(7):701-4. [Medline].
Oates E, Austin JM, Becker JL. Technetium-99m-sulfur colloid SPECT imaging in infants with suspected heterotaxy syndrome. J Nucl Med. Aug 1995;36(8):1368-71. [Medline]. [Full Text].
Geva T, Vick GW 3rd, Wendt RE, Rokey R. Role of spin echo and cine magnetic resonance imaging in presurgical planning of heterotaxy syndrome. Comparison with echocardiography and catheterization. Circulation. Jul 1994;90(1):348-56. [Medline]. [Full Text].
Jelinek JS, Stuart PL, Done SL, Ghaed N, Rudd SA. MRI of polysplenia syndrome. Magn Reson Imaging. Nov-Dec 1989;7(6):681-6. [Medline].
Merran S, Karila-Cohen P, Servois V. [CT anatomy of the normal spleen: variants and pitfalls]. J Radiol. Apr 2007;88(4):549-58. [Medline].
Kouwenhoven JW, Bartels LW, Vincken KL, et al. The relation between organ anatomy and pre-existent vertebral rotation in the normal spine: magnetic resonance imaging study in humans with situs inversus totalis. Spine. May 1 2007;32(10):1123-8. [Medline].
Carmi R, Boughman JA, Rosenbaum KR. Human situs determination is probably controlled by several different genes. Am J Med Genet. Sep 15 1992;44(2):246-9. [Medline].
Casey B, Hackett BP. Left-right axis malformations in man and mouse. Curr Opin Genet Dev. Jun 2000;10(3):257-61. [Medline].
Debich DE, Devine WA, Anderson RH. Polysplenia with normally structured hearts. Am J Cardiol. May 15 1990;65(18):1274-5. [Medline].
Horgan JG, Lock JH Jr, Cioffi-Ragan D. Horseshoe adrenal in Ivemark (asplenia) syndrome. J Ultrasound Med. Oct 1995;14(10):785-6. [Medline].
Kataria R, Bhatnagar V, Wadhwa S, Mitra DK. Gastric pneumatosis associated with preduodenal portal vein, duodenal atresia, and asplenia. Pediatr Surg Int. Nov 1998;14(1-2):100-1. [Medline].
Lundstedt C, Lyttkens K, Andrén-Sandberg. Intraluminal duodenal diverticulum causing pancreatitis in a patient with a polysplenia syndrome. Eur Radiol. 1998;8(3):454-7. [Medline].
Maggard MA, Goss JA, Swenson KL, McDiarmid SV, Busuttil RW. Liver transplantation in polysplenia syndrome: use of a living-related donor. Transplantation. Oct 27 1999;68(8):1206-9. [Medline].
McChane RH, Hersh JH, Russell LJ, Weisskopf B. Ivemark's "asplenia" syndrome: a single gene disorder. South Med J. Oct 1989;82(10):1312-3. [Medline].
Nakada K, Kawaguchi F, Wakisaka M, et al. Digestive tract disorders associated with asplenia/polysplenia syndrome. J Pediatr Surg. Jan 1997;32(1):91-4. [Medline].
Phoon CK, Neill CA. Asplenia syndrome--risk factors for early unfavorable outcome. Am J Cardiol. Jun 15 1994;73(16):1235-7. [Medline].
Further Reading
Related eMedicine topics
Heterotaxy, Asplenia
Heterotaxy, Polysplenia
Situs Inversus
Intestinal Malrotation
Biliary Atresia
Keywords
asplenia, polysplenia, heterotaxy, heterotaxia, laterality, isomerism, right-sided isomerism, left-sided isomerism, right isomerism, left isomerism, Ivemark syndrome, situs ambiguus, situs ambiguous, partial situs inversus, polyasplenia, polyasplenia syndrome, situs solitus, visceral symmetry, visceral asymmetry, situs inversus, laterality, situs inversus totalis, Kartagener syndrome, total anomalous pulmonary venous connection, TAPVC, viscerovascular anomalies, Xq26, 18p, interrupted inferior vena cava
