What Determines Whether the Great Arteries Are Normally or Abnormally Related?

The situs, or pattern of anatomic organization, of the subarterial infundibulum and of the great arteries and the degree of development of the subarterial infundibulum largely determine whether the great arteries are normally or abnormally related. There are 2 types of situs: solitus (normal) and inversus (a mirror image of solitus). Situs ambiguus means that the pattern of anatomic organization is uncertain or unknown. Infundibular development varies from absent, to atretic, to severely stenotic, to mildly or moderately stenotic; great arteries are solitus normally related or inversus normally related, respectively. When the situs of the subarterial infundibulum and the situs of the great arteries are discordant (different), then the great arteries are abnormally related. Equations indicating the situs of the infundibulum and the situs of the great arteries show whether infundibuloarterial (IA) situs concordance or discordance is present. Many types of IA anomalies typically have IA situs discordance, including transposition of the great arteries, double-outlet right ventricle, double-outlet left ventricle, and anatomically corrected malposition of the great arteries. However, tetralogy of Fallot and truncus arteriosus typically have IA situs concordance, with hypoplasia or atresia of the subpulmonary infundibulum. The relation between the great arteries in tetralogy of Fallot and in truncus arteriosus is almost normal. The IA equations demonstrate the infundibular situs, the great arterial situs, the IA situs concordance or discordance, and the degree of development of the infundibulum. The infundibular situs and the great arterial situs are the formulas or "recipes" for each of the abnormal types of conotruncal malformation.

Hairy cell leukemia in a patient with situs inversus totalis: an extremely rare combination.

Hairy cell leukemia is a rare cancer of the blood. The occurrence of hairy cell leukemia with another very rare genetic disorder makes us question whether it is just a coincidence. This article reports the first case of hairy cell leukemia in a patient with situs inversus totalis in western literature. There have been studies into the pathogenesis of situs inversus totalis that suggest it is caused by the failure of embryonic cells to properly rotate during embryogenesis. On the molecular level, the nodal cilia, which are responsible for embryonic rotation, are built by transport through the KIF3 complex - a kinesin superfamily of molecular motors. The KIF3 complex is also responsible for N-cadherin movement in cells. Furthermore, it is well known that these cell adhesion molecules play an important role in carcinogenesis and its progression. This report attempts to link the rare conditions and propose a possible genetic relationship between the two.

Prenatal echocardiographic diagnosis of cardiac right/left axis and malpositions according to standardized Cordes technique.

OBJECTIVE: The aim of this study was to evaluate distinguishing the right/left side of the fetus, cardiac axis and position according to the standardized Cordes technique in 20 cases with cardiac malposition. METHODS: We studied retrospectively 1536 cases whose fetal echocardiographic examinations were performed between 1999 and 2006 in prenatal cardiology unit. Among these, cardiac malpositions were determined in 20 cases. The cardiac axis and position were determined according to the Cordes technique. All cases were followed-up by serial fetal echocardiograms until birth or intrauterine death occurred. In cases of intrauterine death, an autopsy was performed. After birth, physical and echocardiographic examinations were done and prenatal and postnatal diagnoses were compared. RESULTS: Of 1536 fetal echocardiograms performed, 144 revealed congenital heart diseases (9.4%), among these cases 20 were diagnosed with cardiac malposition. Of cases with cardiac malposition, 16 had congenital heart disease, and four had extracardiac malformation. There were six cases of isolated dextrocardia, three cases of situs inversus totalis, six cases of situs ambiguous, and one case of situs inversus with isolated levocardia. Of four cases with extracardiac malformations, two cases had mesoposition, one had dextroposition, and one had extreme levoposition. In six cases the autopsy findings were the same as that their prenatal echocardiographic findings. When postnatal echocardiographic results of the remaining cases with cardiac malposition due to congenital heart disease were compared with prenatal diagnoses, the same echocardiographic findings were verified. CONCLUSION: The fetal right/left axis must be determined correctly for the accurate diagnosis of cardiac malpositions. Therefore, we recommend that Cordes technique provides a simple and reliable determination of the fetal right/left axis and fetal situs.

Craniorachischisis and heterotaxia with heart disease in twins: link or change nature?

Craniorachischisis is a rare neural tube defect in which both acrania and a complete schisis of the vertebral column are present. Heterotaxy results from failure to establish normal left-right asymmetry during embryonic development and is characterized by a variable group of congenital anomalies that include complex cardiac malformations and situs inversus or situs ambiguous. We report a diamniotic twin pregnancy with two malformed fetuses affected one by craniorachischisis and the other by heterotaxya with paired right-sided viscera, asplenia, and complex congenital heart disease. The occurrence of severe congenital anomalies in both members of the twin pair implies a strong influence of genetic factors. At present, the genetic basis determining the different phenotypes observed in our twins is unknown. Our case with the simultaneous presence of both midline and laterality defects in twins supports the hypothesis that the midline plays a critical role in establishing left-right asymmetry in the body and that a mutation in a gene responsible for both heterotaxy and midline defects may be strongly supposed.

Pitchfork regulates primary cilia disassembly and left-right asymmetry.

A variety of developmental disorders have been associated with ciliary defects, yet the controls that govern cilia disassembly are largely unknown. Here we report a mouse embryonic node gene, which we named Pitchfork (Pifo). Pifo associates with ciliary targeting complexes and accumulates at the basal body during cilia disassembly. Haploinsufficiency causes a unique node cilia duplication phenotype, left-right asymmetry defects, and heart failure. This phenotype is likely relevant in humans, because we identified a heterozygous R80K PIFO mutation in a fetus with situs inversus and cystic liver and kidneys, and in patient with double-outflow right ventricle. We show that PIFO, but not R80K PIFO, is sufficient to activate Aurora A, a protooncogenic kinase that induces cilia retraction, and that Pifo/PIFO mutation causes cilia retraction, basal body liberation, and overreplication defects. Thus, the observation of a disassembly phenotype in vivo provides an entry point to understand and categorize ciliary disease. AUTHOR AUDIO:

[A rare cause of left lower quadrant abdominal pain: acute appendicitis with situs inversus totalis]. / Karin sol alt kadran agrisinin nadir bir sebebi: Situs inversus totalisli hastada akut apandisit.

For the patient admitted with right lower quadrant abdominal pain, acute appendicitis is the most frequently considered diagnosis. Appendectomy is the most common of all emergency operations. However, there may be several reasons for left lower quadrant abdominal pain. Situs inversus totalis is an anomaly that occurs during embryonic development when intraabdominal and intrathoracic organs have reverse localization. In this case report, we present a patient who was admitted with left lower quadrant abdominal pain and was diagnosed as situs inversus totalis and acute appendicitis. In view of the legal repercussions for doctors as a result of erroneous diagnosis and treatment, we think that adequate evaluation of the studies in the emergency service is important and that the radiological investigations have to be used appropriately and sufficiently.

Chiral blastomere arrangement dictates zygotic left-right asymmetry pathway in snails.

Most animals display internal and/or external left-right asymmetry. Several mechanisms for left-right asymmetry determination have been proposed for vertebrates and invertebrates but they are still not well characterized, particularly at the early developmental stage. The gastropods Lymnaea stagnalis and the closely related Lymnaea peregra have both the sinistral (recessive) and the dextral (dominant) snails within a species and the chirality is hereditary, determined by a single locus that functions maternally. Intriguingly, the handedness-determining gene(s) and the mechanisms are not yet identified. Here we show that in L. stagnalis, the chiral blastomere arrangement at the eight-cell stage (but not the two- or four-cell stage) determines the left-right asymmetry throughout the developmental programme, and acts upstream of the Nodal signalling pathway. Thus, we could demonstrate that mechanical micromanipulation of the third cleavage chirality (from the four- to the eight-cell stage) leads to reversal of embryonic handedness. These manipulated embryos grew to 'dextralized' sinistral and 'sinistralized' dextral snails-that is, normal healthy fertile organisms with all the usual left-right asymmetries reversed to that encoded by the mothers' genetic information. Moreover, manipulation reversed the embryonic nodal expression patterns. Using backcrossed F(7) congenic animals, we could demonstrate a strong genetic linkage between the handedness-determining gene(s) and the chiral cytoskeletal dynamics at the third cleavage that promotes the dominant-type blastomere arrangement. These results establish the crucial importance of the maternally determined blastomere arrangement at the eight-cell stage in dictating zygotic signalling pathways in the organismal chiromorphogenesis. Similar chiral blastomere configuration mechanisms may also operate upstream of the Nodal pathway in left-right patterning of deuterostomes/vertebrates.

An interrupted inferior vena cava in a situs inversus. Case report and review of the literature.

Situs inversus with interrupted inferior vena cava is an uncommon anatomic variant found in the abdominal and thoracic viscera. In this report, we present a 59-year-old woman with this variation, found during gross anatomical dissection. While this type of variation has been variable, in the present case the hepatic veins drained directly into a very short (2.2 cm) inferior vena cava. The infrarenal component of the inferior vena cava was present and drained into the azygos and hemiazygos veins. Clinical considerations of this variant anatomy are of interest, as they may present in patients as pathology on cross sectional imaging.

[Embryological and genetic mechanisms of cardiac great arteries malformations]. / Mécanismes embryologiques et génétiques des malformations des gros vaisseaux de la base du coeur.

Developmental genetics of congenital heart diseases have evolved from analysis of embryonic hearts towards molecular genetics of cardiac morphogenesis with a dynamic view of cardiac development. Ablation techniques, transgenic animal models and clonal analysis of the developing heart led to identification of different cardiac lineages and their respective roles. The mechanistic approach for great arteries anomalies has led to emerging concepts such as common embryological origin of anatomically different cardiac defects, phenotypic continuum of left heart obstructive defects, or developmental algorithms for cardiac isomerisms. Recent experiments that demonstrated the myocardial rotation of the outflow tract in mouse embryos led to a better understanding of the origin of transposition of the large arteries. This has also raised the hypothesis of a new group of congenital heart anomalies defined as laterality defects limited to a segment of the embryonic heart. These results confirm that genetic heterogeneity of congenital heart defects is related to the heterogeneity of the mechanisms that finally produce the same phenotype.

[Contemporary opinions on pathogenesis, genetics and clinical picture of laterality disorders - left-right axis development defects]. / Wspólczesne poglady na patogeneze, podstawy genetyczne oraz aspekty kliniczne zespolów zaburzonej lateralizacji u czlowieka - nieprawidlowosci rozwoju osi lewo-prawej.

Congenital malformations pose a great challenge to all medical specialities. Laterality defects belong to the group of congenital anomalies resulting from left-right axis development disturbances which arise at an early stage of embryogenesis. The authors discuss selected embryological, epidemiological, genetic and clinical aspects of left-right axis malformations. Furthermore recent knowledge concerning new genes involved in left-right asymmetry development is presented.

Caudal dysgenesis, sirenomelia, and situs inversus totalis: a primitive defect in blastogenesis.

Caudal dysgenesis (CD) constitutes a heterogeneous spectrum of congenital caudal anomalies, including varying degrees of agenesis of the vertebral column, as well as anorectal and genitourinary anomalies. Sirenomelia, characterized by a fusion of the lower limbs, could represent the most severe end of this spectrum. The two main debated pathogenic hypotheses are an aberrant vascular supply versus a primary axial mesoderm defect. We present the autopsy findings of two fetuses of non-diabetic mothers, with normal karyotype. Both fetuses presented situs inversus associated with a CD, in one case consisting of sirenomelia, establishing a very rare association profile that might be random. This association also suggests the occurrence of a common pathogenic mechanism, in accordance to recent genetic data, such as displayed in the Kif3A murine mutation phenotype. Some cases of sirenomelia and CD could represent developmental field defects of blastogenesis involving the caudal mesoderm, rather than being related to vascular insufficiency.

Early morphogenesis of the sinuatrial region of the chick heart: a contribution to the understanding of the pathogenesis of direct pulmonary venous connections to the right atrium and atrial septal defects in hearts with right isomerism of the atrial appendages.

The morphogenesis of the sinuatrial region of embryonic hearts is still not well understood. Current matters of dispute are the topogenesis of the future pulmonary vein orifice and the topogenesis of the primary atrial septum. We analyzed the development of the sinuatrial region in chick embryos ranging from Hamburger and Hamilton (HH) stage 14 to 25. Our study disclosed three features of sinuatrial development. First, the primitive atrium of the HH stage 16 chick embryo heart has a separate inflow component. This inflow component takes up the mouth of the confluence of the systemic veins (sinus venosus) as well as the future mouth of the common pulmonary vein (pulmonary pit). The left portion of the atrial inflow component becomes incorporated into the left atrium and its right portion becomes incorporated into the right atrium. Rightward growth of the sinuatrial fold separates the sinus venosus from the left atrium. Second, the pulmonary pit originally forms as a bilaterally paired structure. Its left and right portions are connected to the left and right portions of the atrial inflow component, respectively. Normally, only the left portion of the pulmonary pit deepens to form the common pulmonary vein orifice, whereas the right portion disappears. Third, the primary atrial septum of the chick heart is not formed at the original midline of the embryonic heart, but is formed to the left of the original midline. This finding is in accord with molecular data suggesting that the primary atrial septum derives from the left heart-forming field. Our findings shed new light on the pathogenesis of direct pulmonary venous connections to the right atrium and atrial septal defects in hearts with right isomerism of the atrial appendages.

Type ID unconventional myosin controls left-right asymmetry in Drosophila.

Breaking left-right symmetry in Bilateria embryos is a major event in body plan organization that leads to polarized adult morphology, directional organ looping, and heart and brain function. However, the molecular nature of the determinant(s) responsible for the invariant orientation of the left-right axis (situs choice) remains largely unknown. Mutations producing a complete reversal of left-right asymmetry (situs inversus) are instrumental for identifying mechanisms controlling handedness, yet only one such mutation has been found in mice (inversin) and snails. Here we identify the conserved type ID unconventional myosin 31DF gene (Myo31DF) as a unique situs inversus locus in Drosophila. Myo31DF mutations reverse the dextral looping of genitalia, a prominent left-right marker in adult flies. Genetic mosaic analysis pinpoints the A8 segment of the genital disc as a left-right organizer and reveals an anterior-posterior compartmentalization of Myo31DF function that directs dextral development and represses a sinistral default state. As expected of a determinant, Myo31DF has a trigger-like function and is expressed symmetrically in the organizer, and its symmetrical overexpression does not impair left-right asymmetry. Thus Myo31DF is a dextral gene with actin-based motor activity controlling situs choice. Like mouse inversin, Myo31DF interacts and colocalizes with beta-catenin, suggesting that situs inversus genes can direct left-right development through the adherens junction.

Left-right lineage analysis of the embryonic Xenopus heart reveals a novel framework linking congenital cardiac defects and laterality disease.

The significant morbidity and mortality associated with laterality disease almost always are attributed to complex congenital heart defects (CHDs), reflecting the extreme susceptibility of the developing heart to disturbances in the left-right (LR) body plan. To determine how LR positional information becomes ;translated' into anatomical asymmetry, left versus right side cardiomyocyte cell lineages were traced in normal and laterality defective embryos of the frog, Xenopus laevis. In normal embryos, myocytes in some regions of the heart were derived consistently from a unilateral lineage, whereas other regions were derived consistently from both left and right side lineages. However, in heterotaxic embryos experimentally induced by ectopic activation or attenuation of ALK4 signaling, hearts contained variable LR cell composition, not only compared with controls but also compared with hearts from other heterotaxic embryos. In most cases, LR cell lineage defects were associated with abnormal cardiac morphology and were preceded by abnormal Pitx2c expression in the lateral plate mesoderm. In situs inversus embryos there was a mirror image reversal in Pitx2c expression and LR lineage composition. Surprisingly, most of the embryos that failed to develop heterotaxy or situs inversus in response to misregulated ALK4 signaling nevertheless had altered Pitx2c expression, abnormal cardiomyocyte LR lineage composition and abnormal heart structure, demonstrating that cardiac laterality defects can occur even in instances of otherwise normal body situs. These results indicate that: (1) different regions of the heart contain distinct LR myocyte compositions; (2) LR cardiomyocyte lineages and Pitx2c expression are altered in laterality defective embryos; and (3) abnormal LR cardiac lineage composition frequently is associated with cardiac malformations. We propose that proper LR cell composition is necessary for normal morphogenesis, and that misallocated LR cell lineages may be causatively linked with CHDs that are present in heterotaxic individuals, as well as some 'isolated' CHDs that are found in individuals lacking overt features of laterality disease.

Roles of the Foxj1 and Inv genes in the left-right determination of internal organs in mice.

In Foxj1 knockout mice, half show situs solitus while the other half show situs inversus, which means a random determination of the left-right axis. In contrast, the inv mutant mice show a mirror-image configuration of the internal organs, which means a reversal of the left-right axis. Although these two mutant mice have primary cilia on the nodal cells, their phenotypes are different in laterality determination. We thus made Foxj1/inv double mutant mice and analyzed their phenotype. We found the phenotypes of Foxj1/inv double mutant mice to be more similar to those of the Foxj1 mutant mice than those of the inv mutant mice. We also found right pulmonary isomerism to be a major phenotype of the Foxj1 mutant mice and the Foxj1/inv double mutant mice, which is likely due to the absence of the Pitx2 expression at both lateral plate mesoderms. These results indicate that a random signal of laterality (Foxj1) is dominant over the reversal signal of laterality (Inv).

Left-right lineage analysis of AV cushion tissue in normal and laterality defective Xenopus hearts.

The majority of complex congenital heart defects occur in individuals who are afflicted by laterality disease. We hypothesize that the prevalence of valvuloseptal defects in this population is due to defective left-right patterning of the embryonic atrioventricular (AV) canal cushions, which are the progenitor tissue for valve and septal structures in the mature heart. Using embryos of the frog Xenopus laevis, this hypothesis was tested by performing left-right lineage analysis of myocytes and cushion mesenchyme cells of the superior and inferior cushion regions of the AV canal. Lineage analyses were conducted in both wild-type and laterality mutant embryos experimentally induced by misexpression of ALK4, a type I TGF-beta receptor previously shown to modulate left-right axis determination in Xenopus. We find that abnormalities in overall amount and left-right cell lineage composition are present in a majority of ALK4-induced laterality mutant embryos and that much variation in the nature of these abnormalities exists in embryos that exhibit the same overall body situs. We propose that these two parameters of cushion tissue formation-amount and left-right lineage origin-are important for normal processes of valvuloseptal morphogenesis and that defective allocation of cells in the AV canal might be causatively linked to the high incidence of valvuloseptal defects associated with laterality disease.

Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination.

Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal failure in children. The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped. The kidney phenotype of NPHP2 combines clinical features of NPHP and polycystic kidney disease (PKD). Here, we identify inversin (INVS) as the gene mutated in NPHP2 with and without situs inversus. We show molecular interaction of inversin with nephrocystin, the product of the gene mutated in NPHP1 and interaction of nephrocystin with beta-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and beta-tubulin colocalize to primary cilia of renal tubular cells. Furthermore, we produce a PKD-like renal cystic phenotype and randomization of heart looping by knockdown of invs expression in zebrafish. The interaction and colocalization in cilia of inversin, nephrocystin and beta-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to left-right axis determination.

Notch activity induces Nodal expression and mediates the establishment of left-right asymmetry in vertebrate embryos.

Left-sided expression of Nodal in the lateral plate mesoderm is a conserved feature necessary for the establishment of normal left-right asymmetry during vertebrate embryogenesis. By using gain- and loss-of-function experiments in zebrafish and mouse, we show that the activity of the Notch pathway is necessary and sufficient for Nodal expression around the node, and for proper left-right determination. We identify Notch-responsive elements in the Nodal promoter, and unveil a direct relationship between Notch activity and Nodal expression around the node. Our findings provide evidence for a mechanism involving Notch activity that translates an initial symmetry-breaking event into asymmetric gene expression.