ZIC3 in Heterotaxy.

Mutation of ZIC3 causes X-linked heterotaxy, a syndrome in which the laterality of internal organs is disrupted. Analysis of model organisms and gene expression during early development suggests ZIC3-related heterotaxy occurs due to defects at the earliest stage of left-right axis formation. Although there are data to support abnormalities of the node and cilia as underlying causes, it is unclear at the molecular level why loss of ZIC3 function causes such these defects. ZIC3 has putative roles in a number of developmental signalling pathways that have distinct roles in establishing the left-right axis. This complicates the understanding of the mechanistic basis of Zic3 in early development and left-right patterning. Here we summarise our current understanding of ZIC3 function and describe the potential role ZIC3 plays in important signalling pathways and their links to heterotaxy.

Comparing levocardia and dextrocardia in fetuses with heterotaxy syndrome: prenatal features, clinical significance and outcomes.

BACKGROUND: To investigate the differences in cardiovascular disease, extracardiac anomalies and outcomes between fetuses with levocardia and dextrocardia. METHODS: Clinical demographics, prenatal features, postnatal characteristics and the outcomes of fetuses with levocardia or dextrocardia were recorded and analyzed. RESULTS: Sixty-five fetuses with dextrocardia and thirty-eight fetuses with levocardia were enrolled. Right ventricle outlet obstruction, atrioventricular septal defect and intestinal malrotation were common in both groups. Univentricular physiology, transposition of the great arteries and esophageal atresia were more frequent in fetuses with levocardia, whereas abnormal pulmonary venous connection, double outlet of right ventricle, left ventricle outlet obstruction and brain abnormalities were more frequent in the dextrocardia group. The accuracy of evaluating cardiac malformations was high, but the sensitivity in assessing extracardiac abnormalities was low. CONCLUSIONS: Although the disorders have certain overlapping features, there are several differences between fetuses with levocardia and dextrocardia. These findings might improve patient counseling and perinatal management.

Zic3 is required in the migrating primitive streak for node morphogenesis and left-right patterning.

In humans, loss-of-function mutations in ZIC3 cause isolated cardiovascular malformations and X-linked heterotaxy, a disorder with abnormal left-right asymmetry of organs. Zic3 null mice recapitulate the human heterotaxy phenotype but also have early gastrulation defects, axial patterning defects and neural tube defects complicating an assessment of the role of Zic3 in cardiac development. Zic3 is expressed ubiquitously during critical stages of left-right patterning but its later expression in the developing heart remains controversial and the molecular mechanism(s) by which it causes heterotaxy are unknown. To define the temporal and spatial requirements, for Zic3 in left-right patterning, we generated conditional Zic3 mice and Zic3-LacZ-BAC reporter mice. The latter provide compelling evidence that Zic3 is expressed in the mouse node and absent in the heart. Conditional deletion using T-Cre identifies a requirement for Zic3 in the primitive streak and migrating mesoderm for proper left-right patterning and cardiac development. In contrast, Zic3 is not required in heart progenitors or the cardiac compartment. In addition, the data demonstrate abnormal node morphogenesis in Zic3 null mice and identify similar node dysplasia when Zic3 was specifically deleted from the migrating mesoderm and primitive streak. These results define the temporal and spatial requirements for Zic3 in node morphogenesis, left-right patterning and cardiac development and suggest the possibility that a requirement for Zic3 in node ultrastructure underlies its role in heterotaxy and laterality disorders.

Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects.

All vertebrates display a characteristic asymmetry of internal organs with the cardiac apex, stomach and spleen towards the left, and the liver and gall bladder on the right. Left-right (L-R) axis abnormalities or laterality defects are common in humans (1 in 8,500 live births). Several genes (such as Nodal, Ebaf and Pitx2) have been implicated in L-R organ positioning in model organisms. In humans, relatively few genes have been associated with a small percentage of human situs defects. These include ZIC3 (ref. 5), LEFTB (formerly LEFTY2; ref. 6) and ACVR2B (encoding activin receptor IIB; ref. 7). The EGF-CFC genes, mouse Cfc1 (encoding the Cryptic protein; ref. 9) and zebrafish one-eyed pinhead (oep; refs 10, 11) are essential for the establishment of the L-R axis. EGF-CFC proteins act as co-factors for Nodal-related signals, which have also been implicated in L-R axis development. Here we identify loss-of-function mutations in human CFC1 (encoding the CRYPTIC protein) in patients with heterotaxic phenotypes (randomized organ positioning). The mutant proteins have aberrant cellular localization in transfected cells and are functionally defective in a zebrafish oep-mutant rescue assay. Our findings indicate that the essential role of EGF-CFC genes and Nodal signalling in left-right axis formation is conserved from fish to humans. Moreover, our results support a role for environmental and/or genetic modifiers in determining the ultimate phenotype in humans.

Dextrocardia: practical clinical points and comments on terminology.

Dextrocardia is defined by the authors as a right-sided heart with a base-apex axis directed rightward, resulting from a variation in cardiac development, and not used as a general term indicating any heart in the right chest. Dextrocardia occurs in approximately 0.01% of live births and can be discovered in various clinical settings and at various patient ages. The authors review their experience with dextrocardia, discuss useful clinical points that aid in evaluating complex anatomy, recount the history of dextrocardia terminology, and note the current inconsistent nomenclature.

A role of the cryptic gene in the correct establishment of the left-right axis.

During vertebrate embryogenesis, a left-right axis is established. The heart, associated vessels and inner organs adopt asymmetric spatial arrangements and morphologies. Secreted growth factors of the TGF-beta family, including nodal, lefty-1 and lefty-2, play crucial roles in establishing left-right asymmetries [1] [2] [3]. In zebrafish, nodal signalling requires the presence of one-eyed pinhead (oep), a member of the EGF-CFC family of membrane-associated proteins [4]. We have generated a mutant allele of cryptic, a mouse EGF-CFC gene [5]. Homozygous cryptic mutants developed to birth, but the majority died during the first week of life because of complex cardiac malformations such as malpositioning of the great arteries, and atrial-ventricular septal defects. Moreover, laterality defects, including right isomerism of the lungs, right or left positioning of the stomach and splenic hypoplasia were observed. Nodal gene expression in the node was initiated in cryptic mutant mice, but neither nodal, lefty-2 nor Pitx2 were expressed in the left lateral plate mesoderm. The laterality defects observed in cryptic(-/-) mice resemble those of mice lacking the type IIB activin receptor or the homeobox-containing factor Pitx2 [6] [7] [8] [9], and are reminiscent of the human asplenic syndrome [10]. Our results provide genetic evidence for a role of cryptic in the signalling cascade that determines left-right asymmetry.

A population-based study of cardiac malformations and outcomes associated with dextrocardia.

The incidence of dextrocardia and its associated cardiac and noncardiac malformations is not known. There is inadequate information about outcomes to counsel parents about prognosis. A retrospective review of all diagnoses of dextrocardia due to embryologic development at a tertiary care hospital from 1985 to 2001 was performed. Eighty-one cases were identified (48 antenatally). The incidence of dextrocardia was estimated to be 1 in 12,019 pregnancies. Twenty-seven cases were situs solitus, 30 situs inversus, and 24 situs ambiguous or isomerism. Cardiac malformations were found in 26 of 27 cases of situs solitus, 7 of 30 cases of situs inversus, and 24 of 24 cases of isomerism. Noncardiac malformations were identified in 10 of 27 cases of situs solitus, 6 of 30 cases of situs inversus, and 14 of 24 cases of isomerism. Twelve pregnancies were terminated, 3 fetuses were stillborn, and 2 women chose compassionate care. All terminated fetuses were diagnosed with dextrocardia before termination, and all had >1 cardiac anomaly; 7 also had noncardiac anomalies. There were 43 subjects in the intention-to-treat group (20 situs solitus, 10 solitus inversus, 13 isomerism). Thirty-two had >or=1 cardiac operation, and 21 had >or=3. Thirty-nine subjects were alive at most recent follow-up. In conclusion, the incidence of dextrocardia was 1 in 12,019 pregnancies. In conclusion, in our cohort, the numbers of cases of situs solitus, situs inversus, and isomerism were similar. Cardiac and noncardiac malformations were most common in the isomerism group. Cardiac malformations were often complex in the situs solitus and isomerism groups. Ninety-one percent of those in the intention-to-treat cohort were alive at follow-up.

Diagnosis and outcome of dextrocardia diagnosed in the fetus.

A retrospective review of 5,539 fetal echocardiograms over a 22-year period revealed 85 cases of dextrocardia. In primary dextrocardia (46 cases), the incidence of situs solitus, inversus, and ambiguous, was similar and associated with a high incidence of complex cardiac malformations in situs solitus and situs ambiguous. Secondary dextrocardia (39 cases) was due to intrathoracic displacement and, when caused by diaphragmatic hernia, was associated with cardiac malformations in 31% of cases. Even in complex cases, fetal echocardiography was highly accurate; therefore, specific counseling can be given to parents.

Angular homeostasis. VIII. Pursuit of a slowly moving target in a plane: relevance to lateralization in cardiovascular ontogeny.

We explore the pursuit in a plane of a target moving at constant slow speed in a straight line. Two models of the pursuit are given. In the continuous case, the pursuer is moving at constant speed and is subject to proportionate angular homeostasis with correction constant b. In the discrete version movement occurs at a constant speed in a sequence of straight line segments of constant length (called the step size, s) the end of the segments being called the vertices. The pattern considered is not the absolute position of the pursuer, but its distance and orientation relative to the target. Both the transients and the asymptotic orbit are addressed. A key quantity is r, the speed of the target expressed as a fraction of that of the pursuer. If the speed of the pursuer is defined as unity, r is also the ratio of the speeds. There exists a critical speed fraction, R(b,s), a function of b and s, that defines what the term slow designates. R(b,s), which has to be found numerically, has the following property. For r less than R(b,s), the asymptotic path is a simple closed curve. In the discrete case the vertices converge to a simple closed curve. The larger r, the more the path (or in the discrete analogue its set of vertices) departs from a circle, and the more eccentric the target is with respect to it. Interest centers on two issues. First we address the transient patterns of the path, notably whether or not the sense of any particular path (clockwise or counterclockwise) is the same throughout, or changes at some stage.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Fetal cardiac dextroposition in the absence of an intrathoracic mass: sign of significant right lung hypoplasia.

We reviewed our experience of fetal cardiac dextroposition in the absence of an intrathoracic mass. Ten cases were found by fetal echocardiography to have a normal cardiac axis, but the heart was shifted into the right chest and the amount of right lung tissue was reduced. At birth seven of the infants had confirmed structural heart disease (70%), including three with scimitar syndrome. Two infants had additional extracardiac anomalies (20%). Seven infants born at term had clinical pulmonary hypertension with a diagnosis of right lung hypoplasia in all of them. Two neonates died owing to significant heart disease (one with scimitar syndrome and the other with hypoplastic left heart syndrome). Of the three pregnancies that were terminated, the two fetuses with autopsies had severe right lung hypoplasia. Fetal cardiac dextroposition and right pulmonary artery hypoplasia in the absence of an intrathoracic mass are important signs of right lung hypoplasia, which can be associated with significant pathologic cardiac and extracardiac conditions.

Horses lung: Report of two cases.

Two cases of horseshoe lung are described; one was suspected and the other was diagnosed preoperatively. Both underwent successful surgical treatment. The embryology of this anomaly is briefly reviewed with reference to the closely related scimitar syndrome (anomalous venous return of right lung to inferior atriocaval junction). Diagnostic studies are discussed with stress on the need for a thorough functional evaluation of both the heart and lungs before the surgical indication is made.