A Zebrafish Loss-of-Function Model for Human CFAP53 Mutations Reveals Its Specific Role in Laterality Organ Function.

Establishing correct left-right asymmetry during embryonic development is crucial for proper asymmetric positioning of the organs. Congenital heart defects, such as dextrocardia, transposition of the arteries, and inflow or outflow tract malformations, comprise some of the most common birth defects and may be attributed to incorrect establishment of body laterality. Here, we identify new patients with dextrocardia who have mutations in CFAP53, a coiled-coil domain containing protein. To elucidate the mechanism by which CFAP53 regulates embryonic asymmetry, we used genome editing to generate cfap53 zebrafish mutants. Zebrafish cfap53 mutants have specific defects in organ laterality and randomization of asymmetric gene expression. We show that cfap53 is required for cilia rotation specifically in Kupffer's vesicle, the zebrafish laterality organ, providing a mechanism by which patients with CFAP53 mutations develop dextrocardia and heterotaxy, and confirming previous evidence that left-right asymmetry in humans is regulated through cilia-driven fluid flow in a laterality organ.

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.

CLINICAL CASE OF THE MONTH: A Review of Situs Inversus and Dextrocardia.

A 21-year-old woman at 25 weeks gestation presented to the emergency department with chief complaints of decreased appetite for one week, fever, runny and stuffy nose, and generalized muscle pains.

Visceral heterotaxy in the developing world.

BACKGROUND: The challenge of visceral heterotaxy (VH) in the developing world has not been analysed in detail. METHOD: Retrospective chart review of 69 consecutive patients over ten years assessed the clinical profile and surgical outcome of VH. Median age: 3 years; median weight: 15kg. Diagnosis was made by echocardiography supplemented with blood smear (Howell Jolly bodies), Multi-Detector Computed Tomography (MDCT) angiogram and/or surgical inspection. RESULTS: In right isomerism (RI) group (n=32), 12 patients did not undergo surgery, five had Blalock Taussig shunt, 14 had bidirectional Glenn and one had Fontan completion, with surgical mortality of 5%. In left isomerism (LI) group (n=31), 11 patients underwent two ventricle repair (35%) and 15 (48%) had single ventricle repair, with surgical mortality of 3.8%; five did not have surgery. On follow up (median period 1.5 years), 33% of un-operated patients and 25% of operated patients died, mortality being higher for RI patients. Late mortality was due to sepsis, heart failure or arrhythmia. CONCLUSION: VH can be diagnosed by imaging based criteria. VH tends to present late in the developing world with a significant percentage inoperable. LI had better surgical outcome and higher long term survival.

Off-pump coronary artery bypass grafting in an octogenarian with situs inversus and dextrocardia: report of a case.

Dextrocardia associated with situs inversus totalis is a rare condition. A small number of patients with the condition have been reported after undergoing myocardial revascularization. We experienced a case of this rare disorder in an 83-year-old man. He was successfully treated by off-pump coronary artery bypass grafting with bilateral internal thoracic arteries and a saphenous vein. Except for the mirror-image anatomy, the surgical technique was similar to that used for a patient with situs solitus.

Congenitally corrected transposition of the great arteries: a unique case from Iraq.

A severely cyanotic 27-month-old Iraqi child was transferred to the United States for surgical treatment of suspected tetralogy of Fallot. Her diagnostic studies showed dextrocardia, congenitally corrected transposition of the great arteries, hypoplastic left-sided ventricle, interrupted inferior vena cava, and severe pulmonic stenosis. Given the anatomic constraints as well as the absence of long-term medical care, the decision was made to pursue single-ventricle palliation. The patient recovered from a superior cavopulmonary anastomosis without event and has since returned to her native Iraq.

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.

Right heterotaxy with Hirschsprung's disease - a new association.

A baby girl with prenatal diagnosis of complex cardiac anomalies and diaphragmatic hernia was born at 36 weeks of gestation. At 4 hr of life, the baby developed respiratory distress and was intubated. She was found to have right hetetrotaxy with total anomalous pulmonary venous drainage into the portal vein, five hepatic veins draining the liver and intrathoracic herniation of the stomach. The child also developed abdominal distension on the second day of life with passage of scanty meconium. The diagnosis of Hirschsprung's disease (HD) was confirmed by histology. HD in association with right heterotaxy has not been reported earlier. The association of heterotaxy with HD in our patient raises a possible genetic link between the two anomalies that needs further research.

Rare association of Klippel Feil syndrome with cleft palate and congenital cardiac deformities: a case report.

Klippel Feil Syndrome comprises of three characteristic deformities of short neck, a low dorsal hair line and restricted neck mobility. This is a case report of Klippel Feil Syndrome and its rare association with cleft of hard and soft palate, coarctation of aorta, dextrocardia and situs inversus. An interdisciplinary approach towards the management included cardiac surgery, cleft repair and complete oral rehabilitation of the patient. Presently the patient is undergoing speech therapy and is under regular follow up.

Dextrocardia and coronal alignment of thoracic curve: a population study.

The objective of this study was to evaluate the coronal alignment of the thoracic spine in persons with dextrocardia. Generally, the thoracic spine is slightly curved to the right. It has been suggested that the curve could be triggered by pulsation forces from the descending aorta. Since no population study has focused on the alignment of the thoracic spine in persons with situs inversus, dextrocardia, and right-sided descending aorta, we compared the radiographs of the thoracic spine in persons with dextrocardia to those having normal levocardia. Among 57,440 persons in a health survey, 11 cases of dextrocardia were identified through standard radiological screening. The miniature chest radiographs of eight persons were eligible for the present study. The study was carried out as a nested case-control study. Four individually matched (age, gender, and municipality) controls with levocardia were chosen for each case. Coronal alignment of the thoracic spine was analyzed without knowledge of whether the person had levo- or dextrocardia. A mild convexity to the left was found in all persons with dextrocardia and right-sided descending aorta (mean Cobb angle 6.6 degrees to the left, SD 2.9). Of the 32 normal levocardia persons, 29 displayed a convexity to the right, and the remaining three had a straight spine (mean Cobb angle 5.2 degrees to the right, SD 2.3). The difference (mean 11.8 degrees , SD 3.5) differed significantly from unity (P = 0.00003). In conclusion, it seems that a slight left convexity of the thoracic spine is frequent in dextrocardia. We assume that the effect of the repetitive pulsatile pressure of the descending thoracic aorta, and the mass effect of the heart may cause the direction of the convexity to develop opposite to the side of the aortic arch.

Off-pump coronary artery bypass surgery in dextrocardia: a report of two cases.

Dextrocardia is a rare condition that may be congenital (situs inversus) or acquired (pseudodextrocardia). Since individuals with this ailment have normal cardiac physiology and function, they may live normal lives. Similar to the general population, however, they might be susceptible to ischemic heart disease and present to a cardiothoracic surgical department for coronary artery bypass surgery. We report two cases: one of dextrocardia (situs inversus) and another resulting from an elevation of the left hemidiaphragm, causing pseudodextrocardia. To operate on patients with dextrocardia, surgeons may need to make a few modifications. These include using the right internal mammary artery as a conduit for the "left" anterior descending artery, lengthening the left internal mammary artery to reach the left anterior descending artery, and sometimes the operating surgeon may need to stand at the left side of the operating table. The careful planning of work on the conduits in the preoperative period requires prudence. This report highlights the surgical difficulties during operations on patients with situs inversus or pseudodextrocardia.

Diagnostic imaging approach to dextrocardia: self-assessment module.

The educational objectives for this self-assessment module are for the participant to exercise, self-assess, and improve his or her understanding of the diagnostic imaging approach to dextrocardia.

An Unusual Combination of Mirror-Image Dextrocardia with Familial Medulloblastoma: Is There a Histogenetic Relationship?

BACKGROUND: The occurrence of medulloblastoma in the absence of hereditary syndromes is rare. Dextrocardia with situs inversus is also called mirror-image dextrocardia. A combination of mirror-image dextrocardia with medulloblastoma has not been reported previously. To the best of our knowledge, this is the first report of this rare combination in a family with medulloblastoma. METHODS: The clinical manifestation, radiographic characteristics, treatment, and outcomes of 3 medulloblastoma cases in 2 cousins and their maternal uncle was described. Tumor samples of the 2 cousins were first examined for histologic subtypes. Total RNA of their tumors was extracted from formalin-fixed and paraffin-embedded samples. Then, expression of 22 subgroup-specific genes and 3 housekeeping genes was analyzed by the NanoString nCounter Analysis System. The posttest data were normalized by NanoStringNorm package for molecular subgroup prediction. RESULTS: The proband remains tumor free and alive up to the latest follow-up. His cousin, who had combined mirror-image dextrocardia with situs inversus, died of anoxia after surgery and his uncle died of tumor 2.5 years after surgery. Medulloblastoma of the 2 cousins was classified as classic and molecular group 4 subtype. CONCLUSIONS: The same classic and molecular group 4 subtype of the 2 cousins may suggest a similar genetic predisposition. Involvement of the Otx2 gene dysfunction in both group 4 subtype medulloblastoma and mirror-image dextrocardia with situs inversus points to a possible mechanism that dysfunction of a shared signaling pathway such as Otx2 might be the underlying cause of these 2 conditions in this family.

Cantrell syndrome in one of a set of monozygotic twins.

Cantrell syndrome is a rare syndrome of congenital defects involving the abdominal wall, sternum, diaphragm, pericardium and the heart. The spectrum of anomalies varies widely. A full syndrome, probable syndrome and incomplete expression have been described. Less than 160 cases have been described in the world literature. Only one set of monozygotic twins concordant with the syndrome has been reported. To our knowledge, the syndrome affecting only one of a set of twins has not been reported. We report a premature infant, the first-born twin, with the syndrome. The omphalocoele was large, and heart abnormalities included dextrocardia with atrial septal defect. The co-twin is normal.

[A neonate with the heart in the right hemithorax]. / Een pasgeborene met het hart in de rechter thoraxhelft.

Three neonates presented with the heart in the right hemithorax: a newborn girl with a chest deformity and secondary dextrocardia (Poland sequence), a prematurely born girl with uncomplicated Kartagener's syndrome, and a newborn boy with cyanosis and the heart in the right hemithorax, in whom a surgical correction was indicated. A diagnosis ofdextrocardia should include the differentiation between primary and secondary dextrocardia. Secondary dextrocardia, or dextroposition, is the result of chest deformities, diaphragmatic defects, severe lung disease, or the presence of a mass displacing the heart from its normal position, usually without any cardiac abnormalities. In primary dextrocardia, the position of the organs in the abdomen is important for the differential diagnosis and the prognosis. The incidence of congenital cardiac malformations in primary dextrocardia varies from 10%, in situs inversus totalis, up to 90% in solitary dextrocardia.

When hepatoma rupture happens in situs inversus totalis: side matters.

The authors reported a 73-year-old alcoholic man with previously-unrecognized situs inversus totalis suffering from left upper quadrant pain. Acute myocardial infarction was diagnosed and coronary angioplasty was performed immediately. However, the massive bleeding from the previously-unfound hepatomas caused hypovolemic shock and fatal outcome. Situs inversus totalis is a rare congenital anomaly with a complete mirror image of the thoracic and abdominal organs. Although being considered a benign entity, it would disturb diagnosis-making of the visceral diseases owing to the altered anatomy. To our knowledge, the coexistence of the coronary artery disease and ruptured hepatomas in situs inversus totalis, as in our patient, is never described. Recognition of any situs anomalies in time is the key to avoid misdiagnosis, inappropriate managements, and unwanted consequences.

The surgical anatomy of pulmonary atresia with ventricular septal defect: pseudotruncus.

This is a study of 172 heart specimens with pulmonary atresia and ventricular septal defect (VSD)--pseudotruncus. These are divided into simple and complicated types. In the simple type the following may be of importance from the surgical standpoint: (1) the size of the pulmonary arteries, (2) the origin of the aorta, (3) the amount of pulmonary flow, (4) the size of the left side of the heart, (5) the presence of bronchial and/or abnormal systemic supply to the lungs, (6) the coronary circulation, and (7) the presence of intra- and extracardiac associated abnormalities. The following factors may be important in the complicated types: (1) Complete transposition may accompany the complex; (2) instead of the VSD there may be a common atrioventricular (AV) orifice; (3) the pulmonary atresia with VSD may be associated with tricuspid or mitral atresia or with common or single ventricle; (4) the entity may be associated with abnormal position of the entire heart or some of its component chambers.

An ultrasonic approach to the diagnosis of cardiac situs, connections, and malpositions.

Two-dimensional echocardiography of cardiac situs, connections, and malpositions from a variety of planes is discussed.

Unguarded tricuspid orifice: a rare malformation of tricuspid valve diagnosed by echocardiography. Report of two cases and review of the literature.

In this report we present two cases with unguarded tricuspid orifice, and review the literature. The complete absence of tricuspid valvular structures is a very rare anomaly coexisting with pulmonary atresia and intact ventricular septum, and is termed unguarded tricuspid orifice. Double tricuspid orifices and isolated dextrocardia were distinguishing features of our first case. The second patient of this report, a 5-year-old boy, is the first case in the literature with this malformation of the tricuspid valve as an isolated anomaly, in addition to being the first surviving case in the literature.

An unusual type of anomalous pulmonary venous drainage associated with a complex left heart hypoplasia and a variety of divided left atrium ("cor triatriatum").

A previously unreported complex congenital cardiac malformation was noted in which a vestigial left atrium consisted of two completely separate portions, one of which was connected to the pulmonary veins but had no outlet orifice. The pulmonary venous drainage was through an anomalous intrapulmonary vein within the displaced right lung into the inferior caval vein above a deformed diaphragm. The left atrioventricular connexion was absent. Some points of terminology are considered.