Situs Abnormalities Research Articles

Comparison of Outcomes in Adults With Congenitally Corrected Transposition With Situs Inversus Versus Situs Solitus

The long-term outcome of patients with congenitally corrected transposition of the great arteries is mainly determined by progressive morphologically tricuspid valve regurgitation, heart block, atrial arrhythmias, and/or systemic ventricular dysfunction. Situs abnormalities have been reported in ≤34% of cases, but whether clinical differences exist between a situs inversus and situs solitus arrangement has not yet been studied. The clinical records of 38 adults with congenitally corrected transposition of the great arteries (mean age 40 ± 15 years) followed for a mean period of 7.4 years were reviewed. Of these 38 patients, 8 presented with situs inversus and 30 with situs solitus. No significant differences were found between the 2 groups in age, gender, ventricular septal defect, pulmonary tract stenosis, previous surgical repair, or duration of follow-up. However, none of the patients with situs inversus presented with an Ebstein-like anomaly of the morphologically tricuspid valve and none developed nonoperative-related complete atrioventricular block compared to 15 (50%; p = 0.013) and 11 (42%; p = 0.032) of the patients with situs solitus, respectively. At follow-up, 2 patients with situs inversus (25%) presented with sustained atrial arrhythmia, severe tricuspid regurgitation, or severe systemic right ventricular systolic dysfunction compared to 22 (73%) of 30 those with situs solitus (p = 0.034). No patient with situs inversus presented with cardiac death or severe heart failure compared to 12 (40%) of 30 with situs solitus (p = 0.038). In conclusion, Ebstein-like anomaly or spontaneous complete atrioventricular block are rare in patients with congenitally corrected transposition of the great arteries with situs inversus, and late complications are uncommon. The long-term outcome of patients with situs inversus was significantly better than that for patients with situs solitus.

Prenatal Diagnosis of Isolated Levocardia and a Structurally Normal Heart: Two Case Reports and a Review of the Literature

Isolated levocardia (ILC) is a developmental abnormality involving an abnormal abdominal situs with a normal cardiac situs. This abnormality is especially rare when it is associated with a normal cardiac anatomy. The prenatal diagnoses of seven cases were reported in the English literature. This report presents two cases referred to the authors' echocardiography laboratory for maternal diabetes mellitus in case 1 and suspected dextrocardia in case 2. In both cases, ILC with a structurally normal heart was diagnosed prenatally. The child in the first case was found to have a normal inferior vena cava (IVC) prenatally. Postnatally, he was found to have intestinal malrotation with duodenal obstruction and multiple splenules. Interruption of the IVC was shown by abdominal ultrasound. The child in the second case was found to have an interrupted IVC with azygos continuation prenatally. Postnatally, intestinal malrotation with no evidence of intestinal obstruction or asplenia was detected. Neither of the cases had reported cardiac arrhythmias. Early diagnosis is crucial in these cases due to the high incidence of associated anomalies and potential life-threatening conditions. Management of patients with ILC is dictated by the associated anomalies. Long-term follow-up assessment is recommended for these patients to monitor the development of rhythm abnormalities.

Static respiratory cilia associated with mutations in Dnahc11/DNAH11: a mouse model of PCD.

Primary ciliary dyskinesia (PCD) is an inherited disorder causing significant upper and lower respiratory tract morbidity and impaired fertility. Half of PCD patients show abnormal situs. Human disease loci have been identified but a mouse model without additional deleterious defects is elusive. The inversus viscerum mouse, mutated at the outer arm dynein heavy chain 11 locus (Dnahc11) is a known model of heterotaxy. We demonstrated immotile tracheal cilia with normal ultrastructure and reduced sperm motility in the Dnahc11(iv) mouse. This is accompanied by gross rhinitis, sinusitis, and otitis media, all indicators of human PCD. Strikingly, age-related progression of the disease is evident. The Dnahc11(iv) mouse is robust, lacks secondary defects, and requires no intervention to precipitate the phenotype. Together these findings show the Dnahc11(iv) mouse to be an excellent model of many aspects of human PCD. Mutation of the homologous human locus has previously been associated with hyperkinetic tracheal cilia in PCD. Two PCD patients with normal ciliary ultrastructure, one with immotile and one with hyperkinetic cilia were found to carry DNAH11 mutations. Three novel DNAH11 mutations were detected indicating that this gene should be investigated in patients with normal ciliary ultrastructure and static, as well as hyperkinetic cilia.

Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure

RationalePrimary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterised by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients...

The Emerging Genetics of Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is an autosomal recessive, rare, genetically heterogeneous condition characterized by oto-sino-pulmonary disease together with situs abnormalities (Kartagener syndrome) owing to abnormal ciliary structure and function. Most patients are currently diagnosed with PCD based on the presence of defective ciliary ultrastructure. However, diagnosis often remains challenging due to variability in the clinical phenotype and ciliary ultrastructural changes. Some patients with PCD have normal ciliary ultrastructure, which further confounds the diagnosis. A genetic test for PCD exists but is of limited value because it investigates only a limited number of mutations in only two genes. The genetics of PCD is complicated owing to the complexity of axonemal structure that is highly conserved through evolution, which is comprised of multiple proteins. Identifying a PCD-causing gene is challenging due to locus and allelic heterogeneity. Despite genetic heterogeneity, multiple tools have been used, and there are 11 known PCD-causing genes. All of these genes combined explain approximately 50% of PCD cases; hence, more genes need to be identified. This review briefly describes the current knowledge regarding the genetics of PCD and focuses on the methodologies used to identify novel PCD-causing genes, including a candidate gene approach using model organisms, next-generation massively parallel sequencing techniques, and the use of genetically isolated populations. In conclusion, we demonstrate the multipronged approach that is necessary to circumvent challenges due to genetic heterogeneity to uncover genetic causes of PCD.

Spectrum of clinical diseases caused by disorders of primary cilia.

The ciliopathies are a category of diseases caused by disruption of the physiological functions of cilia. Ciliary dysfunction results in a broad range of phenotypes, including renal, hepatic, and pancreatic cyst formation; situs abnormalities; retinal degeneration; anosmia; cerebellar or other brain anomalies; postaxial polydactyly; bronchiectasis; and infertility. The specific clinical features are dictated by the subtype, structure, distribution, and function of the affected cilia. This review highlights the clinical variability caused by dysfunction of motile and nonmotile primary cilia and emphasizes the genetic heterogeneity and phenotypic overlap that are characteristics of these disorders. There is a need for additional research to understand the shared and unique functions of motile and nonmotile cilia and the pathophysiology resulting from mutations in cilia, basal bodies, or centrosomes. Increased understanding of ciliary biology will improve the diagnosis and management of primary ciliary dyskinesia, syndromic ciliopathies, and cilia-related cystic diseases.

Kartagener Syndrome

A 40-year-old female came to our outpatient department with the chief complaints of cough with blood-tinged sputum and nasal bleeding for several days. She had suffered from chronic cough and rhinorrhea since adolescence and usually received treatment from local medical doctors. She had had a chest radiograph once before, but her situs abnormality was not identified because of wrong labeling. On auscultation, her maximal heart beats were heard through the right fifth intercostal space. Chest roentgenography showed situs inversus totalis (Figure 1).

Study on relation between the fetal abdominal great vessels anormalities and heterotaxy

Objective To investigate the relation between anormalities of fetal abdominal great vessels and heterotaxy, the clinical significance of screening fetal heterotaxy by the abnormalities of fetal abdominal great vessels. Methods 6532 fetuses from our hospital were scanned and the fetuses with abdominal great vessels abnormalities were included. Parameters of fetal growth, abdominal great vessels and anatomical survey were detected. Results Forty-five cases (0.7%) of fetal abdominal great vessels abnormalities were detected prenatally. Forty-two cases were confirmed postnatally, including 35 cases of heterotaxy syndrome and 7 cases of situs inversus totalis and 3 cases missed. The incidences of the abnormal fetus,heterotaxy syndrome and situs inversus totalis of the fetuses with abnormal abdominal great vessels were higher than that of the fetuses with normal abdominal great vessels, the differences were statistically significant( P＜ 0.001). The incidence of both type Ⅰ and type Ⅱ of the heterotaxy syndrome were significantly higher than that of type Ⅳ (P＜0.001). There was a high incidence of left isomerism in abnormal type Ⅰ and of right isomerism in abnormal type Ⅱ , the differences were statistically significant (P＜ 0.001). Conclusions Abnormal great vessels abnormalities have strong relations to heterotaxy and situs inversus which can be used as effective and simple indicator in screening heterotaxy syndrome. Key words: Ultrasonography, prenatal; Cardiovascular abnormalities; Situs inversus

Increased postoperative and respiratory complications in patients with congenital heart disease associated with heterotaxy

Patients with heterotaxy and complex congenital heart disease underwent cardiac surgery with high mortality and morbidity. Recent studies have revealed an association among heterotaxy, congenital heart disease, and primary ciliary dyskinesia. We undertook a retrospective review of patients undergoing cardiac surgery at Children's National Medical Center between 2004 and 2008 to explore the hypothesis that there is increased mortality and respiratory complications in heterotaxy patients. Retrospective review was performed on postsurgical outcomes of 87 patients with heterotaxy and congenital heart disease exhibiting the full spectrum of situs abnormalities associated with heterotaxy. As controls patients, 634 cardiac surgical patients with congenital heart disease, but without laterality defects, were selected, and surgical complexities were similar with a median Risk Adjustment in Congenital Heart Surgery-1 score of 3.0 for both groups. We found the mean length of postoperative hospital stay (17 vs 11 days) and mechanical ventilation (11 vs 4 days) were significantly increased in the heterotaxy patients. Also elevated were rates of tracheostomies (6.9% vs 1.6%; odds ratio, 4.6), extracorporeal membrane oxygenation support (12.6% vs 4.9%: odds ratio, 2.8), prolonged ventilatory courses (23% vs 12.3%; odds ratio, 2.1) and postsurgical deaths (16.1% vs 4.7%; odds ratio, 3.9). Our findings show heterotaxy patients had more postsurgical events with increased postsurgical mortality and risk for respiratory complications as compared to control patients with similar Risk Adjustment in Congenital Heart Surgery-1 surgical complexity scores. We speculate that increased respiratory complications maybe due to ciliary dysfunction. Further studies are needed to explore the basis for the increased surgical risks for heterotaxy patients undergoing cardiac surgery.

Familial isolated congenital asplenia: case report and literature review

Congenital asplenia is a rare life-threatening condition, often presenting with pneumococcal sepsis. It may arise as part of situs abnormalities or result from an unrelated specific defect of spleen development. The mode of inheritance is usually autosomal dominant, though sporadic cases are also reported. In affected individuals, the use of appropriate antibiotic prophylaxis and immunisations could save lives. In our report, we describe a family of three siblings with isolated congenital asplenia and unaffected parents, suggestive of recessive inheritance. The diagnosis in the proband was made post mortem following overwhelming pneumococcal sepsis. We also review the literature and compare the eight families previously reported with congenital isolated asplenia.

Multiple anatomical malformations in 25-year old patient with heterotaxy: Case report

Heterotaxy or situs ambiguus is a rare congenital disorder, characterized by abnormal situs with either left or right isomerism that usually coincides with A complex malformation. The classic left isomerism or bilateral left-sidedness or heterotaxy syndrome with polysplenia implies that patients have bilateral bilobed lungs, bilateral pulmonary atria, a centrally located liver, a stomach in indeterminate position, and multiple spleens, occasionally associated with interruption of the inferior cava with azygos or hemiazygos continuation. We present a case of situs ambiguus associated with severe heart and vascular abnormalities in a 25-year-old male patient. On the admittance to our clinic the patient had history of biliary colic, moderate jaundice of the conjunctive and sclerae, and severe central cyanosis. The echocardiography revealed a large atrial septal defect, complete absence of the interventricular septum resulting in the single ventricle and the inversion of atria. The angiography obtained the hypoplastic inferior vena cava continuing with azygos vein that flowed into the left superior vena cava. The computerized tomography scans showed three splenuli in the right upper quadrant of the abdomen, and a single gallstone appeared in the left-positioned gallbladder. The contrast radiography showed complete transposition of the guts and stomach. To our knowledge, our patient with described severity of the anomalies had the longest life span in this part of Europe, although the longer survivors have been described in the other parts of the world. Furthermore, clinical characteristics of both left and right isomerism have been obtained in the patients with anatomically pronounced left isomerism.

A genetic screen for situs abnormalities

A genetic screen for situs abnormalities

Three‐ and four‐dimensional ultrasound: new methods for evaluating fetal thoracic anomalies

To study three- (3D) and four-dimensional (4D) ultrasound applications for the evaluation of fetal thoracic anomalies. Volume datasets of 23 fetuses with thoracic anomalies were acquired with static 3D and cine 4D ultrasound, i.e. spatiotemporal image correlation (STIC) mode. The volumes were analyzed and displayed by multiplanar and tomographic ultrasound imaging (TUI) modes and static volume contrast imaging (VCI). Color Doppler was added to the volumes acquired, and various rendering modes were used to display the volume datasets. The mean gestational age at evaluation was 22 (range, 14-34) weeks. The anomalies were identified as: diaphragmatic hernia (n = 5), lung dysplasia (n = 11), skeletal dysplasia with small thorax/thanatophoric dysplasia (n = 2), abnormal situs (n = 2), hydrothorax (n = 2) and esophageal atresia (n = 1). The TUI mode achieved optimal display of the thorax, thereby aiding the diagnosis of diaphragmatic hernia and lung dysplasia. In right diaphragmatic hernias, the VCI mode proved invaluable as it distinguished liver from lung tissue. High-definition color Doppler with glass-body rendering significantly contributed to the detection of abnormal vascularization in lung dysplasia. Maximal transparent mode with a transvaginal transducer provided accurate diagnosis of skeletal dysplasia in the first trimester. Situs abnormalities were best viewed with a minimal transparent mode, in which abnormal organs and positions of vessels were clearly identified. Pleuroamniotic shunt localization was monitored precisely by 3D in a fetus with hydrothorax, and inversion mode added important information regarding the size of an esophageal pouch in a fetus with esophageal atresia. The 3D-4D technique is a novel, useful sonographic tool for evaluating the fetal thorax. It enhances precise diagnosis and provides better spatial visualization of the anomalies involved.

Mouse Model of Heterotaxy with Single Ventricle Spectrum of Cardiac Anomalies

Heterotaxy arises from a failure of the embryo to establish normal left-right asymmetry and is known to affect 3% of infants with congenital heart disease. A recessive mutation causing heterotaxy was recovered in a mouse mutagenesis screen focused on congenital heart defects. Homozygote mutants exhibit abnormal situs in the thoracic and abdominal cavities. Dextrocardia, levocardia, or mesocardia was seen together with right pulmonary isomerism and complex structural heart defects in the single ventricle spectrum. A dominant chamber of left ventricular morphology positioned on the left or right is seen together with transposition of the great arteries. Right atrial isomerism with or without total anomalous pulmonary venous connection was observed in half of the mutants. Because ciliary motion at the embryonic node is required for the specification of laterality, we examined the tracheal epithelia of newborn mice as a proxy for the nodal cilia. However, videomicroscopy showed no defect in ciliary motion. Genome scanning using polymorphic microsatellite markers mapped the mutation to a 3.3 Mb interval on mouse chromosome 7. None of the genes previously described for familial heterotaxy were found in this interval, indicating a novel mutation in this mouse model of heterotaxy.

Interventional Electrophysiology in Patients With Congenital Heart Disease

“The treatment of congenital heart disease is unsatisfactory. As a rule, nothing can be done to improve patients symptomatically; in some instances digitalis may be of help.” — —L. Emmett Holt, MD, 1933 On August 26, 1938, Dr Robert Gross performed the first successful surgery for a congenital heart defect by closing a patent ductus arteriosus in a 7-year-old girl. The event marked the beginning of an interventional approach to congenital heart disease (CHD) that forever banished the sort of pessimism expressed by Dr Holt in his classic pediatric textbook only 5 years earlier.1 Subsequent diagnostic and operative innovations ultimately led to surgical solutions for nearly all anatomic heart defects, allowing the vast majority of infants born with CHD in the modern era to survive into adulthood. However, improved hemodynamic longevity has exposed alternate sources of morbidity and mortality for this population, central among which are cardiac rhythm disorders. In some instances, arrhythmias are intrinsic to the CHD lesion itself, but in most cases, they arise as an unintended consequence of prior corrective surgery whenever patches and suture lines function in conjunction with hypertrophy and fibrosis to create the substrate for reentrant tachycardias. It is fortunate that improved understanding of rhythm abnormalities in CHD has coincided with the emergence of interventional electrophysiological techniques. Catheter ablation, arrhythmia surgery, pacemakers, and implantable defibrillators have now become indispensable treatment options for this group. It is the purpose of this article to review the application of these tools to CHD with an emphasis on unique technical challenges. Congenital heart defects occur in roughly 0.8% of live births, and in 30% to 50% of cases, the malformations are severe enough to warrant ≥1 surgical procedures during early childhood.2 Arrhythmia mechanisms vary according to the underlying anatomic defect and method of surgical repair. The …

Heterotaxia, Congenital Heart Disease, and Primary Ciliary Dyskinesia

The human heart is strikingly asymmetrical along the left-right body axis. If one begins with the position of the heart in the left chest, continues through asymmetrical venous drainage into the atria and asymmetrical orientation of the 2 anatomically and functionally distinct ventricles, and finally proceeds through the highly asymmetrical coil of semilunar valves and great vessels, the structure and function of the human heart are precisely aligned to the left-right axis. When cardiac asymmetries either fail to develop or align incorrectly relative to each other or relative to other organs, a plethora of congenital heart disease results. This group of heart diseases is called heterotaxy syndrome and represents both a difficult clinical challenge and a fascinating window into the biology underlying one of the most fundamental embryological processes, namely, the mechanism by which an organism establishes the 3 body axes. Positioning of organs along the left-right axis can be divided into 3 broad classes: situs solitus, in which all organs are positioned normally; situs inversus, in which there is mirror image reversal of all organs; and heterotaxy, in which there is any positioning of organs along the left-right axis differing from situs solitus and situs inversus (Figure). Pure situs inversus is found in 1 of 8500 in the general population and is usually not associated with intracardiac defects. In contrast, heterotaxy has a high degree of association with intracardiac defects. It has a reported incidence of 1 of 10 000 and is associated with at least 3% of cases of congenital heart disease.1 The anatomic spectrum of organ laterality. A, Situs solitus. B, Right atrial isomerism. The liver is midline, there are 2 eparterial bronchi, the position of the stomach and cardiac apex is indeterminate, and there is asplenia. C, Left atrial isomerism. The liver is midline, there …

Congenital Heart Disease and Other Heterotaxic Defects in a Large Cohort of Patients With Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a recessive genetic disorder that is characterized by sinopulmonary disease and reflects abnormal ciliary structure and function. Situs inversus totalis occurs in approximately 50% of PCD patients (Kartagener's syndrome in PCD), and there are a few reports of PCD with heterotaxy (situs ambiguus), such as cardiovascular anomalies. Advances in diagnosis of PCD, such as genetic testing, allow the systematic investigation of this association. The prevalence of heterotaxic defects was determined in 337 PCD patients by retrospective review of radiographic and ultrasound data. Situs solitus (normal situs) and situs inversus totalis were identified in 46.0% and 47.7% of patients, respectively, and 6.3% (21 patients) had heterotaxy. As compared with patients with situs solitus, those with situs abnormalities had more ciliary outer dynein arm defects, fewer inner dynein arm and central apparatus defects (P<0.001), and more mutations in ciliary outer dynein arm genes (DNAI1 and DNAH5; P=0.022). Seven of 12 patients with heterotaxy who were genotyped had mutations in DNAI1 or DNAH5. Twelve patients with heterotaxy had cardiac and/or vascular abnormalities, and most (8 of 12 patients) had complex congenital heart disease. At least 6.3% of patients with PCD have heterotaxy, and most of those have cardiovascular abnormalities. The prevalence of congenital heart disease with heterotaxy is 200-fold higher in PCD than in the general population (1:50 versus 1:10 000); thus, patients with PCD should have cardiac evaluation. Conversely, mutations in genes that adversely affect both respiratory and embryological nodal cilia are a significant cause of heterotaxy and congenital heart disease, and screening for PCD is indicated in those patients.

Sustained cell proliferation of renal epithelial cells in mice with inv mutation

A tubule system is an important component of the nephron, which is the structural and functional unit of the kidney. Expansion of renal tubules results in renal cysts. Hereditary forms of renal cystic diseases suggest that tubular size is determined genetically. The inv was discovered as a mutant with renal cysts and situs inversus. Inv/inv, inv deltaC::GFP (inv deltaC) mouse was created by the introduction of the inv gene lacking the C-terminus (inv deltaC) into inv/inv mice. The mouse develops multiple renal cysts without situs abnormality, giving us an opportunity to study inv function in renal tubular structure maintenance. In the present study, we showed that inv suppresses cyst progression in a dose-dependent manner and that the inv deltaC cystic kidneys showed increased cell proliferation and apoptosis. Cell cycle regulators for G1-S progression were activated in the cystic kidney. Furthermore, cDNA microarray and semiquantitative RT-PCR analysis showed that growth-related genes maintained a high level of expression in the cystic kidney at 4 weeks of age whereas they were decreased in control kidneys, suggesting that cells in inv deltaC kidney are still active in the cell cycle. One of the inv protein functions may provide a stop signal for renal epithelial cell proliferation.

Diagnosis and prognosis of fetuses with double outlet right ventricle

To examine the echocardiographic features, associated anomalies, and outcomes of fetuses diagnosed with double outlet right ventricle (DORV). Fetuses with DORV were identified from 987 fetal echocardiograms performed from August 1, 2002 to August 1, 2004. The medical records of 19 fetuses with DORV were reviewed. Nineteen fetuses were diagnosed with DORV. The pregnancy was terminated in 15.8% (3/19) of cases. Postnatal assessment was not obtained in 26.3% (5/19) cases. Accurate prenatal diagnosis of the relationship of the ventricular septal defect (VSD) with the great arteries was achieved in 14 of 14 cases (100%). Chromosomal abnormalities (21.4%), abnormalities of body situs (35.7%), and other extracardiac abnormalities were diagnosed in association. Only 4 of 13 (30.8%) infants with confirmed DORV survived beyond 28 days. DORV is found in fetuses with a large spectrum of associated cardiac and extracardiac lesions. The overall prognosis for fetuses with DORV is poor throughout the spectrum of these lesions, not only related to the primary lesion but also depending on the associated intra- and extracardiac abnormalities. While the complexity of the heart disease in fetuses with DORV makes detailed fetal diagnosis challenging, it can be accomplished with a high degree of accuracy.

Abnormal abdominal situs: what and how should we look for?

Prenatal management of abnormal abdominal situs is challenging since prognosis is highly variable depending on the associated malformations. The authors report on two cases of ambiguous abdominal situs. Prenatal management included specialized ultrasound examination of fetal anatomy and heart, amniocentesis for determination of the fetal karyotype and fetal abdominal MR. In both cases, abnormal situs was associated with other abdominal anomalies such as azygous continuation, biliary atresia, bowel obstruction and polysplenia. Fetal MR was a useful additional tool in the assessment of fetal abdominal anatomy in both cases. On the basis of these reports, the literature is reviewed and a prenatal management scheme is proposed.