Situs Anomalies Research Articles

Primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is arare genetic disorder with avariable clinical phenotype that is accompanied by reduced motility of the cilia in the respiratory tract and numerous other organs. This leads to various characteristic symptoms and disease manifestations, primarily affecting the lungs (chronic persistent productive cough, bronchiectasis), the nose and paranasal sinuses (chronic persistent rhinitis or rhinosinusitis) as well as the middle ear (chronic otitis media, middle ear effusion). Moreover, PCD is associated with impaired fertility or lateralization defects (situs anomalies, congenital heart defects). The diagnostics of PCD are complex and require acombination of several sophisticated instrument-based diagnostic procedures. Through thorough history taking and evaluation, suspected cases can be comparatively well identified based on typical clinical features and referred to further diagnostics. In recent years, molecular genetic analysis through panel diagnostics or whole exome and whole genome sequencing, has gained in importance as this enables affected individuals to participate in disease-specific and genotype-specific clinical trials. Although the current treatment is purely symptomatic, the earliest possible diagnosis is crucial for connecting patients to specialized PCD centers, which can have asignificant impact on the clinical course of the affected individuals.

Intussusception in a child with situs inversus totalis – A rare occurrence

Intussusception is when section of bowel is drawn into another. It is considered the commonest cause of intestinal obstruction in children. It is associated with a favorable outcome when diagnosis and management are prompt. Non-operative management techniques are employed in most cases with surgical reduction occurring in a third of cases. Situs anomalies are a rare spectrum of congenital anomalies involving malpositioning of the thoracoabdominal viscera. Situs inversus totalis is the commoner of the subdivision of the situs inversus spectrum. The condition is associated with several anomalies including, katagener's syndrome. Its association with intestinal obstruction is however extremely rare. There is no known reported case of intussusception occurring in a child with situs inversus totalis. Here, we report a case of seven (7) months old female diagnosed with intussusception and situs inversus totalis following clinical and radiological evaluation. She underwent open reduction and Ladd's procedure and made an uneventful recovery.

Fontan procedure on deep hypothermic circulatory arrest: Short-term results and technique.

Various operative strategies are described for the Fontan procedure. In this study, we describe our short-term results and technique of Fontan procedure on cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). This was a retrospective study of 32 patients, median age of 6 years (4-19 years) and median weight of 20 kg (13-51 kg), who underwent Fontan procedure on CPB and DHCA from July 2016 to July 2021. The median CPB time was 125 min (77-186 min), the median DHCA time was 42 min (27-50 min), and the median Fontan pressure was 14 mmHg (10-18 mmHg). The median time to extubation was 4 h (1-20 h), the duration of chest tube drainage was 8 days (5-24 days), and the median intensive care unit stay was 4 days (3-8 days). The presence of heterotaxy was associated with longer duration of pleural drainage (P = 0.01). There was no operative mortality and no major adverse events such as seizures, gross neurological deficits, or arrhythmias in the postoperative period. Fontan procedure can be safely performed on CPB and DHCA with good operative results. This operative strategy may be used in special circumstances like in patients with situs and systemic venous anomalies and those requiring repair of a complex intracardiac defect. Long-term follow-up will be required to evaluate if this strategy has any impact on the neurodevelopmental outcome and the long-term sequelae of Fontan.

Prenatal diagnosis of hepatic interruption of the inferior vena cava with azygos/hemiazygos continuation without structural heart defects: A case series.

To describe fetal spectrum and echocardiographic characteristics of interrupted inferior vena cava (IIVC) with azygos/hemiazygous continuation without other structural heart defects and to evaluate its association with visceral heterotaxy and isomerism, extracardiac and genetic anomalies, and to review neonatal outcome. This was a retrospective study of 14 fetuses with a confirmed diagnosis of IIVC with normal intracardiac anatomy. The following variables were collected; indication for referral, gestational age at diagnosis; associated isomerism and visceral heterotaxy, heart rhythm, genetic and extracardiac abnormalities, and fetal/neonatal outcome. Among 36 fetuses with IIVC, 14 cases (38.8%) had normal intracardiac anatomy. These IIVC cases correspond to 0.19% (14/7250) of all fetal cardiac examinations, and to 1.5% (14/922) of all cardiac abnormalities. Six patients had visceral abnormalities. Atrial appendage morphology was clearly depicted in three fetuses, both appendages were left. One fetus had bradyarrhythmia revealing atrial ectopic rhythm. Six fetuses did not have any concomitant cardiac or visceral abnormalities, therefore regarded as isolated. All babies were delivered at term with a good prognosis. Our study has shown that almost half of the IIVC cases without intracardiac structural anomalies displayed other findings of isomerism while the other half was isolated benign vascular variant. Therefore, prenatal diagnosis of IIVC should prompt a comprehensive evaluation for cardiac, situs, and visceral anomalies. The outcome is favorable.

Post-operative Morbidity and Mortality After Fontan Procedure in Patients with Heterotaxy and Other Situs Anomalies

Heterotaxy is a complex, multisystem disorder associated with single ventricle heart disease and decreased survival. Ciliary dysfunction is common in heterotaxy and other situs abnormalities (H/SA) and may increase post-operative complications. We hypothesized that patients with H/SA have increased respiratory and renal morbidities and increased in-hospital mortality after Fontan procedure. We queried the Pediatric Health Information System database for hospitalizations with ICD-9/10 codes for Fontan procedure in patients aged 1 through 11years from 2004 to 2019. H/SA was identified by codes for dextrocardia, situs inversus, asplenia/polysplenia, or atrial isomerism and compared to non-H/SA controls. Outcomes were in-hospital mortality or heart transplantation, ECMO, hemodialysis, length of stay (LOS), and mechanical ventilation or vasoactive medication use ≥ 4days. We adjusted estimates with multivariable logistic regression. Of 7897 patients at 50 centers, 1366 (17%) met criteria for H/SA. H/SA had worse outcomes for all study measures: death/transplantation (1.9 vs 1.1%, OR 1.74 (95% CI 1.01-3.03); p = 0.047), ECMO (3.7 vs 2.3%, OR 1.74 (1.28-2.35); p < 0.001), hemodialysis (2.1 vs 1.2%, OR 1.66 (1.06-2.59); p = 0.026), prolonged mechanical ventilation (13.2% vs 7.6%, OR 1.85 (1.53-2.25); p < 0.001) and vasoactive medication use (29.4 vs 19.7%, OR 1.65 (1.43-1.90), and longer LOS (11 (8-17) vs 9 (7-14) days; p < 0.001). H/SA is associated with increased cardiovascular, renal, and respiratory morbidity, as well as in-hospital mortality after Fontan procedure. Attention to renal and respiratory needs may improve outcomes in this difficult population. The relationship between ciliary dysfunction and lung and renal morbidity should be explored further.

Acute Necrotising Pancreatitis in a Patient with Situs Inversus TotalisA Rare Case Report

Situs inversus totalis is a rare congenital anomaly occurring in one per 4000-20000 live births. It can present in early life due to gut rotation abnormality, however majority of them are asymptomatic and identified later in life when they undergo imaging for other reasons. Although acute pancreatitis is a common disease in young adults, presence of situs inversus alters the approach for necrosectomy when it is necessary. The author reports a 29-year-old male patient who had acute necrotising pancreatitis and incidentally found to have situs inversus totalis. Since the patient required drainage of necrotic collection there was a change in approach to right flank region rather than the routine left flank. This case was reported to emphasise on identification of situs anomalies and need to alter surgical approach.

Discovery of a genetic module essential for assigning left-right asymmetry in humans and ancestral vertebrates.

The vertebrate left-right axis is specified during embryogenesis by a transient organ: the left-right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left-right organizer metallopeptide (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus, CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5, the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans.

Complicated acute appendicitis in a child with left atrial isomerism: a case report

BackgroundHeterotaxy syndrome is a rare clinical entity that is characterized by abnormal visceral organ arrangement in the chest and abdomen. Left atrial isomerism is a subcategory of heterotaxy syndrome characterized by the presence of multiple spleens with or without cardiac anomalies. Patients may remain asymptomatic their whole lives until they are diagnosed incidentally. Given that patients with left atrial isomerism might demonstrate atypical presentations of acute intrabdominal pathologies, it is important to keep a high index of suspicion when encountering such cases.Case presentationIn this report, we present a case of a 9-year-old boy with a known history of left atrial isomersim who presented with left lower quadrant pain and positive McBurney, psoas, and obturator signs on the left side. A computed tomography scan of the abdomen confirmed the diagnosis of perforated acute appendicitis on the left, which prompted an emergent laparoscopic appendectomy.ConclusionOur case highlights the importance of keeping a high index of suspicion for a heterotaxy syndrome that is complicated by acute appendicitis in pediatric patients presenting with vague abdominal pain. Planning the location of trocar placement in patients with situs anomalies is of paramount importance to avoid technical difficulties in laparoscopic procedures.

Atypical Brain Asymmetry in Human Situs Inversus: Gut Feeling or Real Evidence?

The alignment of visceral and brain asymmetry observed in some vertebrate species raises the question of whether this association also exists in humans. While the visceral and brain systems may have developed asymmetry for different reasons, basic visceral left–right differentiation mechanisms could have been duplicated to establish brain asymmetry. We describe the main phenotypical anomalies and the general mechanism of left–right differentiation of vertebrate visceral and brain laterality. Next, we systematically review the available human studies that explored the prevalence of atypical behavioral and brain asymmetry in visceral situs anomalies, which almost exclusively involved participants with the mirrored visceral organization (situs inversus). The data show no direct link between human visceral and brain functional laterality as most participants with situs inversus show the typical population bias for handedness and brain functional asymmetry, although an increased prevalence of functional crowding may be present. At the same time, several independent studies present evidence for a possible relation between situs inversus and the gross morphological asymmetry of the brain torque with potential differences between subtypes of situs inversus with ciliary and non-ciliary etiologies.

Imaging findings in a case of situs inversus totalis

Situs inversus is an uncommon condition in which there is transposition of thoracic and abdominal structures. We report a case of situs inversus totalis detected incidentally in a 72-year-old female under investigation for haematuria. The imaging findings and role of imaging in this condition have been described in detail. This article emphasises the need for the clinicians to be aware of situs anomalies before planning surgical or radiological interventions in these patients.

Abstract 15410: Post-operative Outcomes After Fontan Procedure in Patients With Heterotaxy and Other Situs Anomalies

Background: Heterotaxy is a multisystem disorder of situs often associated with cardiac, immune, and gastrointestinal abnormalities. Heterotaxy and other situs abnormalities (H/SA) may share ciliary dysfunction as an embryologic origin. Extracardiac manifestations of H/SA may contribute to increased morbidity and mortality after total cavopulmonary connection (Fontan) procedure. We hypothesized that patients with H/SA have worse postoperative outcomes after Fontan than patients without H/SA. Methods: We queried the Pediatric Health Information System (PHIS) database for hospitalizations with ICD-9/10 codes for Fontan procedure in patients aged 1 to 12 years from 2004 to 2019. Those coded for dextrocardia, situs inversus, asplenia/polysplenia, and atrial isomerism were defined as H/SA. Outcomes were in-hospital all-cause mortality or heart transplantation, post-operative ECMO, dialysis, postsurgical length of stay (LOS), and mechanical ventilation &gt;4 days. Outcomes were compared between H/SA and non-H/SA controls with chi-squared or rank-sum test (reported as median (IQR)), and statistically adjusted for surgical center, age, sex, race, genetic anomaly, and pre-operative support with multivariate logistic regression (reported as adjusted odds-ratio (95% CI)). Results: Of 7,897 patients who underwent Fontan at 50 PHIS centers, 1,366 (17%) met criteria for H/SA. Patients with H/SA versus non-H/SA were older (3.7 (2.9-4.8) vs 3.4 (2.7-4.2) years; p&lt;0.001), more female (44 vs 40%, p=0.005), and Asian or Hispanic (35% vs 24%, p&lt;0.001). H/SA had higher rates of discharge death/transplantation (1.9 vs 1.1%, aOR 1.76 (1.02-3.04); p=0.042), post-operative ECMO (3.7 vs 2.3%, aOR 1.73 (1.28-2.33); p&lt;0.001), dialysis (2.1 vs 1.2%, aOR 1.66 (1.06-2.59); p=0.026), prolonged intubation (13.2% vs 7.6%, aOR 1.86 (1.53-2.25); p&lt;0.001), and longer LOS (11 (8-17) vs 9 (7-13) days; p&lt;0.001). Conclusions: We observed increased mortality and postoperative complications in this largest report to date on patients with H/SA after Fontan. We postulate that ciliary dysfunction may contribute to increased lung and renal morbidity, and should be explored further. Adjustment for anatomic complexity and hemodynamics are required for further study .

Late Diagnosis of Infants with PCD and Neonatal Respiratory Distress.

Neonatal respiratory distress (NRD) is common among infants with primary ciliary dyskinesia (PCD), but we do not know whether affected neonates receive a timely diagnosis. We used data from the international PCD cohort and assessed the proportion of patients with PCD who had a history of NRD and their age at diagnosis, stratifying by presence of laterality defects. First we analyzed data from all participants diagnosed after 2000, followed by individuals from a subgroup diagnosed using stricter criteria. Among the 1375 patients in the study, 45% had a history of NRD and 42% had laterality defects. Out of the 476 children with definite PCD diagnosis, 55% had a history of NRD and 50% had laterality defects. Overall, 30% of children with PCD were diagnosed during the first 12 months of life. This varied from 13% in those with situs solitus and no NRD, to 21% in those with situs solitus and NRD, 33% in those with situs anomalies but no NRD, and 52% in those with both situs anomalies and NRD. Our results suggest that we need to improve our knowledge of the neonatal presentation of infants with PCD and apply it so that these patients will receive appropriate care sooner.

Phenotypic features of ciliary dyskinesia among patients with congenital cardiovascular malformations.

Cilia are cell membrane-bound organelles responsible for airway mucus clearance, establishment of left-right organ asymmetry, cardiogenesis, and many other functions in utero. Phenotypic features suggestive of respiratory ciliary dyskinesia among patients with heterotaxy syndrome, defined as complex cardiovascular malformations (CVM) and situs ambiguus (SA), has not been adequately explored. We hypothesized that there is a greater incidence of phenotypic features consistent with ciliary dyskinesia among patients with heterotaxy syndrome compared to patients with other CVM and laterality defects without heterotaxy syndrome. Thirty six subjects were identified by medical record search and divided into four groups based on situs status and type of CVM as follows: SA and complex CVM (group 1); SA and simple CVM (group 2); situs solitus and complex CVM (group 3); and situs solitus and simple CVM (group 4). Phenotype was assessed with a clinical questionnaire, nasal nitric oxide (NO) level, and pulmonary function testing. Those with complex CVM underwent additional testing for variants in genes involved in ciliary structure and function. The mean nasal NO level was significantly lower among all subjects with complex CVM regardless of situs anomalies (groups 1 and 3). There was no significant difference in respiratory symptoms or lung function among the four groups. No bi-allelic genetic mutations were detected among patients with complex CVM. This study identified a relatively lower mean nasal NO level, suggestive of relative ciliary dyskinesia, among subjects with complex CVM. Pulmonary function and clinical symptoms did not reflect significant pulmonary disease among those with complex CVM.

Situs ambiguous anomaly during laparoscopic cholecystectomy in an adult female

Situs anomalies are rare structural defects affecting 0.01% of general population. They present with multisystem structural defects mostly involving cardiovascular, respiratory and GI systems. Situs abnormality with presence of multiple spleen is termed as left atrial isomerism with anatomical and structural differences to its countertype situs ambiguous with asplenia (right atrial isomerism). In this case report, we present an adult case of situs ambiguous anomaly which was diagnosed incidentally during laparoscopic cholecystectomy. The patient had enlarged left lobe of liver, multiple splenules on right side, malrotated small and large gut, interrupted inferior vena cava with azygos continuation, and bilateral bilobed lungs. It is concluded that variations in situs ambiguous cases differ and a single description is not possible. It is crucial to reveal these variations by using imaging modalities and being aware of them prior to surgery and invasive intervention to prevents the possible risks and complications.

Pipeline embolization device implantation in large carotid cavernous aneurysm associated with situs inversus totalis.

Situs anomalies are a heterogenous class of inborn visceral and vascular abnormalities with a broad range of radiographic characteristics. Situs inversus totalis is characterized by mirror image location of the heart and viscera relative to situs solitus (normal position). Few aberrations involving the neuraxis, and rarely intracranial aneurysms, have been reported in association with situs inversus totalis. We describe the radiological findings and endovascular management of one of the first of its kind: the association of bilateral carotid cavernous aneurysms (one large and the other small-sized) with situs inversus totalis.

Acute appendicitis in a patient with heterotaxy syndrome

Abstract Heterotaxy syndrome, also known as situs ambiguous, is a congenital condition that results in an abnormal distribution of visceral organs in the chest and abdomen. Heterotaxy syndrome has generally been categorized into two forms: a left-atrial isomerism form with a polysplenic association and a right-atrial isomerism form with an asplenic association. The polysplenic form has a high degree of co-occurrence (80%–90%) with fatal and non-fatal cardiac abnormalities. Of patients afflicted with the polysplenic form of heterotaxy syndrome, only 10% reach adulthood without complications. However, situs anomalies can cause a confusing clinical picture for the physician when the patient's pain does not correlate with the expected location due to organ dislocation. The differential diagnosis can prove to be unclear, incorrect, and unfitting when the physician does not know that certain organs are situated in abnormal locations. We present a case of a young male that was unaware of his heterotaxy syndrome. He presented with atypical signs of appendicitis secondary to an abnormal position of his appendix. Incidentally, his rare and fairly unheard of condition, heterotaxy syndrome, was only discovered because he was afflicted with a well-known and common condition, appendicitis.

Heterotaxy Syndrome with Intestinal Malrotation, Polysplenia and Azygos Continuity

Heterotaxy syndrome is a situs anomaly that comprises a large spectrum of cardiac and extracardiac malformations. Its association with intestinal malrotation is frequent. This later might be asymptomatic or manifest by signs of abdominal discomfort or of intestinal obstruction. We report on the case of a full term, small for gestational age neonate in whom heterotaxy syndrome with partial situs inversus abdominalis, intestinal malrotation, polysplenia and vena azygos continuity was diagnosed at prenatal echography. Due to the high risk of volvulus carried by the malrotation, Ladd’s procedure was performed at the age of two months. Follow-up examination at the age of four years shows excellent post-operative result and normal development of the child.

Association Between Tetralogy of Fallot and Tracheobronchial Branching Abnormalities: A New Clue for Pathogenesis?

BackgroundIn our practice, we noticed an increased frequency of tracheobronchial branching abnormalities (TBAs) in patients with tetralogy of Fallot (ToF). This study aimed to determine whether an association exists between congenital TBAs and ToF with or without pulmonary atresia.Methods and ResultsThe frequency of TBAs on chest computed tomography was assessed in 55 patients with ToF without pulmonary atresia, 34 patients with ToF with pulmonary arteria, and 100 control patients. We then looked for a possible association between TBAs and pulmonary artery branch hypoplasia, the presence of major aortopulmonary collateral arteries, and the presence of the chromosome 22q11 deletion. TBAs were significantly more frequent in patients with ToF with or without pulmonary atresia than in the control group (any TBAs, 21% versus 2% [P<0.001]; bronchial situs anomalies, 6% versus 0% [P=0.002]; right tracheal bronchus, 4% versus 0% [P=0.04]; left eparterial bronchus, 8% versus 0% [P=0.005]); and tended to be more frequent in those with ToF without pulmonary atresia than in those with ToF with pulmonary atresia (any TBAs, 27% versus 12% [P=0.11]; left eparterial bronchus, 13% versus 0% [P=0.04]). TBAs were readily multiple (8 patients of 19 with TBA) and concerned essentially the upper lobes. TBAs were not associated with pulmonary branch hypoplasia, major aortopulmonary collateral arteries, or the chromosome 22q11 deletion.ConclusionsWe demonstrated a significantly increased frequency of tracheobronchial abnormalities in patients with ToF with or without pulmonary atresia compared with a control group. These results suggest an interaction between abnormalities in conotruncal septation and tracheobronchial branching and may provide a new clue to the pathogenesis of conotruncal heart diseases.

EP04.32: Left atrial isomerism (LAi) without serious heart defect: first trimester diagnosis and delayed postnatal development of the heart block at the age of 11 months

Left atrial isomerism (LAi) represents a wide spectrum of fetal situs and cardiac anomalies. Whereas severe forms of LAi are easily detectable even at early stages of pregnancy, diagnosis of mild forms of LAi is challenging. We present a case of first-trimester diagnosis of LAi without complex heart defect, which ended in persistent bradycardia at the age of 11 months postnatally. The 24-year-old mother presented for routine ultrasound examination at 13 weeks (CRL 73 mm) in her first pregnancy. On the scan middle-positioned stomach and interruption of the inferior vena cava with azygos continuation were detected. The views of the heart were normal and the fetus had normal sinus rhythm. NT thickness was 1.8 mm and the mother had low risk chromosomal screening. The findings were suspicious for LAi. After appropriate counselling, the parents opted to continue the pregnancy. At 19 weeks the previous findings were confirmed and persistent right umbilical vein and small VSD were detected. The pregnancy was followed by regular scans and fetal heart rate remained normal sinus. After the birth the diagnosis of LAi was confirmed. At the time of writing the child is 16 months of age. The child has persistent bradycardia of 70 beats per minute, which manifested at 11 months of infancy and is waiting for pacemaker implantation. Small VSD has tendency for spontaneous closure. Examination of gastrointestinal tract has confirmed middle position of the stomach and has not revealed significant intestinal malrotation. Polysplenia was seen on abdominal scan. This case provides an evidence that typical for LAi heart block resulting in persistent bradycardia can develop postnatally. This case illustrated feasibility of identification of minor LAi features in the first trimester. Early detection is critical for proper counselling and planning of antenatal and postnatal cardiac follow-up in order to exclude associated heart anomalies and development of the heart block.

Choledochal cyst, polysplenia and situs ambiguous: A rare and new association

Abstract Introduction Situs ambiguous (SA) is a rare clinical entity that includes a spectrum of abnormalities in which organs and vessels are opposed to their normal arrangement. SA is frequently associated with other malformations such as splenic alterations, biliary atresia and vascular abnormalities. We report two cases of patients with SA, polysplenia and choledochal cyst. This association has never been described to date. Case reports Two patients, both males, came to our attention at the ages of 7 and 8 months after ultrasound identification of choledochal cysts. One patient, who had a prenatal suspicion of situs ambiguous and dextrocardia, presented with failure to thrive and increased hepatic enzymes. The other patient was asymptomatic, but prenatal evaluation showed gastric malposition. Post-natal laboratory tests were normal. Preoperative radiological diagnostic work-up showed polysplenia, intestinal anomaly of rotation and fixation, pre-duodenal portal vein in one baby. Both patients underwent surgical correction by cyst excision and Roux-en-Y hepaticojejunostomy. Follow-up (3 months and 3.5 years respectively) was uneventful. Biochemical hepatic parameters normalized soon after surgery. Discussion Situs anomalies in children are often associated with other malformations. The most common are splenic and cardiac defects but intestinal malformations and hepatico-biliary abnormalities have been reported too. Above all, the BASM (biliary atresia splenic malformation) syndrome has been extensively examined, obtaining important information on the etiology of the cystic form of biliary atresia. Conclusions A careful evaluation of patients with situs ambiguous is important to exclude associated anomalies and to plan the most appropriate surgical approach. The association with choledochal cyst should be taken into account.