Search Results (11)

Background/Objectives: The failure of physiological left-right (LR) patterning, a critical embryological process responsible for establishing the asymmetric positioning of internal organs, leads to a spectrum of congenital abnormalities characterized by laterality defects, collectively known as “heterotaxy”. MMP21 biallelic variants have recently been associated with heterotaxy syndrome and congenital heart defects (CHD). However, the genotype–phenotype correlations and the underlying pathogenic mechanisms remain poorly understood. Methods: Patients harboring biallelic MMP21 missense variants who underwent diagnostic genetic testing for CHD or heterotaxy were recruited at the Institute for Maternal and Child Health—I.R.C.C.S. “Burlo Garofolo”. Additionally, a literature review on MMP21 missense variants was conducted, and clinical data from reported patients, along with molecular data from in silico and modeling tools, were collected. Results: A total of 18 MMP21 missense variants were reported in 26 patients, with the majority exhibiting CHD (94%) and variable extra-cardiac manifestations (64%). In our cohort, through Whole-Exome Sequencing (WES) analysis, the missense p.(Met301Ile) variant was identified in two unrelated patients, who both presented with heterotaxy syndrome. Conclusions: Our comprehensive analysis of MMP21 missense variants supports the pathogenic role of the p.(Met301Ile) variant and provides significant insights into the disease pathogenesis. Specifically, missense variants are distributed throughout the gene without clustering in specific regions, and phenotype comparisons between patients carrying missense variants in compound heterozygosity or homozygosity do not reveal significant differences. These findings may suggest a potential loss-of-function mechanism for MMP21 missense variants, especially those located in the catalytic domain, and highlight their critical role in the pathogenesis of heterotaxy syndrome. Full article

Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease characterized by hypoplasia of left-sided heart structures. The developmental basis for restriction of defects to the left side of the heart in HLHS remains unexplained. The observed clinical co-occurrence of rare organ situs defects such as biliary atresia, gut malrotation, or heterotaxy with HLHS would suggest possible laterality disturbance. Consistent with this, pathogenic variants in genes regulating left–right patterning have been observed in HLHS patients. Additionally, Ohia HLHS mutant mice show splenic defects, a phenotype associated with heterotaxy, and HLHS in Ohia mice arises in part from mutation in Sap130, a component of the Sin3A chromatin complex known to regulate Lefty1 and Snai1, genes essential for left–right patterning. Together, these findings point to laterality disturbance mediating the left-sided heart defects associated with HLHS. As laterality disturbance is also observed for other CHD, this suggests that heart development integration with left–right patterning may help to establish the left–right asymmetry of the cardiovascular system essential for efficient blood oxygenation. Full article

Splenic torsion is an unusual condition that results in congenital abnormality, especially in the visceral abnormal arrangement. We report the case of an 8.5-year-old boy with features in the right upper quadrant. Radiological investigations revealed heterotaxy syndrome with polysplenia and a hypodense tumor in the right upper quadrant adjacent to several spleens. We initially treated it as an intra-abdominal tumor. Laparoscopy was performed to check the tumor condition and revealed a congestive tumor located in the abdomen of the right upper quadrant below the central liver, which was suspected to be a torsion spleen without attaching ligaments. Laparoscopic splenectomy was successfully carried out without complications. The pathological report shows splenic tissue with hemorrhagic infarction. Physicians should be vigilant of the differential diagnosis of the acute abdomen in adolescents. Full article

Congenital heart diseases (CHD) result from abnormal development of the cardiovascular system and usually involve defects in specific steps or structural components of the developing heart and vessels. The determination of left–right patterning of our body proceeds by the steps involving the leftward “nodal flow” by motile cilia in the node and molecules that are expressed only on the left side of the embryo, eventually activating the molecular pathway for the left-side specific morphogenesis. Disruption of any of these steps may result in left–right patterning defects or heterotaxy syndrome. As for the outflow tract development, neural crest cells migrate into the cardiac outflow tract and contribute to form the septum of the outflow tract that divides the embryonic single truncus arteriosus into the aortic and the pulmonary trunk. Reciprocal signaling between neural crest cells and another population of myocardial precursor cells originated from the second heart field are essential for the steps of outflow tract development. To better understand the etiology of CHD, it is important to consider what kind of CHD is caused by abnormalities in each step during the complex development of the cardiovascular system. Full article

Heterotaxy is a rare syndrome associated with cardiac complexity, anatomic variability and high morbidity and mortality. It is often challenging to visualize and provide an accurate diagnosis of the cardiac anatomy prior to surgery with the use of conventional imaging techniques. We report a unique case demonstrating how the use of three-dimensional (3D) cardiac printed model allowed us to better understand the anatomical complexity and plan a tailored surgical approach for successful biventricular repair in a patient with heterotaxy syndrome. Full article

In this paper, the author enumerates cardiac defects with a functionally single ventricle, summarizes single ventricle physiology, presents a summary of management strategies to address the single ventricle defects, goes over the steps of staged total cavo-pulmonary connection, cites the prevalence of inter-stage mortality, names the causes of inter-stage mortality, discusses strategies to address the inter-stage mortality, reviews post-Fontan issues, and introduces alternative approaches to Fontan circulation. Full article

The objective of our paper is to underline the importance of assessing microarray genetic analysis for the detection of chromosomal abnormalities in rare cases such as left atrial isomerism, mostly in the context of antenatally detected syndromes. We present the case of a 26-year-old primipara, at 26 weeks of gestation, with prior first trimester normal anomaly scan, who presented in our department accusing lower abdominal pain. An anomaly ultrasound examination of the fetus revealed cardiomegaly with increased size of the right atrium, non-visualization of the atrial septum or the foramen ovale, malalignment of the three-vessel view, location of the superior vena cava above the two-vessel view, slight pericardial effusion, and no interruption of the inferior vena cava nor presence of azygos vein being noted. Associated extracardiac abnormalities, such as small kidneys at the level of the iliac fossa, micrognathia, dolichocephaly with hypoplasia of the cerebellum, increased nuchal fold, and reduced fetal movements were also reported. A diagnostic amniocentesis was performed, and, while the conventional rapid prenatal diagnostic test of the multiplex quantitative fluorescent polymerase chain reaction (PCR) came as normal, the microarray analysis (ChAS, NCBI Built 37 hg 19, detection of microdeletions or microduplications larger than 100 kb) revealed two chromosomal abnormalities: a 22.84 Mb loss of genetic material in the 18q21.31–18q23 chromosomal region and a gain of 22.31 Mb of genetic material in the 20p13–20p11.21 chromosomal region. After the termination of pregnancy, a necropsy of the fetus was performed, confirming heterotaxy syndrome with a common atrium, no atrial septum, superior vena cava draining medianly, and pulmonary veins that drained into the lower segment of the left atrium due to an anatomically enlarged single common atrium. The extracardiac findings consisted of two bilobar lungs, dysmorphic facies, low-set ears, nuchal fold edema, and small kidneys located in the iliac fossa. These findings are conclusive evidence that left atrial isomerism is a more complex syndrome. The genetic tests of the parents did not reveal any translocations of chromosomes 18 and 20 when the Fluorescent in situ Hybridization (FISH) analysis was assessed. The antenatal detection of corroboration between different structural abnormalities using serial ultrasound examinations and cardiac abnormalities, together with the detection of the affected chromosomes, improves the genetic counseling regarding the prognosis of the fetus and the recurrence rate of the condition for siblings. Full article

The outer shape of most vertebrates is normally characterized by bilateral symmetry. The inner organs, on the other hand, are normally arranged in bilaterally asymmetric patterns. Congenital deviations from the normal organ asymmetry can occur in the form of mirror imagery of the normal arrangement (situs inversus), or in the form of arrangements that have the tendency for the development of bilateral symmetry, either in a pattern of bilateral left-sidedness (left isomerism) or bilateral right-sidedness (right isomerism). The latter two forms of visceral situs anomalies are called “heterotaxy syndromes”. During the past 30 years, remarkable progress has been made in uncovering the genetic etiology of heterotaxy syndromes. However, the pathogenetic mechanisms causing the spectrum of cardiovascular defects found in these syndromes remain poorly understood. In the present report, a spontaneous case of left cardiac isomerism found in an HH-stage 23 chick embryo is described. The observations made in this case confirmed the existence of molecular isomerism in the ventricular chambers previously noted in mouse models. They, furthermore, suggest that hearts with left cardiac isomerism may have the tendency for the development of non-compaction cardiomyopathy caused by defective development of the proepicardium. Full article

Human beings are characterized by a left–right asymmetric arrangement of their internal organs, and the heart is the first organ to break symmetry in the developing embryo. Aberrations in normal left–right axis determination during embryogenesis lead to a wide spectrum of abnormal internal laterality phenotypes, including situs inversus and heterotaxy. In more than 90% of instances, the latter condition is accompanied by complex and severe cardiovascular malformations. Atrioventricular canal defect and transposition of the great arteries—which are particularly frequent in the setting of heterotaxy—are commonly found in situs solitus with or without genetic syndromes. Here, we review current data on morphogenesis of the heart in human beings and animal models, familial recurrence, and upstream genetic pathways of left–right determination in order to highlight how some isolated congenital heart diseases, very common in heterotaxy, even in the setting of situs solitus, may actually be considered in the pathogenetic field of laterality defects. Full article

Pediatric cardiologists treating patients with severe congenital cardiac defects define “visceral heterotaxy” on the basis of isomerism of the atrial appendages. The isomeric features represent an obvious manifestation of disruption of left-right asymmetry during embryonic development. Thus, there are two subsets of individuals within the overall syndrome, with features of either right or left isomerism. Within the heart, it is only the atrial appendages that are truly isomeric. The remainder of the cardiac components shows variable morphology, as does the arrangement of the remaining body organs. Order is provided in this potentially chaotic arrangement simply by describing the specific features of each of the systems. These features as defined by clinicians, however, seem less well recognized by those investigating the developmental origins of the disruption of symmetry. Developmental biologists place much greater emphasis on ventricular looping. Although the direction of the loop can certainly be interpreted as representing an example of asymmetry, it is not comparable to the isomeric features that underscore the clinical syndromes. This is because, thus far, there is no evidence of ventricular isomerism, with the ventricles distinguished one from the other on the basis of their disparate anatomical features. In similar fashion, some consider transposition to represent abnormal lateralization, but again, clinical diagnosis depends on recognition of the lateralized features. In this review, therefore, we discuss the key questions that currently underscore the mismatch in the approaches to “lateralization” as taken by clinicians and developmental biologists. Full article

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. Full article