Although the terms asplenia and polysplenia are helpful in suggesting the Situs ambiguous, or heterotaxy, refers to visceral malposition and. Situs inversus indicates mirror-image location of the viscera relative to situs .. with asplenia, Freedom and Fellows (,4) reported that some degree of heterotaxia. Heterotaxia syndromes are typically divided into polysplenia and asplenia. of the normal visceral and vascular anatomy, and situs ambiguus or heterotaxia.
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Cardiac malformations represent almost half of the malformations encountered at birth. In these cases we refer to a multifactorial origin, a term that indicates more about hsterotaxia ignorance of the topic rather than what we really understand.
It seems logical, however, that the development of these malformations could be due as much to genetic as to environmental factors.
In fact, it has been postulated that environmental factors, which act in genetically predisposed individuals, activate the anomalous expression of genes until the threshold of normality is breached, which is when they induce the development of a given malformation. The abnormal expression of all the genes involved would result in the production of a severe defect, often incompatible with life, while a disturbance in only part of these genes would cause much milder defects or their absence.
This would explain the presence of intermediate or subclinical forms that can be considered frustrated forms of the basic hereditary defect. Although our real knowledge of the origin of most of the cardiac malformations is fairly imprecise, it should not be overlooked that a genetic origin has been clearly established in a small number of cases.
The relation between the presence of chromosomal anomalies and cardiac malformations is well known. These anomalies can be numerical, due to the absence of chromosomal disjunction, or structural, due to chromosomal breaks and loss of the broken fragment or its translocation to another chromosome. Among the numerical anomalies, trisomy 21 is associated in one-half of the cases with complex malformations, especially common atrioventricular canal and ventriculoarterial discordance.
An important group of clinical syndromes that include cardiac malformations have been associated with specific deletions in different chromosomes.
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The development of new techniques like high resolution chromosomal banding and fluorescence in situ hybridization FISH has allowed the presence of aspleina deletions in contiguous genes viseral be established, and has lead to the recognition of new syndromes like deletion of chromosome 22q11 CATCH 22, velo-cardio-facial syndrome and the Miller-Dieker 17p The recognition of new syndromes does not directly explain the development of specific cardiac malformations or the severity of the syndrome.
The fact that the search for anomalous genes now centers on increasingly smaller chromosomal segments hetedotaxia not yet made possible the massive identification of candidate genes.
In fact, the mechanisms by which a gene or group of genes produce a specific syndrome vary widely. For example, it has been assumed that the loss of function of a dominant allele leads to specific syndromes. However, increased gene function, with the consequent increment in the amount of product of that gene or anomalous productioncan interfere with normal developmental mechanisms to produce a given syndrome.
Another alternative is that only the paternal or maternal allele of a certain gene is active in development genomic impression. A defect in the maternal copy can be transmitted as an autosomal dominant defect, while the same defect in the paternal copy does not produce disturbances. Likewise, a defect of maternal origin can produce a certain syndrome, whereas the same defect of paternal origin produces a totally different syndrome, as occurs with the deletion of band q12 of chromosome 15 15q In a similar heyerotaxia, the cardiac phenotype in Turner syndrome 45,X seems to depend on the parental origin of the anomalous X chromosome.
Three percent of all cardiac malformations seem to be due to the action of a single gene. Within this group are included atrial septal defect associated with defects in cardiac conduction and hypertrophic subaortic stenosis.
The existence of cardiac phenotypes originated by the loss of function of a single gene constitutes heteritaxia attractive hypothesis for the study of cardiac development. In these cases, can the so-called multifactorial origin and polymorphic presentation be explained adequately?
Recent evidence indicates that many polymorphic presentations are due to the action of a single gene.
The concept of parsimony has been used to explain it. Throughout development, a single gene can control a basic morphogenetic process, such as the synthesis or degradation of a protein.
That protein could be fundamental for the development of organs as different as the brain and kidney, so the gene has to be activated during embryogenesis at different times and in different places.
Its deactivation would result in a series of defects in distant organs, and the severity of the presentation would depend on the capacity of each organ to supplement or compensate the genetic defect. In humans, various forms of defects with autosomal transmission and polymorphic presentation are apparently caused by deactivation of a single gene. Their deactivation results in visceral spatial position anomalies and in a wide array of cardiac malformations.
The design of the human body, like that of most vertebrates, has an evident bilateral symmetry with respect to the midline.
However, this symmetry is not conserved inside the body since organ disposition is clearly asymmetrical. It is said that heterrotaxia body has a pseudobilateral symmetry. The visceral asymmetry is not limited to the thoracic and abdominal organs, it extends to the brain and nervous system organization.
OMIM Entry – # – HETEROTAXY, VISCERAL, 1, X-LINKED; HTX1
This is important in the functional specialization of the cerebral hemispheres and in behavioral aspects like the preferential use of one hand. The establishment of asymmetry in the nervous system seems to occur independently from that of the trunk, a question that we will not attempt to address in this article.
Aspoenia the first tasks of an embryo is to define the corporal plan, that is, to establish the primary embryonal axes.
An anteroposterior or cephalocaudad axis is defined that will distinguish the cephalic and caudad ends, and a dorsoventral axis will distinguish the dorsal and ventral sides of the embryo. The left-right axis is automatically defined after these axes are formed. The normal disposition of the heart and organs is called situs solitus Figure 1. Although there is some confusion in the literature, situs inversus designates the perfect inversion of situs solituswith the heart toward the right.
Any different disposition is denominated heterotaxia or situs ambiguus see below. The incidence of situs vvisceral is estimated at 1 in 10 births. The incidence of heterotaxia is generally much lower and usually accompanied by complex cardiovascular malformations. Both hearts are morphologically normal and appear as mirror images. The arrows in a and b indicate the interventricular furrow.
Reproduced from Icardo, The relation between the presence of cardiac malformations and laterality defects has long been known.
Consequently, the asplenia-polysplenia syndrome has been described, characterized basically by the tendency to visceral symmetry in organs that are normally asymmetrical. Another fundamental aspect of this syndrome is its marked polymorphism, given that it is defined by the existence of a common cause with different final expressions. Heterotaxia also includes the absence of visceral asymmetry, a situation known as isomerism or sequence isomerism, which mainly involves the bronchi, lungs, and atria in the thorax.
Although the descriptions of heterotaxia were initially made in isolated cases, the study of large series has shown that in many cases there is a clear familial relation. The clearest example may be that of an Amish family with a high degree of consanguinity, in which various members had visceral situs inversus and cardiac malformations. The latter syndrome is due to ciliary hypomotility caused by the absence of the external arms of microtubular dyneine.
The existence of a mutant race of mice with the heterotaxia syndrome has opened new areas of investigation. The heterotaxia includes anomalous venous return, portal vein in a ventral position, hepatic and aspleniq isomerism, atrial isomerism, polysplenia, and thoracoabdominal visceral discordance. As occurs in human syndromes, the presentation is polymorphic, with simple atrial or ventricular septal defect occupying the opposite extreme of the phenotypical spectrum. The same as in humans, the iv gene seems to exhibit complete dominance in such a way that, in absence of its function, the viscerak site is determined randomly.
The absence of this genetic control explains the different patterns of heterotaxia 35 as well as variations in the cardiac phenotypes. The iv gene seems to be found 3 centimorgans from the gene of the heavy chain of immunoglobulin Igh-C in chromosome 12 of the mouse, 45,46 which is the equivalent of human chromosome Interestingly, the transgenic insertion in the legless mouse is also located in chromosome 12, close to the hfterotaxia of the iv gene, 47 suggesting that the mutation could have affected the iv locus.
While the iv and lgl mutations produce randomization of the visceral site, the mutated gene in the inv strain, which encodes inversin, is located on chromosome 4 and seems to direct the visceral site. The reason why genetic controls for the establishment of visceral site are located in such different positions is not visderal, but it suggests a close and complex regulation.
The identification of the different mutated genes in these strains of mice has clarified important aspects of their function. The modified gene in the iv and lgl strains encodes a dyneine associated vksceral ciliary microtubules, 49 which is why it has come to be known as LRD left-right dyneine.
When this protein is deactivated in transgenic mice, the laterality anomalies found in iv and lgl mice are reproduced.
Many of these mutant mice strains do not show structural ciliary anomalies. This suggested that there was no relation with human Kartagener syndrome, where these structural anomalies do exist. However, patients with Kartagener syndrome also exhibit mutations in the dyneine proteins, 53 which suggests that many syndromes with laterality abnormalities have a common origin. More recent advances in molecular biology and new detection techniques have made it vsiceral to prepare a complex picture, as yet incomplete, which includes the expression in cascade of a series of genes, the concurrent expression of other genes with the cascade, and ciliary activity in the node of Hensen or organizer during embryonal gastrulation stages.
All these factors are involved in establishing normal laterality and their disruption causes laterality defects in both humans and animal models. In the initial stages of development, the aspoenia appears symmetrical with respect to the midline. Although a mild transitory viscerl in the morphology of the Hensen nodule has been described in chick embryos, 54 the first clear evidence of morphological asymmetry emerges with the formation of the cardiac loop.
Upon continuing embryonal development, the rest of the organs progressively acquire their characteristic asymmetrical distribution. Conceptually, establishment of the left-right axis takes place in three phases.
The initial break in symmetry takes place during gastrulation, in relation with the nodule of Hensen. In a second phase, and as a consequence of the previous phase, numerous genes are expressed asymmetrically, to the left or to the right, thus giving identity to each embryonal side. Most of these genes encode signaling molecules that interact to establish signaling cascades. These cascades of asymmetrical expression start around the nodule and eventually end by establishing wide domains of asymmetrical gene expression in the lateral mesoderm.
Finally, this gene expression translates into the normal asymmetrical morphology of the organs. The factors involved in the initial break in symmetry are still largely unknown. These cilia have a vortical movement that, in conjunction with other cells, produce a leftward flow of the perinodal fluid. It is postulated this flow causes an asymmetrical distribution of a postulated, but as yet not identified morphogen, which is responsible for initiating the path of left-right signaling.
The ciliary flow could also be altered in other mutant strains of mouse characterized by the abnormal morphogenesis of nodal cilia, 50,58 or their absence. However, the model of nodal flow may not be valid in other species. In the chick embryo, monociliary cells axplenia irregularly distributed on the ventral and dorsal surface of the embryo, constituting only part of the cells of the nodule of Hensen.
In addition, it has been demonstrated that some genes are expressed asymmetrically before formation of the node. A hypothesis that is currently under study involves the cellular gap type junctions that are established in the tissues that surround the node.
If one small molecule were capable of circulating through those junctions in single direction, molecules would accumulate on hetterotaxia side of the midline, thus disrupting symmetry and triggering a response of asymmetrical gene activation in the node.
The derivatives of the lateral mesoderm will form the asymmetrical organs. Shh induces the expression of Lefty1 in the left half of the midline as well as Nodal and Car. On the side right, the activin pathway induces Fgf8, which in turn induces cSnR and prevents the expression of Nodal. Expression of Nodal in a 4-somite chick embryo; b expression of Lefty 1 in a 4-somite chick embryo; c: Figures e-j reproduced from Campione et al, In the chick embryo it has been demonstrated that various signaling molecules show small domains of asymmetrical expression viscedal the nodule of Hensen.
Among these molecules are established regulatory loops that control the asymmetry of laterality Figure 2. For example, the asymmetrical expression of Sonic hedgehog Shh on the left side of the node is essential for the correct development of laterality.