November 1998
Abnormalities in the Determination of Lateral Symmetry
By ERIC STRONG
he left-right axis is defined very early in embryogenesis. At approximately day 15, the formation
of the prechordal plate and primitive streak define the anteroposterior and dorsoventral axes, and
thus also define left and right. Although subtle asymmetries exist prior, the first major break in
symmetry during development comes when the heart tube loops to the right early in the fourth week. The
initial 90 degree clockwise rotation of the stomach in the fifth week marks what is likely the most
important event in the determination of asymmetry among the structures of the abdomen 1. This
determination of left-right asymmetry is non-random and highly conserved among humans. However,
defects in asymmetry do occur, and there exists a complete spectrum of malformations ranging from
normal asymmetry to reverse asymmetry to a complete lack of asymmetry 2.
The normal orientation of the organs of the trunk is known as situs solitus, and is clearly defined
in the thorax as consisting of a right heart loop. A complete reversal of this orientation with a
left heart loop is known as situs inversus. All possible orientations existing between these two
extremes are grouped under the general tittle of situs ambiguous. Within this general grouping exist
both cases of non-consistent orientation (such as a situs solitus thorax and situs inversus abdomen)
and cases of complete lack of asymmetry.
Complete situs inversus has a prevelance of 1/10000 2. Although the majority of patients with
this trait present with no significant clinical problems, between 3 and 9 percent have cardiac
abnormalities 2. In addition, 1/4 of situs inversus patients suffer from primary ciliary dyskinesia
(PCD) 2. In PCD, cilia in the respiratory epithelium are either immotile or dyskinetic. This leads
to chronic respiratory infection and sinusitis. Also, as a result of immotile sperm flagella, affected
males are usually infertile.
Although the category of situs ambiguous refers to a myriad of related, yet distinct errors in
orientation, there exist two similar conditions in which there is either a complete or partial
lack of asymmetry. The first of these is known as right isomerism sequence. In right isomerism
sequence, there is a general lack of typically left sided structures within the trunk. Thus, both
lungs are trilobed with short eparterial bronchi, both atrial appendages are pyramidal in shape, the
liver is symmetrical, and there is almost always a lack of a spleen 2,3. Patients lacking a spleen
are said to have asplenia, and there have been no recorded cases of asplenia without other signs of
right isomerism sequence. Other characteristics of right isomerism sequence include total anomalous
pulmonary return (35%), single ventricle (70%), bilateral superior vena cava (50%), and a heart apex
to the right of midline (40%) 3. The supradiaphragmatic inferior vena cava will usually drain into
the morphological right atrium, which is not uncommonly located on the left. Interestingly, right
isomerism is more common in males 2.
The second condition within the situs ambiguous category is left isomerism sequence. In this condition,
there is a general lack of typically right sided structures, although there may be greater variation as
compared to right isomerism sequence, and no one pathogenic anomaly is present in all cases. Generally,
both lungs are bilobed with long hyparterial bronchi and there are multiple spleens (often as many as 6)
2,3. Patients having more than one spleen are said to have polysplenia. Unlike asplenia however,
polysplenia is not always associated with isomerism. Additionally, it is common for patients with right
isomerism to suffer from biliary atresia or even have an absent gall bladder 2,4. One third have a
bilateral superior vena cava, one third a right superior vena cava, and one third a left superior vena
cava 3. There is usually an absence of the hepatic segment of the inferior vena cava, in which case
the subhepatic inferior vena cava drains into the azygous vein, eventually emptying into (one of) the
superior vena cava 5. Unlike right isomerism, left isomerism is believed to be found in roughly equal
sex ratios 2.
There are some characteristics which both left and right isomerism sequence share. In half of patients
of either condition there is a complete lack of an interatrial septum, resulting in a common atrium, and
atrioventricular septal defects are present in over half of patients 2,3. The complex cardiac anomalies
associated with isomerism is largely responsible for the high mortality rate of these conditions, with
right isomerism’s mortality rate (79% in the first year) slightly higher than left isomerism’s (61% in the
first year). This is likely due to the increased incidence of total anomalous pulmonary venous return in
right isomerism 3. Anomalies in other systems are common as a whole, but individually rare. The more
common include intestinal fixation and rotation abnormalities, facial defects, CNS defects, hiatal
hernias, horseshoe kidney, and renal hypoplasia 2,4.
The causes of defects of lateral asymmetry are largely unknown, but it is suspected that the large
heterogeneity of such defects points to a largely heterogenous collection of both genetic and
environmental factors 2,6. An increased incidence of consanguinity between parents of children
with symmetry defects indicates a recessive gene is responsible for some cases 7, while the isomerism
trait has also shown dominance inheritance patterns in some pedigrees 8. In addition, the only locus
corresponding to situs abnormalities to be mapped was mapped to the X chromosome 9. These results seem
to indicate that there are at least three distinct genes, and likely many more, that play a role in the
determination of left-right asymmetry. Also, the existence of multiple situs abnormalities within a
single family indicate that the same genetic factor(s) may have the potential to cause situs inversus,
and both right and left isomerism 10. Environmental factors probably also play a role. It has been
shown that a much higher than normal rate of offspring with right isomerism sequence are born to non-obese
diabetic mice, and that the right twin in conjoined newt twins have situs inversus 50% of the time 2.
However, both correlations have yet to be demonstrated in humans.
References:
1. Moore, K.L.; Persaud, T.V.N. : The Developing Human. W.B. Saunders Company. 1998.
2. Splitt, M.P.; Burn, J.; Goodship, J. : Defects in the determination of left-right asymmetry. Journal of Medical Genetics. 33:498-503, 1996.
3. Rose, V.; Izukawa, T.; Moes, C.A.F. : Syndromes of asplenia and polysplenia. British Heart Journal. 37:840-852, 1975.
4. Chandra, R.S. : Biliary atresia and other structural anomalies in the congenital polysplenia syndrome. Journal of Pediatrics. 85:649-655, 1974.
5. Ruscazio, M.; Van Praagh, S.; Marrass, A.R.; Catani, G.; Iliceto, S.; Van Praagh, R. : Interrupted inferior vena cava in asplenia syndrome and a review of the hereditary patterns of visceral situs abnormalities. The American Journal of Cardiology. 81:111-116, 1998.
6. Carmi, R. : Human situs determination is probably controlled by several different genes. American Journal of Medical Genetics. 44:246-247, 1992.
7. Gatrad, A.R.; Read, A.P.; Watson, G.H. : Consanguinity and complex cardiac anomalies with situs amibiguus. Archives of Diseases in Children. 59:242-245, 1984.
8. Casey, B.; Cuneo, B.F.; Vitali, C.; van Hecke, H.; Barrish, J.l Hicks, J.l Ballabio, A.; Hoo, J.J. : Autosomal dominant transmission of familial laterality defects. American Journal of Medical Genetics. 61:325-328, 1996.
9. Srivastava, D. : Left, right...which way to turn? Nature Genetics. 17:252-254, 1997.
10. Niikawa, N.; Kohsaka, S.; Mizumoto, M.; Hamada, I.; Kajii, T. : Familial clustering of situs inversus totalis, and asplenia and polysplenia syndromes. American Journal of Medical Genetics. 16:43-47, 1983.
