Genetics of human left–right axis malformations

doi:10.1006/scdb.1997.0187

Seminars in Cell & Developmental Biology

Volume 9, Issue 1, February 1998, Pages 89-99

https://doi.org/10.1006/scdb.1997.0187 Get rights and content

Abstract

Like all vertebrates, humans establish anatomic left–right asymmetry during embryogenesis. Variation from this normal arrangement (situs solitus) results in heterotaxy, expressed either as randomization (situs ambiguus) or complete reversal (situs inversus) of normal organ position. Familial heterotaxy occurs with autosomal dominant, recessive, and X-linked inheritance. All possible situs variants —solitus, ambiguus,inversus — can appear among some heterotaxy families. Positional cloning has led to the identification of a gene on the X chromosome responsible for some cases of human heterotaxy. In addition to their medical relevance, human studies provide a unique contribution to our understanding of left–right axis development among all vertebrates.

References (0)

Cited by (105)

Morphogenic fields: A coming of age
2022, Explore
Morphogenesis, the coming-into-being of living organisms, was first described in the 4th century BC by Aristotle, progenitor of biology and embryology. Over the centuries it has been the subject of innumerable commentaries by philosophers, theologians and scientists but no consensus has ever been reached as to its causes. In the late 19th century, along with the emergence of cellular and molecular biology, embryology underwent a renaissance and became a topic of great interest and research. Early on the discipline divided into two opposing factions, those who attempted to explain fetal development on the basis of cellular and molecular mechanisms, and those who invoked the presence of organizing fields. The morphogenic field was first articulated in the early decades of the 20th century by multiple researchers independently of each other. The field became an extremely useful conceptual tool by which to explain a wide range of developmental phenomena. While embryology and genetics originally formed a unified discipline, during the 1930s and 1940s geneticists became progressively skeptical of the field notion. The discovery of the DNA structure by Watson and Crick in the early 1950s decisively settled matters and thereafter the two disciplines pursued different lines of inquiry. After World War II embryology and the field concept went into a decades-long decline. By the 1980s an increasing number of scientists began to critically reexamine the morphogenic field concept and it underwent a second renaissance. In this paper I examine the development and evolution of the field concept, both experimentally and conceptually, and highlight the failure of genetic mechanisms to explain morphogenesis. I provide three instances from the medical literature of developmental phenomena which are only explainable on the basis of morphogenic field dynamics and argue that the field concept must be readmitted into mainstream scientific discourse.
Human Laterality Disorders: Pathogenesis, Clinical Manifestations, Diagnosis, and Management
2021, American Journal of the Medical Sciences
Citation Excerpt :
However, in humans the same gene mutation has been associated with different heterotaxy phenotypes. Human genotyping has failed to establish a clear and consistent genotype-to-phenotype link and familial pedigree analysis has shown identical gene mutations in affected and unaffected individuals.2,3,22–33 This does not exclude a genetic basis for human laterality disorders, but rather suggests the presence of an incomplete data base and the need for further research into the genetic basis for these diseases.
Human laterality disorders comprise a group of diseases characterized by abnormal location (situs) and orientation of thoraco-abdominal organs and vessels across the left-right axis. Situs inversus totalis is mirror image reversal of thoraco-abdominal organs/great vessels. Situs ambiguus, better known as heterotaxy, is abnormal arrangement of thoraco-abdominal organs across the left-right axis excluding situs inversus totalis. Heterotaxy, also referred to as atrial or atrial appendage isomerism, is characterized by abnormal location of left-sided or right-sided organs with loss of asymmetry of normally paired asymmetric organs. It is associated with a variety of anomalies involving the heart, great vessels, lungs and intra-abdominal organs. Right and left atrial isomerism are associated with multiple complex congenital cardiac and vascular anomalies, many of which are lethal when untreated. Isomerism may also affect the lungs, spleen, liver, gall bladder, and intestines. Innovative surgical therapy of heterotaxy/isomerism has reduced early mortality and markedly improved long-term prognosis.
Endoscopic Retrograde Cholangiopancretography for bile duct stones with residual cystic duct stones in patients with situs inversus totalis
2020, Asian Journal of Surgery
Atypical brain functional segregation is more frequent in situs inversus totalis
2018, Cortex
Most humans show typical brain functional specialization with language and praxis favoring left hemisphere lateralization and spatial attention and face recognition showing right hemisphere dominance. Lateralization of these cognitive functions was investigated using fMRI in participants with complete visceral reversal and matched control participants. While most participants revealed typical brain organization, atypical functional segregation was significantly more frequent in participants with visceral reversal. Interestingly, some left handers maintained typical functional segregation but showed complete reversal of all cognitive functions regardless of visceral organization. Cognitive performance, as measured with a neuropsychological test battery, was significantly predicted by the degree of atypical functional segregation of praxis and spatial attention. Increased deviation from typical functional segregation paired with lower cognitive performance. The findings suggest that typical functional segregation reflects an optimal evolutionary solution with deviations being associated with reduced cognitive performance.
Ampullectomy for an unexpected ampullary hamartoma in a heterotaxic patient
2013, International Journal of Surgery Case Reports
Citation Excerpt :
Heterotaxy designates rare congenital disorders of organ positioning in the thoracic and abdominal cavities.1,2 More precisely, situs inversus totalis defines the full transposition of organs in a mirror image, while situs ambiguus includes any defect of lateralization along the cephalo-caudal axis.1 Numerous other anomalies may be associated with heterotaxy, in particular concerning the digestive tract, complicating the surgical management because of the loss of conventional anatomic landmarks.
Heterotaxy designates rare congenital disorders of organ positioning in the thoracic and abdominal cavities, which can be associated with numerous anomalies, complicating the surgical management because of the loss of conventional anatomic landmarks.
A 72-year-old man was found to have asymptomatic cholestasis. Further workup included computed tomography and magnetic resonance cholangiopancreatography that revealed anomalies of lateralization of digestive organs associated with intestinal malrotation and polysplenia, and a stone-like element in the main bile duct. Endoscopic retrograde cholangiopancreatography failed to extract the lesion. Laparotomy found no stone, but a polypoid tumor with ampullary implantation. Pancreaticoduodenectomy was judged unreasonable due to the presence of macroscopic cirrhosis and a complete ampullectomy was performed. Histopathological examination revealed a hamartomatous polyp.
The unusual angle of the duodenoscope in a left-sided duodenum may have contributed to the improper pre-operative diagnosis. Endosonography could have recognized the tissular origin of the lesion and prompted a more detailed preoperative planning. It was fortunate that the patient ended up receiving the appropriate treatment despite the absence of an adequate pre-operative diagnosis, as the option of performing an extended resection was ruled out due to the presence of cirrhosis.
Although heterotaxy leads to increased technical difficulties in performing usual endoscopic and surgical procedures, it can be safely managed by experienced surgeons as illustrated by the present case. Imaging modalities have limited sensitivity in the diagnosis of small ampullary tumors. As false-negatives are likely to occur, this possibility should guide the choice of the best operation.
Genetic basis of human left-right asymmetry disorders
2014, Expert Reviews in Molecular Medicine

View all citing articles on Scopus

View full text

Regular ArticleGenetics of human left–right axis malformations

Abstract

Regular Article
Genetics of human left–right axis malformations