Clinical aspects of defects in the determination of laterality

Of individuals in the human population, 99.99% have developed identical thoracoabdominal asymmetry with the cardiac apex, a bilobed lung, the stomach, and the spleen on the left side of the midline, and the vena cavae, a trilobed lung, the appendix, and the larger liver lobe on the right. This arrangement of organs is situs solitus. Occasionally, individuals have a complete, mirror-image reversal of this asymmetry called situs inversus, and 20-25% of those individuals have an autosomal recessive condition, Kartagener syndrome, with ciliary dyskinesia, bronchiectasis, sinusitis, and infertility. Between these extremes of situs solitus and situs inversus lies the spectrum of situs ambiguus, characterized by isomerism, heterotaxy, and multiple malformations in one or more thoracic or abdominal organs. Although most abnormal situs in humans occurs sporadically, growing evidence suggests that interference with normal genetic mechanisms and pathways may be responsible for most cases. Familial cases suggest major effects of both autosomal and X-linked genes with both dominant and recessive expression. Situs inversus and situs ambiguus (SI/SA) occurring in probands who have close relatives with "isolated," nonsyndromic birth defects suggests that some of the pathways important in situs determination may also be involved in causing sporadic malformations not obviously associated with a defect in laterality determination. Human phenotypes of interest include the association of SI/SA with short rib-polydactyly syndromes and renal-hepatic-pancreatic dysplasia, and with agnathia and holoprosencephaly. Further elucidation of the developmental pathways involved in left-right axis determination should shed light on the causes of and relationships among these human phenotypes.