Clinical aspects of defects in the determination of laterality

Of individuals in the human population, 99.99% have developed identical tho racoabdominal 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 tril obed lung, the appendix, and the larger liver lobe on the right. This arran gement of organs is situs solitus. Occasionally, individuals have a complet e, mirror-image reversal of this asymmetry called situs inversus, and 20-25 % of those individuals have an autosomal recessive condition, Kartagener sy ndrome, with ciliary dyskinesia, bronchiectasis, sinusitis, and infertility . Between these extremes of situs solitus and situs inversus lies the spect rum of situs ambiguus, characterized by isomerism, heterotaxy, and multiple malformations in one or more thoracic or abdominal organs. Although most a bnormal situs in humans occurs sporadically, growing evidence suggests that interference with normal genetic mechanisms and pathways may be responsibl e for most cases. Familial cases suggest major effects of both autosomal an d X-linked genes with both dominant and recessive expression, Situs inversu s and situs ambiguus (SI/SA) occurring in probands who have close relatives with "isolated," nonsyndromic birth defects suggests that some of the path ways important in situs determination may also be involved in causing spora dic malformations not obviously associated with a defect in laterality dete rmination. Human phenotypes of interest include the association of SI/SA wi th short rib-polydactyly syndromes and renal-hepatic-pancreatic dysplasia, and with agnathia and holoprosencephaly. Further elucidation of the develop mental pathways involved in left-right axis determination should shed light on the causes of and relationships among these human phenotypes. (C) 2001 Wiley-Liss, Inc.