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Orpha number ORPHA450
Synonym(s) Heterotaxy syndrome
Lateralization defect
Visceral heterotaxy
Prevalence 1-9 / 100 000
  • Autosomal dominant
  • Autosomal recessive
  • X-linked recessive
Age of onset Neonatal/infancy
ICD-10 -
  • C3178805
MeSH -
  • 10067265
  • 24614000


Heterotaxia (coming from the Greek 'heteros' meaning different and 'taxis' meaning arrangement) is the right/left transposition of thoracic and/or abdominal organs. It encompasses a wide variety of disorders since there are multiple possibilities of right/left reversals, which may be complete (situs inversus totalis or situs inversus i.e. all the organs normally found on the right are on the left and vice versa) or partial (incomplete situs inversus i.e. a limited number of organs are inversed - or situs inversus ambiguous i.e. a normally lateral organ is centrally located). The incidence of all lateralization defects is approximately 1/15 000. The severity of malformations is highly variable among members of a family. Complete situs inversus is not, in itself, a problem. On the contrary, partial situs inversus can be associated with any type of cardiac malformation, as well as renal, biliary, midline anomalies, etc. Asplenia and polysplenia are frequent. Asplenia refers to a lateralization defect with a small or absent spleen. It is thought to be due to the presence of a double right side (consequently, the left side is identical to the right). This is also referred to as right isomerism. Polysplenia describes a lateralization defect with multiple small spleens. It is thought to be due to the presence of a double left side (the right side is identical to the left). This is referred to as left isomerism. In 1955, Björn Ivemark described a series of autopsies of hearts from patients with asplenia. Thus, Ivemark syndrome corresponds to heterotaxia with asplenia. In some cases, the heart malformation is isolated, without any other anomaly; it is often a transposition of great vessels or a double outlet right ventricle, both resulting from a defective rotation of the heart outflow. In pair organs (which are not quite symmetrical) such as the lungs, kidneys or suprarenal glands, the symmetry is inversed or absent. The origin of lateralization defects can be genetic and three types of pattern of transmission have been proposed: autosomal recessive (the most frequent), autosomal dominant (rare) and X-linked (very rare with few families reported). In patients with heterotaxia, mutations have been identified in several genes (LEFTY A, ACVR2B, NODAL, CFC1, INVERSINE). All patients were heterozygous (neither compound heterozygous nor homozygous). Autosomal recessive transmission has only been reported in genetically modified mice. This suggests the existence of digenism in humans. Finally, the gene involved in X-linked transmission has been identified: it encodes ZIC3 (Zinc-finger protein of cerebellum) and is located at Xq26.2. In X-linked heterotaxia, abnormalities in the development of the midline are present. They can manifest as arhinencephalia, myelomeningocele, urological anomalies, hypertelorism, cleft palate and mostly, anomaly of the sacral spine and the anus. Heterotaxia with recurrent respiratory infections are named ciliary dyskninesia (see this term). Diagnosis relies on medical imaging or on the identification of mutations in the ZIC3 gene, in the case of X-linked forms. Prenatal scan can show lateralization abnormality and is systematically performed in case of a positive family history. Heart malformations and associated lesions require a specific management, but the lateralization defect itself does not require any particular treatment.

Expert reviewer(s)

  • Dr Patrice BOUVAGNET

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