The portal for rare diseases and orphan drugs

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. 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).

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.

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.

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).

Heart malformations and associated lesions require a specific management, but the lateralization defect itself does not require any particular treatment.