Atrioventricular canal defect and associated genetic disorders: new insights into polydactyly syndromes

Atrioventricular canal defect (AVCD) is a common congenital heart defect (CHD), representing 7.4% of all cardiac malformations, considered secondary to an extracellular matrix anomaly. The AVCD is associated with extracardiac defects in about 75% of the cases. In this review we analyzed different syndromic AVCDs, in particular those associated with polydactyly disorders, which show remarkable genotype-phenotype correlations. Chromo - some imbalances more frequently associated with AVCD include Down syndrome, deletion 8p23 and deletion 3p25, while mendelian disorders include Noonan syndrome and related RASopathies, several polydactyly syndromes, CHARGE and 3C (cranio-cerebello-cardiac) syndrome. The complete form of AVCD is prevalent in patients with chromosomal imbalances. Additional cardiac defects are found in patients affected by chromosomal imbalances different from Down syndrome. Left-sided obstructive lesions are prevalently found in patients with RASopathies. Patients with deletion 8p23 often display AVCD with tetralogy of Fallot or with pulmonary valve stenosis. Tetralogy of Fallot is the only additional cardiac defect found in patients with Down syndrome and AVCD. On the other hand, the association of AVCD and tetralogy of Fallot is also quite characteristic of CHARGE and 3C syndromes. Heterotaxia defects, including common atrium and anomalous pulmonary venous return, occur in patients with AVCD associated with polydactyly syndromes (Ellis-van Creveld, short rib polydactyly, oral-facial-digital, Bardet-Biedl, and Smith-Lemli-Opitz syndromes). The initial clinical evidence of anatomic similarities between AVCD and heterotaxia in polydactyly syndromes was corroborated and explained by experimental studies in transgenic mice. These investigations have suggested the involvement of the Sonic Hedgehog pathway in syndromes with postaxial polydactyly and heterotaxia, and ciliary dysfunction was detected as pathomechanism for these disorders. Anatomic differences in AVCD in the different groups are probably due to different genetic causes.