Total Anomalous Pulmonary Venous Return 1

Description

Total anomalous pulmonary venous return (TAPVR) is a cyanotic form of congenital heart defect in which the pulmonary veins fail to enter the left atrium and instead drain into the right atrium or one of the venous tributaries (summary by Bleyl et al., 1994).

Clinical Features

Neill et al. (1960) described father and daughter with hypoplastic right lung with systemic arterial supply and venous drainage. They referred to the disorder as the 'scimitar syndrome' because of the radiographic appearance created by the anomalous vein draining the right lower lung and connecting with the inferior vena cava. The father was asymptomatic but had been rejected for military service because his heart was said to be on the right side. The daughter had severe pulmonary hypertension, frequent respiratory infections, and marked hypoplasia of the right lung with dextroposition of the heart.

Vinh et al. (1968) described a brother and sister, offspring of nonconsanguineous parents, with total infradiaphragmatic pulmonary venous return. In 2 brothers and a male paternal first cousin, Paz and Castilla (1971) observed total anomalous pulmonary venous return. Kaufman et al. (1972) described total anomalous pulmonary venous return of the figure-of-eight type in 2 sisters and a daughter of their maternal uncle. Chelius et al. (1962) described partial anomalous pulmonary venous return in 2 brothers whose maternal grandmother died at age 42 of congenital heart disease.

Solymar et al. (1987) reported 3 pairs of sibs with total anomalous pulmonary venous connection. Four of the affected persons were male. Even in the same family, the connection was supracardial in one and infracardial in the other, indicating that genetic regulation deals with the left atrial connection to the intrapulmonary veins. Having failed to establish this connection, the intrapulmonary veins attach themselves to any adjacent venous structure; hence, the variety of connections found at birth.

Raisher et al. (1991) reported total anomalous pulmonary venous connections in a father and his son and daughter. There was no known consanguinity in the family.

Bleyl et al. (1993) and Bleyl et al. (1994) reported a large Utah-Idaho family of Scottish origin in which nonsyndromic TAPVR appeared to be inherited as an autosomal dominant with incomplete penetrance and variable expression. The family contained 14 affected individuals.

Mapping

By linkage mapping with polymorphic microsatellite markers in a large Utah-Idaho family of Scottish origin segregating TAPVR, Bleyl et al. (1994, 1995) localized the TAPVR1 locus to a 30-cM interval on 4p13-q12; maximum lod = 6.51 at theta = 0.0. A vascular epithelial growth factor receptor, thought to have a role in vasculogenesis, also mapped near the centromere and therefore was considered a candidate for the TAPVR gene. Kinase insert domain receptor (KDR; 191306) and its mouse homolog, fetal liver kinase-1, bind vascular endothelial growth factor with high affinity in vitro and are expressed early in development by endothelial cell precursors. The mouse homolog has been implicated in the development of blood and blood vessels. KDR maps to 4q12.

Ward (1996) observed 10 families with multiple cases of TAPVR in Utah; 4 families failed to show linkage to 4q12-q13. The original family and others that derived from Scotland had the same haplotype. The region of mapping was one in which very low recombination occurs.

Bleyl et al. (2006) identified a second Utah family of Scottish origin in which 2 members had TAPVR. Extensive genealogic analysis could not identify a common ancestor with the first large Utah family of Scottish origin reported by Bleyl et al. (1994). However, haplotype analysis demonstrated identity by descent in these 2 families, suggesting a remote Scottish founder. Haplotype analysis and recombination events refined the TAPVR1 locus to a 4.16-cM (2.48-Mb) region on chromosome 4q12 between D4S1630 and D4S3019. The haplotype was not identified in 238 control chromosomes. Penetrance of the anomaly was estimated to be 40%.

Population Genetics

Bleyl et al. (2010) stated that TAPVR affects 1 in 15,000 live births.

Animal Model

In gene expression studies in mouse and chick embryos for both the Pdgfra receptor (PDGFRA; 173490) and its ligand, Pdgfa, Bleyl et al. (2010) showed temporal and spatial patterns consistent with a role in pulmonary vein development. Loss of PDGFRA function in both chick and mouse embryos caused TAPVR with low penetrance (approximately 7%), reminiscent of that observed in human TAPVR kindreds. Intermediate inflow tract anomalies occurred in a higher percentage of embryos (approximately 30%), suggesting that TAPVR may occur at one end of a spectrum of defects.