Aortic Aneurysm, Familial Thoracic 6

A number sign (#) is used with this entry because thoracic aortic aneurysm-6 (AAT6) is caused by heterozygous mutation in the ACTA2 gene (102620), encoding vascular smooth muscle actin, on chromosome 10q23.

For a general phenotypic description and a discussion of genetic heterogeneity of familial thoracic aortic aneurysm, see 607086.

See also moyamoya disease-5 (MYMY5; 614042), another vascular disorder caused by mutation in the ACTA2 gene.

Clinical Features

Guo et al. (2007) identified a large family with autosomal dominant inheritance, with decreased penetrance, of thoracic aortic aneurysms leading to acute aortic dissections (TAAD). Segregation of the disorder was not linked to any known locus. On examination, the only physical feature present in all family members was pronounced and persistent livedo reticularis (see 182410), a purplish skin discoloration in a network pattern due to constriction or occlusion of deep dermal capillaries, clearly visible on arms and legs. In other families with a similar phenotype, iris flocculi was also present. Patent ductus arteriosus (PDA) was present in 6 affected individuals from 2 families, and bicuspid aortic valve (BAV) in 4 individuals from 3 families.

The majority of individuals with AAT6 studied by Guo et al. (2007) presented with acute ascending (type A) or descending (type B) aortic dissections, and 16 of the 24 deaths were due to type A dissections. Two individuals experienced type A dissections with documented ascending aortic diameters at 4.5 and 4.6 cm, whereas 11 individuals dissected at aortic diameters greater than 5.0 cm. Aortic dissections occurred in 3 individuals under 20 years of age, and 2 women died of dissections postpartum. In 3 young men, type B dissection complicated by rupture or aneurysm formation occurred at the ages of 13, 16, and 21 years. Despite the young age of death of some family members, the Kaplan-Meier survival curve of the cohort estimated a median survival of 67 years, suggesting that the disease is less deadly than Loeys-Dietz syndrome (see 609192) and similar to treated Marfan syndrome (MFS; 154700).

Bixler and Antley (1976) reported an association of familial aortic dissection and ectopia of the pigment layer of the iris onto the anterior surface of the iris. In 1 patient this created an appearance suggesting coloboma. McKusick (1986) observed a similar eye finding in a family seen with Dr. Robert L. Berger in the Moore Clinic. Lewis and Merin (1995) noted the association of livedo reticularis and iris flocculi with familial thoracic aortic aneurysms.

Using a retrospective study of medical records, Regalado et al. (2014) identified 53 women with ACTA2 mutations who had a total of 137 pregnancies. Eight women (6% of pregnancies) had aortic dissections during the third trimester or postpartum period (6-14 days after delivery). Three dissections were fatal. One woman had a myocardial infarction during pregnancy, independent of her aortic dissection. Six women had a family history of aortic dissection, and 5 had hypertension before or during the pregnancy. Three dissections occurred with aortic diameters of less than 5 cm. Aortic pathology showed that dissection occurred with minimal medial degeneration and with increased proteoglycan accumulation. Regalado et al. (2014) concluded that pregnancy in women with ACTA2 mutations is associated with an increased risk of aortic dissection with minimal aortic dilatation.

Mapping

Using genomewide linkage analysis followed by typing of microsatellite markers, Guo et al. (2007) mapped the phenotype in a family with TAAD and livedo reticularis to chromosome 10q23-q24. The authors designated this locus TAAD4.

Molecular Genetics

In a family with thoracic aortic aneurysms and dissections and livedo reticularis linked to 10q23-q24, Guo et al. (2007) identified a heterozygous mutation in the ACTA2 gene (R149C; 102620.0001). The mutation segregated with livedo reticularis in the family with a lod score of 5.85. These results suggested that the R149C ACTA2 mutation was responsible for both thoracic aortic aneurysm and livedo reticularis in this family. Sequencing of the ACTA2 gene in 97 unrelated families with a similar phenotype identified 14 additional families with ACTA2 mutations. A total of 5 families carried the R149C mutation, which was shown by haplotype analysis to have arisen de novo in each. The authors commented that another form of thoracic aortic aneurysm with dissection (AAT4; 132900), caused by mutations in another component of the smooth muscle cell contractile unit, MYH11 (160745), is also associated with PDA in some affected individuals. Structural analyses and immunofluorescence of actin filaments in smooth muscle cells (SMCs) derived from individuals heterozygous for ACTA2 mutations illustrated that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial thoracic aortic aneurysm, indicated the importance of SMC contraction in maintaining the structural integrity of the ascending aorta.

Guo et al. (2009) studied 20 families with 127 members harboring heterozygous ACTA2 mutations and phenotyped them for premature vascular disease, defined as an age of onset less than 55 years in men and less than 60 years in women. Thoracic aortic aneurysm had been reported in 14 of these 20 families by Guo et al. (2007). Thoracic aortic aneurysm was the primary vascular disease in ACTA2 mutation carriers (76 individuals); 26 individuals had premature onset of coronary artery disease, and 15 had ischemic strokes.

In 40 German probands with thoracic aortic aneurysms, 21 of whom had clinical features suggestive of Marfan syndrome, but all of whom were negative for mutation in the FBN1 (134797) and TGFBR2 (190182) genes, Hoffjan et al. (2011) sequenced the ACTA2 gene and identified heterozygous mutations in 3 patients (see, e.g., 102620.0005 and 102620.0006). None of the 21 individuals with features suggestive of MFS were found to carry a mutation in ACTA2. Among the remaining 19 patients, there were no differences between the 3 patients with ACTA2 mutations and the nonmutated patients. The authors also noted that there was no history of premature stroke or coronary artery disease in the mutation-positive families.