Aortic Aneurysm, Familial Thoracic 10

A number sign (#) is used with this entry because of evidence that thoracic aortic aneurysm-10 (AAT10) is caused by heterozygous mutation in the LOX gene (153455) on chromosome 5q23.

For a general phenotypic description and a discussion of genetic heterogeneity of thoracic aortic aneurysm, see AAT1 (607086).

Clinical Features

Guo et al. (2016) studied 6 families segregating autosomal dominant thoracic aortic aneurysm with or without dissection. Thoracic aneurysms in affected individuals were either aortic root aneurysms or fusiform aneurysms that involved both the aortic root and ascending aorta. Some mutation carriers died of ascending aortic dissections, but there were no reports of aortic dissections with minimal enlargement of the ascending aorta, and none of the affected individuals presented with descending thoracic aortic aneurysms or dissections. Three patients had bicuspid aortic valve. In addition, 2 unrelated probands who underwent thoracic aortic aneurysm repair at ages 11 years and 16 years, respectively, also exhibited features of Marfan syndrome (MFS; 154700), including high-arched palate, pectus excavatum, dolichostenomelia, scoliosis, joint hypermobility, and skin striae. Some family members of the latter proband also exhibited marfanoid features, including dural ectasia, pectus deformity, joint hypermobility, and skin striae; however, Guo et al. (2016) stated that the features were not sufficient to meet diagnostic criteria for Marfan syndrome in either family. Histologic examination of aortic tissue from 2 unrelated patients showed mild medial degeneration characterized by focal loss of elastin fibers and smooth muscle cells, but limited deposition of proteoglycans. There was disorganization of the elastic fiber deposition, and collagen deposition appeared to be increased.

Lee et al. (2016) reported a family segregating autosomal dominant thoracic aortic aneurysm, in which the proband was a 39-year-old man who had a 10.5-cm ascending aortic aneurysm with contained rupture at age 19 years. He was 6 feet 8 inches tall and exhibited features of Marfan syndrome, including pectus excavatum, scoliosis, positive thumb sign, high-arched palate, dental crowding, and skin striae. The proband's mother, who had ascending aortic aneurysm with dissection at age 52 years, had also undergone repair of an abdominal hernia at age 34 and had myopia. The proband had 2 affected male cousins, 1 of whom had aortic arch dissection at age 41 years and also had an aneurysm of the hepatic artery; the other, who was 6 feet 5 inches tall, had an infrarenal abdominal aneurysm. The cousins' 73-year-old mother had normal serial echocardiograms, and arterial tortuosity seen on total body magnetic resonance angiography was deemed to be 'compatible with aging.' The maternal grandfather, who died at age 60 with emphysema, was reported to have had pectus excavatum and scoliosis. Histopathologic analysis of resected aortic tissue from both the proband and his mother showed cystic medial necrosis and fragmented external elastic lamella, with a disorganized appearance of collagen and elastic lamellae.

Molecular Genetics

In 3 patients from a family segregating autosomal dominant thoracic aortic aneurysm with or without dissection, who were negative for mutation in known thoracic aortic aneurysm-associated genes, Guo et al. (2016) performed whole-exome sequencing and identified heterozygosity for a missense mutation in the LOX gene (S280R; 153455.0002) that segregated with disease in the family. Exome and Sanger sequencing of an additional 410 probands with thoracic aortic aneurysm revealed heterozygous LOX mutations in 5 more families (see, e.g., W42X, 153455.0003, and Q267P, 153455.0004). Overall, of 15 mutation-positive individuals in the 6 families, 3 were asymptomatic. Guo et al. (2016) concluded that LOX variants are responsible for approximately 1% of familial thoracic aortic disease and are associated with decreased penetrance.

In 2 first cousins with thoracic aortic aneurysm and dissection or rupture, one of whom exhibited features of Marfan syndrome but was negative for mutation in the FBN1 (134797), TGFBR1 (190181), and TGFBR2 (190182) genes, Lee et al. (2016) performed whole-genome sequencing and identified heterozygosity for a missense mutation in the LOX gene (M298R; 153455.0005). The mutation was also detected in the proband's affected mother and in his cousin's affected brother, as well as in the cousins' mother, who exhibited only age-related arterial tortuosity.