Familial patterns of thoracic aortic aneurysms

Hypothesis: To provide evidence that genetic factors contribute to the deve lopment of thoracic aortic aneurysms (TAA) by demonstrating familial patter ns of the disease. Design: Retrospective review. Setting: University hospital. Patients and Methods: We sought to identify familial patterns of TAA from a database of 598 patients evaluated or treated for TAA at the Yale Center f or Thoracic Aortic Disease, New Haven, Conn, from January 1985 to August 19 98. Of the 598 patients, 45 patients had a diagnosis of Marfan syndrome and 553 patients had no known history of any collagen vascular disorder. Of th e 553 patients in the latter category, 398 patients had confirmed TAA, 66 h ad TAA with concomitant aortic dissections, and 89 had aortic dissections. From the group of 464 patients with TAA with or without concomitant aortic dissections, 2 interviewers attempted to contact 150 randomly selected pati ents for telephone screening to determine the presence of familial patterns of aortic disease. Fifteen of these patients were lost to follow-up. Compl ete medical and family histories of the remaining 135 patients (85 men, 50 women) were reviewed. Of the 135 individuals screened, 26 (18 men, 8 women) (19.3%) were found to belong to multiplex pedigrees. These 26 patients wit h familial nonsyndromic TAA were compared with the remaining 109 patients w ith sporadic TAA and the 45 patients with Marfan syndrome-associated TAA. Main Outcome Measures: Groups were examined for statistical differences in age and aortic size at the time of diagnosis, growth rates of TAA, and rate s of concomitant diseases. Nonsyndromic family pedigrees were analyzed and potential modes of inheritance were determined. Results: The mean age at presentation for patients with familial nonsyndrom ic TAA (56.8 years) was significantly younger than the mean age of presenta tion in sporadic cases (64.3 years, P less than or equal to.03), and signif icantly older than that of patients with Marfan syndrome (24.8 years, P les s than or equal to.001). Patients with a family history of aortic aneurysms had faster growth rates (0.22 cm/y) compared with patients with sporadic T AA (0.03 cm/y) (P less than or equal to.001) and patients with Marfan syndr ome (0.10 cm/y) (P less than or equal to.04). Familial nonsyndromic TAA in patients with a concomitant aortic dissection had a growth rate of 0.33 cm/ y, which was greater than that of patients with sporadic TAA (0.10 cm/y) an d patients with Marfan syndrome (0.08 cm/y) with associated aortic dissecti on. This growth of 0.33 cm/y was significantly faster than the overall grow th rate estimate of aneurysms in patients with aortic dissection (0.14 cm/y ) (P less than or equal to.05). Ten pedigrees (38.5%) showed direct father to son transmission, consistent with an autosomal dominant mode of inherita nce. Six family pedigrees (23.1%) suggested an autosomal dominant or X-link ed mode of inheritance. Seven pedigrees (26.9%) suggested a recessive mode of inheritance; 2 an autosomal recessive mode, and 5 an X-linked recessive or autosomal recessive mode. The remaining 3 pedigrees displayed more compl ex modes of inheritance. Conclusions: This study supports the role of genetic factors influencing fa milial aggregation of TAA. Thoracic aortic aneurysms in association with mu ltiplex pedigrees represent a new risk factor for aneurysm growth. Pedigree analysis suggests genetic heterogeneity. The primary mode of inheritance s eems to be autosomal dominant, but X-linked dominant and recessive modes ar e also evident.