SMAD4 gene mutation increases the risk of aortic dilation in patients with hereditary haemorrhagic telangiectasia

Background Mutations in the genes ENG, ACVRL1 and SMAD4 that are part of the transforming growth factor-beta signalling pathway cause hereditary haemorrhagic telangiectasia (HHT). Mutations in non-HHT genes within this same pathway have been found to associate with aortic dilation. Therefore, we investigated the presence of aortic dilation in a large cohort of HHT patients as compared to non-HHT controls. Methods Chest computed tomography of consecutive HHT patients (ENG, ACVRL1 and SMAD4 mutation carriers) and non-HHT controls were reviewed. Aortic root dilation was defined as a z-score > 1.96. Ascending and descending aorta dimensions were corrected for age, gender and body surface area. Results In total 178 subjects (57.3% female, mean age 43.9 ± 14.9 years) were included (32 SMAD4, 47 ENG, 50 ACVRL1 mutation carriers and 49 non-HHT controls). Aortopathy was present in a total of 42 subjects (24% of total). Aortic root dilatation was found in 31% of SMAD4, 2% of ENG, 6% of ACVRL1 mutation carriers, and 4% in non-HHT controls (p < 0.001). The aortic root diameter was 36.3 ± 5.2 mm in SMAD4 versus 32.7 ± 3.9 mm in the non-SMAD4 group (p = 0.001). SMAD4 was an independent predictor for increased aortic root (β-coefficient 3.5, p < 0.001) and ascending aorta diameter (β-coefficient 1.6, p = 0.04). Conclusions SMAD4 gene mutation in HHT patients is independently associated with a higher risk of aortic root and ascending aortic dilation as compared to other HHT patients and non-HHT controls.