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

Abstract 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±14.9years) 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 SMAD4 versus 32.7±3.9mm in the non- SMAD4 group (p=0.001). SMAD4 was an independent predictor for increased aortic root ( β -coefficient 3.5, p 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.