Persistence of the suspect of vascular EDS, Loeys-Dietz, or arterial tortuosity syndromes should be further investigated by extensive vascular imaging (i.e., whole-body angio-MRI; or brain angio-MRI plus thoracic and abdominal angio-TC; or heart, abdominal aorta, epiaortic and limb vessels Doppler ultrasound) followed by molecular testing (COL3A1, TGFBR1, TGFBR2, SMAD3, TGFB2, and SLC2A10) in specialized laboratories. Here, SMAD3 is linked to Down syndrome.