A combined vascular surgical and clinical genetics approach to diffuse aneurysmal disease

Abstract

We report two patients who presented with extensive aneurysmal disease, in association with minimal external physical signs. Patient 1 remained genetically undiagnosed despite multiple structural, biochemical and genetic investigations. He made a good recovery following surgery for popliteal and left axillary artery aneurysms. Patient 2 was diagnosed with vascular type Ehlers-Danlos syndrome, associated with a high degree of tissue and blood vessel fragility, and is being managed conservatively. Early multidisciplinary assessment of such patients facilitates accurate diagnosis and management. The presence of multiple arterial aneurysms is relatively rarely described, and has been previously reported in association with autoimmune vasculitis, infection and a small number of heritable disorders of connective tissue (HDCTs).1 Vascular type Ehlers-Danlos syndrome (EDS) carries a high risk of morbidity and mortality associated with operative and intravascular procedures. 2 For this reason, the identification of individuals with a potential underlying genetic diagnosis is important for surgical planning. Both patients we present had no prior genetic diagnosis. We outline the differential diagnoses for patients with multiple aneurysms and discuss relevant HDCTs. Case 1A 54-year-old Sri Lankan man presented with painful, pulsatile, bilateral axillary masses. He had last visited a tuberculosis (TB) endemic area 13 years previously and had a prior diagnosis of latent TB, with a positive Mantoux test (22mm) 18 months before his presentation. There was no history of claudication or rest pain. Popliteal aneurysms were palpable but pedal pulses were strong, with no evidence of distal embolism or ischaemia.Computed tomography angiography revealed aneurysms throughout the arterial tree, including both axillary arteries (Fig 1). Diffuse and unexplained aneurysms prompted urgent referral for a genetic and infectious disease review. Inflammatory, infective and autoimmune differential diagnoses were considered but serological and positron emission tomography screening and antineutrophil cytoplasmic antibody serology were negative. Although the patient had raised immunoglobulin E titres, Strongyloides was also excluded. He was negative for human immunodeficiency virus (HIV). He was treated with standard TB therapy (rifampicin, isoniazid) prior to surgery.

Case report: Characterization of a rare pathogenic variant associated with loss of COL3A1 expression in vascular Ehlers Danlos syndrome

“…Visualization of this variant in Integrative Genome Viewer (IGV) suggested heterozygosity (Supplementary Data 1 in Supplementary Figure 1). This variant has been previously found to be associated with vascular subtype of Ehlers Danlos syndrome in one case report (7). Since this variant has not been reported in the 1000 genomes (8), Exome Aggregation Consortium (9) (ExAC) and other databases (10) and no functional data was available regarding this variant, we further proceeded to analyze the pathogenic basis of this variant using molecular techniques.…”