VESS21 - Aortic and Arterial Aneurysms and Dissections in Patients with Loeys-Dietz Syndrome Vary by the Causative Variant Gene

Objectives:

Objectives: Loeys Dietz syndrome (LDS) is a heterogeneous group of syndromic connective tissue disorders due to pathogenic variants in the genes coding for the TGF signaling pathway. We aim to describe the aortic and arterial pathology in this population, define the phenotypic clinical exam features, and evaluate the interval to aortic/arterial aneurysms/dissections and extent of repair.

Methods:

Methods: The medical records were reviewed for patients with LDS type I-V receiving care at a single academic health care system between 2000 and 2021. Individuals with pathogenic and likely pathogenic variants for LDS I-V (TGFR1, TGFR2, SMAD3, TGF2, and TGF3 respectively) were included for analysis. Individuals with variants of unknown significance were excluded. Demographics, aortic/arterial pathology, surgical repairs, and survival were abstracted. Groups were compared by presence of aortic/arterial pathology and were also compared by genotype (LDS I-II vs. LDS III-V). Kaplan-Meier survival estimation was used to evaluate event free survival.

Results:

Results: A total of 63 patients with LDS 46% male, 77.8 % White were identified: 28.6% LDS I, 23.8% LDS II, 31.7% LDS III, 8% LDS IV, and 8% LDS V. Mean age at the time of the study was 45.8+14.4 years with a mean follow up of 7+7 years, Aortic/arterial pathology was diagnosed in 38 patients including 18 aortic dissections and 26 arterial aneurysms/dissections. Aortic dissection was predominantly type A (n=14), with type B aortic dissection occurring in 5 individuals, one was superimposed on a chronic type A. Carotid and iliac were the most common arterial pathology (N=7 each). There were no differences in the extra-aortic phenotypic clinical exam characteristics among patients with and without aortic/arterial pathology. However, the affected gene and hypertension were associated with aortic/arterial pathology (Table). Comparing patients with LDS I-II (N=33) vs. LDS III-V (N=30), it became apparent that this group of patients is more severely affected with significantly more aortic/arterial pathology (75.8% vs. 43.3%, P=.009) and younger age at occurrence (33.0+15.3 vs. 47.3+5.9 years, P=.003, Figure). Surgical repairs included 31 root, ascending, and/or arch repair (49.2%) and 11 descending thoracic and/or thoracoabdominal aortic repair (17.5%). There were 8 deaths in the cohort (mean age 46.29+10.9 years) with cause of death confirmed (N=6) or suspected (N=1) due to aortic rupture or dissection (N-6) and one unknown.

Conclusions: Genetic heterogeneity exists in LDS. Extra-aortic clinical exam phenotype does not seem to be associated with aortic/arterial pathology. The underlying genotype and hypertension appears to be associated with aortic/arterial pathology.