Impact of Genotype-Phenotype Interactions on Cardiovascular Function in Paediatric Loeys-Dietz Syndrome

Area of Science:

• Cardiovascular Medicine
• Genetics
• Pediatric Cardiology

Background:

• Loeys-Dietz syndrome (LDS) is a genetic disorder affecting connective tissue.
• The genotype-phenotype relationship in pediatric LDS, particularly concerning vascular and cardiac traits, requires further elucidation.
• Specific mutations in TGFBR1 and TGFBR2 genes are associated with distinct clinical manifestations in LDS.

Purpose of the Study:

• To investigate and compare the aortic and cardiac phenotypes in pediatric patients with Loeys-Dietz syndrome harboring TGFBR1 versus TGFBR2 mutations.
• To identify genotype-specific differences in aortic dimensions, distensibility, strain, and stiffness.
• To assess variations in cardiac structural and functional parameters based on the specific genotype.

Main Methods:

• A cohort of 32 pediatric LDS patients with either TGFBR1 (n=17) or TGFBR2 (n=15) mutations was analyzed.
• Comprehensive echocardiographic assessments were performed, measuring aortic dimensions and biomechanical properties (distensibility, strain, stiffness) at multiple levels.
• Left ventricular size and function parameters were also evaluated.

Main Results:

• Patients with TGFBR2 mutations exhibited significantly larger aortic dimensions (z-scores) at the aortic valve annulus, sinuses of Valsalva, sinotubular junction, and ascending aorta compared to the TGFBR1 group.
• TGFBR2 mutations were associated with reduced aortic distensibility and strain, and increased aortic stiffness in the ascending aorta and at the annulus and sinotubular junction.
• While demographics were similar, TGFBR2 patients were more likely to have undergone aortic surgery and used angiotensin receptor blockers.

Conclusions:

• Pediatric LDS patients with TGFBR2 mutations present with more severe cardiovascular phenotypes, characterized by larger aortic dimensions and increased aortic stiffness, than those with TGFBR1 mutations.
• These findings underscore the critical role of genotype in understanding and managing the cardiovascular manifestations of pediatric Loeys-Dietz syndrome.
• Clinical management strategies for pediatric LDS should consider the specific genetic mutation (TGFBR1 vs. TGFBR2) to tailor patient care effectively.