Marfan Syndrome and Related Disorders: 25 Years of Gene Discovery

Abstract

Marfan syndrome (MFS) is a rare, autosomal-dominant, multisystem disorder, presenting with skeletal, ocular, skin, and cardiovascular symptoms. Significant clinical overlap with other systemic connective tissue diseases, including Loeys-Dietz syndrome (LDS), Shprintzen-Goldberg syndrome (SGS), and the MASS phenotype, has been documented. In MFS and LDS, the cardiovascular manifestations account for the major cause of patient morbidity and mortality, rendering them the main target for therapeutic intervention. Over the past decades, gene identification studies confidently linked the aforementioned syndromes, as well as nonsyndromic aneurysmal disease, to genetic defects in proteins related to the transforming growth factor (TGF)-β pathway, greatly expanding our knowledge on the disease mechanisms and providing us with novel therapeutic targets. As a result, the focus of the developing pharmacological treatment strategies is shifting from hemodynamic stress management to TGF-β antagonism. In this review, we discuss the insights that have been gained in the molecular biology of MFS and related disorders over the past 25 years.

Keywords: FBN1; LDS; Loeys-Dietz syndrome; MFS; Marfan syndrome; SKI; SMAD2; SMAD3; TGF-β signaling; TGFB2; TGFB3; TGFBR1; TGFBR2; thoracic aortic aneurysm.