Ocular Findings as the Most Striking Manifestation of a SMAD3 Variant

Loeys-Dietz syndrome (LDS) is a heritable connective tissue disorder with variable expressivity. It is a multisystemic condition mainly characterized by a propensity for arterial aneurysms and dissections, skeletal manifestations, hypertelorism, bifid uvula, craniosynostosis, and cutaneous features. While LDS has significant clinical overlap with other heritable connective tissue disorders such as Marfan syndrome, the ocular manifestations of LDS have not yet been well characterized. We describe an individual with a variant in SMAD3 with a predominantly ocular phenotype and only mild arterial manifestations. The proband presented with early-onset high myopia (-25 diopters, bilaterally) and bilateral posterior subcapsular cataracts. Ocular phenotype also included esotropia, retinal hemorrhage, glaucoma, bilateral posterior staphylomas, and keratoconjunctivitis sicca. Extensive vascular imaging identified a right internal carotid artery dissection and mild tortuosity of numerous arteries. A molecular gene panel for heritable connective tissue disorders identified a heterozygous SMAD3 c.221G > T; p.(Arg74Leu) variant, initially reported as a variant of uncertain significance and subsequently re-interpreted as likely pathogenic. Other missense variants at this residue have been reported as pathogenic for LDS. High-grade myopia, premature cataracts, and premature glaucoma are part of the phenotypic spectrum in LDS caused by SMAD3 variants. Inclusion of SMAD3 in molecular gene panels for early-onset high-grade myopia should be considered.