Corneal thinning and cornea guttata in patients with mutations in TGFB2

Objective: Human genome-wide association studies and animal models suggest a role for TGFB2 in contributing to the corneal thickness phenotype. No specific mutations, however, have been reported in this gene that affect corneal thickness. We sought to determine if haploinsufficiency of TGFB2 in humans associated with Loeys–Dietz syndrome type 4 is associated with corneal thinning. Design: Observational cohort study of families with Loeys–Dietz syndrome type 4, caused specifically by TGFB2 mutations, in a tertiary care setting. Participants: Three probands with pathogenic mutations in TGFB2 and family members underwent comprehensive ophthalmic examination. Methods: Clinical assessment included Scheimpflug imaging, specular microscopy, and slit-lamp biomicroscopy. We measured visual acuity, axial length, refractive error, and central corneal thickness. Results: Clinical evaluation of 2 probands identified corneal thinning and cornea guttata, despite a young age and distinct mutations in TGFB2 (c.905G>A, p.Arg302His; c.988C>A, p.Arg330Ser). In the third family, corneal thinning co-segregated with a TGFB2 mutation (c.1103G>A, p.Gly368Glu), although without apparent guttae. Conclusions: In this series, participants with TGFB2 mutations associated with Loeys–Dietz syndrome type 4 demonstrated decreased corneal thickness, and in 2 cases with splice site mutations, also demonstrated cornea guttata. The data demonstrate the importance of considering distinct phenotype–genotype correlations within this condition.