RESUMO
PURPOSE: Axenfeld-Rieger malformations of the anterior segment are clinically heterogeneous, and up to 50% of cases are attributable to PITX2 or FOXC1 mutation. In view of PITX2's contribution to corneal development and the altered CCT in some FOXC1-related cases, this study was undertaken to investigate whether a related phenotype is associated with the PITX2/Pitx2 mutation. METHODS: Central corneal thickness (CCT) was measured in patients and mice with PITX2/Pitx2 mutations. CCT in affected individuals and unaffected first-degree relatives from a large PITX2 mutation pedigree was measured with ultrasonic pachymetry. For murine measurements, the optical coherence tomogram (OCT) was calibrated against plastic films whose thickness had been determined with scanning electron microscopy (SEM). Subsequently, CCT was measured in ex vivo eyes from Pitx2(+/-) and wild-type murine littermates by using OCT. RESULTS: CCT in individuals with the PITX2 mutation (mean 484 microm; range, 425-519; n = 8) was significantly lower than in their unaffected first-degree relatives (mean 582 microm; range, 550-590; n = 5; P = 0.0002, t-test). Scanning electron microscopy (SEM) and OCT measurements of reference films correlated closely (r = 0.9995) and subsequent OCT analysis of murine eyes revealed a significant reduction in CCT in Pitx2(+/-) compared with wild-type littermates (Pitx2(+/-): mean, 72 microm; range, 57-87, n = 6; wt: mean, 88 microm; range, 63-100; n = 6, P = 0.035, t-test). CONCLUSIONS: The results show that PITX2/Pitx2 mutation results in reduced corneal thickness and provides the first example of reduced CCT in a genetic subtype of glaucoma. These data will facilitate management of developmental glaucoma and offer potential for guiding molecular genetic testing in patients with Axenfeld-Rieger. The similar CCT reduction observed in patients and mice with comparable mutations emphasizes the utility of this murine model. The technical advance of optical murine CCT measurement also provides scope for serial in vivo imaging of the developing anterior segment and determining the effects of altered CCT on measured IOP.