The patients with duplication of
FOXC1 typically had IGD malformations and an higher incidence of elevated IOP and of glaucoma (usually childhood-onset) than did the patients with
FOXC1 mutations. In contrast, the patients with mutations of
FOXC1 presented with iris hypoplasia, corectopia, peripheral anterior synechiae, and posterior embryotoxon. Thus, the known diversity in clinical presentation found in the patients with
FOXC1 mutations
9 61 62 appeared to be more diverse than that in the patients with
FOXC1 duplication. However, the incidence of elevated IOP and glaucoma was lower in these patients than in the patients with
FOXC1 duplication, and glaucoma developed later in life than in patients with
FOXC1 duplication. Therefore, on the basis of significant differences of glaucoma incidence and age of onset of glaucoma, we suggest that patients with
FOXC1 duplication have a more severe prognosis in glaucoma development than do patients with
FOXC1 mutations
(Fig. 6) . Of interest, patients with nonocular findings appeared likely to have
FOXC1 mutations rather than
FOXC1 duplication. This suggests that the eye is particularly sensitive to duplication of
FOXC1. Because of the small number of patients with the
PITX2 deletion, we could not statistically compare the patients with
PITX2 mutations and
PITX2 deletion. The patients with
PITX2 defects typically had corectopia. VA in the patients with
PITX2 defects was worse than that in the patients with
FOXC1 defects, and they were more likely to have bilateral vision loss due to glaucoma than were the patients with
FOXC1 defects. However, no patients with
FOXC1 defects had polycoria; VA in the patients with
FOXC1 defects was better, and they were more likely to have unilateral vision loss than were patients with
PITX2 defects. The absence of polycoria in patients with
FOXC1 defects is consistent with previous studies.
30 61 62 Patients with
PITX2 defects required multiple surgeries to achieve the same results of treatment as patients with
FOXC1 defects. Therefore, glaucoma in patients with
PITX2 defects was more difficult to treat than that in patients with
FOXC1 defects. Patients with nonocular findings are more likely to have
PITX2 defects than
FOXC1 defects.
63 Taken together, on the basis of significant differences in VA and treatment outcome, the results suggest that patients with
PITX2 defects have a more severe prognosis for glaucoma development than do patients with
FOXC1 defects
(Fig. 6) . In this study also, the patients with
PITX2 defects had a more severe prognosis for glaucoma development than did the patients with
FOXC1 duplication
(Fig. 6) . Taking into consideration the recent finding that
PITX2 inhibits
FOXC1 activity,
1 our model predicts that
PITX2 defects may result in both an inability to activate
PITX2 targets and a gain-of-function activation of
FOXC1 targets. Therefore, the severity of the ocular phenotype in the patients with
PITX2 defects may be the simultaneous consequence of
PITX2 haploinsufficiency and a gain of function of
FOXC1. We suggest that patients with
PITX2 defects may benefit from more frequent periodic ophthalmic examinations, closer monitoring of the disease, and more aggressive treatment—both medical and surgical—when glaucoma appears. This study may also help guide mutation screening process for a patient with newly diagnosed ARM
(Fig. 6) . A potential limitation of our study is the absence of sufficient information regarding visual fields and central corneal thickness to allow statistical testing. Central corneal thickness is a factor with possible impact on IOP measurements by applanation tonometry. Eyes with thin corneas have an underestimation of IOP, and eyes with thick corneas have an overestimation. Recently, a study of corneal thickness in patients with
FOXC1 duplication has shown that patients with
FOXC1 duplication presented with increased central corneal thickness, leading to overestimation of IOP, independent of the tonometric method used.
64 However, because diagnosis of glaucoma in our study was based on the observation of at least two of the following criteria—glaucomatous optic disc damage, glaucomatous visual fields defects, or high IOP (≥22 mm Hg)—it is very unlikely that altered corneal thickness explains the increased rate of glaucoma diagnosis in the patients with
FOXC1 duplication (100%) compared with other gene defects. Nevertheless, a prospective clinical study, following up on the findings reported herein, that includes central corneal thickness would be worthwhile. An obvious limitation of the present study is the large number of patients coming from a small number of families, which may influence some of the results. Nevertheless, this analysis includes the largest cohort of patients with ARM analyzed to date. Our study has revealed that current medical therapies do not successfully lower IOP or prevent progression of glaucoma in patients with ARM with
FOXC1 or
PITX2 alterations. Further comparisons of the underlying genetic defects with glaucoma treatment outcomes, together with the testing of novel glaucoma therapies in cohorts of patient with ARM, could result in improved glaucoma treatment for these patients.