From a developmental standpoint, eye morphogenesis is a complex process, and proper patterning requires extremely well-coordinated temporo-spatial and dosage-dependent interactions between molecules, including PAX6, SHH, PAX2, FGF8, BMP4, and TBX5. Alterations in the signaling of any of these molecules, all of which are also involved in forebrain patterning, have been postulated to produce defects in the antero-posterior and ventral-dorsal development of the eye, resulting in intraocular anomalies [Kobayashi et al., 2010
PAX6, for instance, is the main inducer of the optic vesicle and is expressed in either side of the diencephalon of the developing embryo. PAX6
expression is repressed by the prechordal plate (presumably due to SHH
expression in the ventral midline), maintaining eye-field separation. Variable degrees of loss-of–function within the SHH pathway may explain mild to severe presentation of eye non-separation (ranging from mild hypotelorism to synthophthalmia and cyclopia) [England et al., 2006
On the other hand, PAX2
expression is induced by SHH activity in the ventral aspect of the optic vesicle, and PAX2 [Kobayashi et al., 2010
]has an important role in the closure of the optic fissure along the ventral optic cup and stalk [Carlson, 2009
]. Failure of optic fissure closure results in a uveal coloboma, compromising one or multiple structures of the eye, which can include the iris, ciliary body, choroid, retina, and/or optic nerve [Guercio and Martyn, 2007
]. This supports the role of SHH in the pathogenesis of this defect in patients reported in this and other studies [Bakrania et al., 2010
; Schimmenti et al., 2003
], although, coloboma in patients with mutations in PAX2
occurs at a rather low frequency.
Correlating with the concepts above, four of the patients with mutations in the C-terminus of SHH
presented with craniofacial microforms of HPE and ocular anomalies, but without structural brain anomalies. Two additional studies have demonstrated the occurrence of mutations in the C-terminus of SHH
in patients with isolated ocular anomalies [Bakrania et al., 2010
]. Although the functional consequences of mutations in the C-terminus of SHH
were initially unknown, a recent study demonstrated that mutations in this region of the gene affect autocatalylic cleavage, altering normal processing to mature SHH (SHH-Np). In this scenario, although the full-length (ie, non-cleaved) SHH has activity, its ability to generate further signaling is impaired [Tokhunts et al., 2010
; Traiffort et al., 2004
]. These findings may help explain part of the phenotypic variability observed in patients with mutations in SHH
[Solomon et al., 2010b
], and highlights the role of SHH and the molecules related to its signaling pathway in eye development.
Attempting to correlate the “extraocular anomalies” with the molecular defects in this patient cohort is challenging for a number of reasons, including the small number of patients studied. For instance, strabismus may be seen in patients with structural brain anomalies regardless of the underlying condition, although only 1 of the 4 patients in our cohort who had strabismus had a brain malformation. We observed 2 unrelated proposita with blepharoptosis who had mutations in the C-terminus of SHH; carrier siblings of both patients (not included in this cohort) were observed to have blepharoptosis as well. It is difficult to extrapolate further from this observation, except that patients with SHH
mutations bear scrutiny for this and other ophthalmologic disturbances. Nevertheless, from a developmental standpoint, this observation is interesting, as SHH has been described to regulate the patterning of nuclei in the midbrain in mice[Perez-Balaguer et al., 2009
]. Some of these nuclei are involved in the control of ocular and palpebral motility.
From the clinical standpoint, many of these ocular anomalies cause complications that may be anticipated and managed through follow-up by a specialized ophthalmologist familiar with HPE. For instance, besides the visual defects, a severe coloboma compromising the retina or optic nerve increases the risk of retinal detachment and choroidal neovascularization. Moreover, patients with microphthalmia are at risk of closed-angle glaucoma due to a smaller anterior chamber [Guercio and Martyn, 2007
]. Although patients in this cohort did not present with high degree myopia (defined as a refraction index less than -5D), the natural history of myopia in individuals with HPE-associated mutations is not well characterized, and comparisons with “unaffected” individuals are difficult, hence the incidence of complications are not known. Certain patients, especially those with brain anomalies, present with cortical visual impairment; for these patients, vision does not improve despite adequate correction of the refraction error.
Strabismus appears to be relatively frequent in patients within the HPE phenotypic spectrum; it is of extreme importance to detect heterotropias, since, even slit deviations may result in amblyopia and loss of stereopsis. Patients presenting with documented ocular deviations (and presumably without major brain anomalies) should be treated appropriately, with the goal of establishing binocular vision and orthophoria (proper eye alignment) [Olisky et al., 2007
]. In summary, we show that subtle intraocular anomalies such as refraction errors, borderline microcornea, retinal thinning or positioning of the optic nerve, uveal and chorioretinal coloboma, microphthalmia (including nanophthalmia), and extraocular anomalies such as strabismus and blepharoptosis are common in patients within the HPE phenotypic spectrum and with mutations in SHH
or genes related to its signaling pathway. Therefore, routine and careful ophthalmologic evaluation of these patients is indicated, as some of these subtle anomalies require intervention and follow-up. Further, these findings may provide insights into potential genotype-phenotype correlations and our understanding of the broad and emerging clinical spectrum of HPE.