Successful embryologic development of the eye requires normal development of the brain and visual pathway. Malformations, degenerations, and arrests in growth secondary to genetic mutations, in utero infections, and teratogenic exposures commonly coexist in the brain and eyes. In our report, we demonstrate the retinal dysplasia and optic nerve findings in a newborn with holoprosencephaly.
A female infant was born at 34 weeks’ gestational age with holoprosencephaly, complete cleft lip and palate, absence of the nasolabial septum, microcephaly, panhypopituitarism, rocker-bottom feet, and persistent refractory seizures. The patient’s holoprosencephaly had been noted on prenatal ultrasound. The mother’s labor was induced secondary to early preeclampsia. There was no history of perinatal drug use or infection. Magnetic resonance imaging of the brain 3 days after birth confirmed a semilobar form of holosprocencephaly with a monoventricle and fused thalami with a dorsal cyst and inferior vermian agenesis (Figure 1).
(A) Coronal and (B) sagittal magnetic resonance imaging demonstrating holosprocencephaly with a monoventricle and deep optic nerve colobomas, respectively.
As part of a genetic work-up, the ophthalmology service was consulted. On examination, the patient was noted to have shallow orbits with mild exophthalmos, mild microphthalmos, and hypotelorism. The anterior segment examination was normal except for a small focal cortical cataract in the right eye and bilateral Mittendorf dots. Posterior segment examination revealed complete optic nerve colobomas with an associated serous detachment surrounding the optic nerve of the right eye. The retinas of both eyes demonstrated absent foveal depressions, normally oriented but attenuated vessels, and diffuse stippled pigmentation with a slightly greenish discoloration consistent with dysplasia (Figure 2). The patient did not appear light averse, although a lack of visual function could not be confirmed at the bedside because the patient was taking multiple anti-epileptic medications.
Retcam (Clarity Medical Systems, Inc., Pleasonton, CA) posterior segment photographs of the (A) right and (B) left eye with deep optic nerve colobomas, diffuse retinal dysplasia, and a lack of foveal contours. There is a small serous detachment around the right optic nerve.
Genetic work-up including microarray analysis and trisomy 13 analysis for Patau syndrome was negative. Unfortunately, the patient’s refractory seizures could not be controlled and the decision was made to remove life support on day 19. A post-mortem examination was declined by the family.
The retina is a stunning illustration of structural polarity. In utero, retinal pigment epithelial cells and ganglion cells are the first to differentiate, providing the scaffold for the remaining retinal cells to migrate and differentiate. This ordered development is often disrupted in holoprosencephaly, leading to retinal dysplasia. The most extreme form of holoprosencephaly, Patau syndrome (or trisomy 13), has a 50% to 75% incidence of retinal dysplasia.1 Less severe forms of holoprosencephaly have reduced incidence of dysplasia. Other ocular findings seen with holoprosencephaly include bilateral microphthalmos, synophthalmos (rarely in extreme cases), cataract, glaucoma, corneal opacities, intra-ocular cartilage, and posterior and anterior segment colobomas.
Holoprosencephaly is a malformation sequence derived from failure of cleavage of the fetal prosencephalon sagittally into cerebral hemispheres and transversally into the diencephalon and. It represents a spectrum associated with other midline defects such as cleft lip and palate. Given the intricacy of fetal brain development, it is not surprising that myriad teratogens and genetic defects have been associated with holoprosencephaly.2 With an estimated prevalence of 1 in 250 during embryogenesis, it is the most common developmental defect of the forebrain. Most cases result in intrauterine demise, leading to a birth prevalence of only 1 in 16,000.3
The mechanism responsible for the pathogenesis of retinal dysplasia is not fully understood. Lahav et al. used the term “retinal dysplasia” to describe the maldevelopment of the retina and provided early descriptions of its rosettes on histology.4 Chan et al. described a specific case of retinal dysplasia in the setting of holoprosencephaly (in this case secondary to trisomy 13).5 In this patient, some areas of the retina demonstrated a near normal laminar structure composed of well-defined inner and outer nuclear layers. However, most regions were disorganized with scattered rosette-like structures that were inside-out compared to normal retina, in that the outer nuclear layer was more central than the inner nuclear layer. These dysplastic rosettes, which may represent an abortive attempt at regeneration or an abnormality in programmed cell death, are derived from the failure of the laminated retina to establish the proper polarity in relation to the retinal pigment epithelium.6 They are not considered preneoplastic or neoplastic and are often found in association with trisomy 13.4
Like the Flexner-Wintersteiner rosette characteristic of retinoblastoma, rosettes in retinal dysplasia secondary to holoprosencephaly contain an outer limiting membrane lining a central lumen. However, unlike in Flexner-Wintersteiner rosettes, dysplastic rosettes contain many differentiated cell types, including Müller cells, and immunohistochemical staining for rod opsin predominates over cone opsin.7 Interestingly, the rosettes in the case of dysplasia associated with holoprosencephaly extended into the anterior portions of the optic nerve heads.
In our patient, the dysplastic appearance of the retina included absence of the normal foveal depression and internal limiting membrane sheen (and presumably ganglion cells) with diffuse stippled pigmentation, a greenish discoloration, and attenuated vasculature. It is possible that these pigmentary changes are a visual reflection of the dysplastic rosettes seen histologically.
The optic nerve colobomas in our patient were deep with full excavation of the nerves. Multiple genes such as PAX6, Sonic hedgehog, and PTCH have been implicated in diseases related to the embryological development of both the optic nerve and retina, supporting the association of these two findings.8,9 Although unfortunately little could be done for our patient from a therapeutic standpoint, the ocular examination provided more information to assist in the difficult care decisions of the patient’s family.
- Yanoff M, Fine BS. Ocular Pathology, 5th ed. St. Louis: Mosby; 2002:47.
- Edison R, Muenke M. The interplay of genetic and environmental factors in craniofacial morphogenesis: holoprosencephaly and the role of cholesterol. Congenit Anom (Kyoto). 2003;43:1–21. doi:10.1111/j.1741-4520.2003.tb01022.x [CrossRef]
- Wallis DE, Muenke M. Molecular mechanisms of holoprosencephaly. Mol Genet Metab. 1999;68:126–138. doi:10.1006/mgme.1999.2895 [CrossRef]
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- Chan A, Lakshminrusimha S, Heffner R, Gonzalez-Fernandez F. Histiogenesis of the retinal dysplasia in trisomy 13. Diagn Pathol. 2007;2:48. doi:10.1186/1746-1596-2-48 [CrossRef]
- Fulton AB, Craft JL, Howard RO, Albert DM. Human retinal dysplasia. Am J Ophthalmol. 1978;85:690–698.
- Gonzalez-Fernandez F, Lopes MB, Garcia-Fernandez JM, et al. Expression of developmentally defined retinal phenotypes in the histogenesis of retinoblastoma. Am J Pathol. 1992;141:363–375.
- Li H, Tierney C, Wen L, Wu JY, Rao Y. A single morphogenetic field gives rise to two retina primordia under the influence of the prechordal plate. Development. 1997;124:603–615.
- Shkumatava A, Fischer S, Muller F, Strahle U, Neumann CJ. Sonic hedgehog, secreted by amacrine cells, acts as a short-range signal to direct differentiation and lamination in the zebrafish retina. Development. 2004;131:3849–3858. doi:10.1242/dev.01247 [CrossRef]