From the Thomas Jefferson Medical College (ESL, BNW, AVL), Philadelphia, Pennsylvania; Wills Eye Institute (BNW, AVL), Philadelphia, Pennsylvania; and the Cooper Medical School of Rowan University, Cooper University Hospital (BNW, JGS, RES), Camden, New Jersey.
This project was partially funded by the Foerderer Fund.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Barry N. Wasserman, MD, 100 Canal Pointe Boulevard, Suite 112, Princeton, NJ 08540. E-mail: Bwasserman@americansurgisite.com
Holoprosencephaly is a neurodevelopmental malformation that occurs in utero, when cleavage of the prosencephalon into the cerebral hemispheres is incomplete. Ophthalmic findings associated with severe holoprosencephaly include synophthalmia/cyclopia, but other ocular anomalies have been reported. We present a case of vertically oval corneas in a child with semilobar holoprosencephaly and review the relevant literature.
Our patient was a male infant born at 39 weeks of gestation and weighing 2,572 grams to a 37-year-old mother. An ultrasound performed at 20 weeks of gestation suggested semilobar holoprosencephaly. The family history was negative for birth defects, learning disability, or single central incisors. No unusual dietary patterns or environmental exposures were reported. On examination, the patient had microcephaly, hypotelorism, and suspected choanal stenosis. Other features included arched eyebrows without synophrys, shallow orbits, a long philtrum, micrognathia, poor visual responses, and abnormal cornea shape. He had wide-spaced nipples, abnormal posturing of the elbows, rocker bottom feet, broad first toes, prominent fetal toe pads, a poor suck, low central tone, and increased peripheral tone. High-resolution chromosome analysis revealed a normal 46, XY male karyotype. The patient died at 2 months of age before additional testing could be pursued and no autopsy was performed.
Ophthalmic examination at 6 days of age revealed normal pupillary responses and ocular motility. External examination showed gross hypotelorism but normal eyelids and adnexae. The corneas were clear and vertically oval shaped, measuring 12.5 mm vertically × 9 mm horizontally in the right eye and 12 mm horizontally × 9 mm vertically in the left eye (Fig. 1). The anterior segments were otherwise normal, including the irises, which were a normal size and shape (any appearance of irregularity in Fig. 1 is artifact). The optic nerves were mildly anomalous with large cups, but were not believed to be clearly colobomatous. Retinal examination was normal. Intraocular pressures were 12 mm Hg bilaterally.
Figure 1. Photographs of the right eye and left eye with vertically oval corneas.
Computed tomography and magnetic resonance imaging scans revealed fused frontal lobes and thalami consistent with semilobar holoprosencephaly (Figs. 2 and 3). In addition, the nasal bone and cavity were deformed and diminutive, respectively. A renal ultrasound was normal.
Figure 2. Computed tomography scan of the brain showing holoprosencephaly. Note the absence of separation of the frontal hemispheres (asterisk).
Figure 3. Magnetic resonance imaging of the brain showing holoprosencephaly (asterisks).
Holoprosencephaly (HPE) results from the incomplete cleavage of the prosencephalon into the right and left cerebral hemispheres between the second and fourth weeks of gestation. HPE describes a spectrum of conditions in which there is a complete or partial separation of the forebrain early in embryonic development. HPE subtypes include, in order of decreasing severity, the alobar, semilobar, lobar, and middle interhemispheric variants. In semilobar HPE, there is fusion of the left and right frontal lobes, with a remnant interhemispheric fissure posteriorly. The etiology is varied and includes both environmental and genetic factors. Common ophthalmic findings of the holoprosencephaly spectrum include synophthalmia/cyclops, hypotelorism, coloboma of the iris and optic nerve, and hypoplasia of the optic nerves and chiasm.
Development of the cornea begins in the fourth week of gestation when the evaginating optic vesicle induces a lens placode to form in the overlying surface ectoderm. After the placode is pinched off into the underlying mesenchyme, the remaining surface ectoderm goes on to differentiate into corneal epithelium. The remainder of the cornea is formed from the neural crest, as is the surrounding sclera (with the exception of a portion of the temporal sclera that derives from mesoderm).
Literature about the etiology of vertically elongated oval corneas is sparse. In the early 20th century, Fuchs reported 28 cases of vertically oval corneas.1 Of these cases, 14 patients had interstitial keratitis, 8 patients had solid evidence of congenital syphilis, and 8 others exhibited some symptoms of congenital syphilis. Our patient had no clinical evidence of perinatal infection, but was not specifically tested for syphilis (the patient’s mother tested negative for syphilis). Alkemade reported 12 cases of vertically oval corneas in a group of 86 patients with Rieger syndrome,2 but our patient had no clinical features of Rieger syndrome. In a male infant with a lumbosacral myelomeningocele, Abou-Jaoude et al. reported unilateral vertical hourglass-shaped cornea and lens duplication.3 A fibrous stalk arose from a hypoplastic optic nerve and terminated at the junction of the two lenses. Chan et al. reported “hypoplastic corneas” in a child with trisomy 13 and holoprosencephaly.4 Although the eyes were fused, there were two separate lenses. They also found variable lamination of the neural retina, with abnormal areas showing neuronal “rosettes” comprising differentiated retinal neurons and Müller cell glia. In the normal retinal areas, the gene sonic hedgehog (SHH) was expressed in retinal ganglion cells and in neurons of the inner zone of the outer nuclear layer, but SHH expression could not be detected in the dysplastic rosettes (hence, SHH’s hypothesized role in the development of normal retina).
Of the genes that can underlie holoprosencephaly, dominant mutations in SHH have been the most frequently investigated.5 In addition to SHH, several other genes have also been implicated in forebrain patterning, both within the hedgehog signaling pathway and in other associated signaling pathways, including ZIC2, SIX3, TGIF1, GLI2, and PTCH1. A variety of chromosome abnormalities have also been associated with holoprosencephaly. In the developing brain, SHH is expressed in the notochord and ventral neural tube. SHH homozygous null mutations may present with cyclopia, the most severe ocular manifestation of holoprosencephaly, whereas attenuated SHH expression may present with hypotelorism or just a single, central-upper incisor. Over-expression of SHH causes hypertrophic growth of the optic stalk, the precursor of the optic nerve.6
In addition to the expression of SHH during central nervous system and eye development, the gene is also expressed specifically in healing corneal tissues.7 To date, SHH expression in the developing cornea has not been directly studied. The lens duplication in the patient presented by Abou-Jaoude et al. may represent a form of synophthalmia. The temporal proximity of the defects causing both the corneal abnormality and synophthalmia in that patient may be due to a single deficiency, perhaps involving SHH. Similarly, semilobar holoprosencephaly is one of the clearest and most dramatic examples of defective midline cleavage. Therefore, we propose that a single gene or cytogenetic defect that affects the hedgehog pathway, or a related signaling pathway, could be causative of both holoprosencephaly and the oval corneas seen in our patient. Unfortunately, we cannot test this hypothesis in our deceased patient. However, other children with holoprosencephaly should be examined with respect to their corneal anatomy, along with evaluations for the underlying molecular or cytogenetic basis of their holoprosencephaly.
- Fuchs E. Malformation of the cornea in cases of inherited syphilis. Ophthal Rev. 1909;28:247–250.
- Alkemade PPH. Dysgenesis Mesodermalis of the Iris and Cornea: A Study of Rieger’s Syndrome and Peters’ Anomaly. Assen, The Netherlands: Van Gorcum; 1969.
- Abou-Jaoude ES, Stevens JL, Katz NR. Oval-shaped cornea, lens duplication, and optic nerve hypoplasia associated with myelomeningocele. J AAPOS. 2000;4:377–378. doi:10.1067/mpa.2000.111229 [CrossRef]
- Chan A, Lakshminrusimha S, Heffner R, Gonzalez-Fernandez F. Histogenesis of retinal dysplasia in trisomy 13. Diagn Pathol. 2007;18:48. doi:10.1186/1746-1596-2-48 [CrossRef]
- Roessler E, Muenke M. The molecular genetics of holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010;154C:52–61. doi:10.1002/ajmg.c.30236 [CrossRef]
- Macdonald R, Barth KA, Xu Q, Holder N, Mikkola I, Wilson SW. Midline signaling is required for Pax gene regulation and patterning of the eyes. Development. 1995;121:3267–3278.
- Saika S, Muragaki Y, Okada Y, et al. Sonic hedgehog expression and role in healing corneal epithelium. Invest Ophthalmol Vis Sci. 2004;45:2577–2585. doi:10.1167/iovs.04-0001 [CrossRef]