Sclerocornea

Sclerocornea is a condition in which the junction between the cornea and sclera is indistinct. Additionally, the cornea appears

FIGURE 1-28. Photograph of congenital corneal opacity involving the temporal half of the cornea. Handheld slit lamp examination revealed iris strands to the cornea, flat peripheral cornea, and a blending of sclera and cornea in the periphery. The diagnosis is anterior chamber dysgenesis syndrome, including sclerocornea, cornea plana, and Peter's anomaly.

FIGURE 1-28. Photograph of congenital corneal opacity involving the temporal half of the cornea. Handheld slit lamp examination revealed iris strands to the cornea, flat peripheral cornea, and a blending of sclera and cornea in the periphery. The diagnosis is anterior chamber dysgenesis syndrome, including sclerocornea, cornea plana, and Peter's anomaly.

to be relatively small, as the limbal cornea is replaced by a mixture of cornea and scleral tissue.67 Sclerocornea may be associated with other anomalies such as microphthalmia, coloboma, and anterior chamber dysgenesis (Fig. 1-28).

Anterior Segment Dysgenesis

Human anterior segment dysgenesis encompasses a broad spectrum of malformations including posterior embryotoxon, anterior displacement of Schwalbe's line, Axenfeld's anomaly (anterior displacement of Schwalbe's line associated with peripheral iris strands to Schwalbe's line), Peters' anomaly (central corneal opacity with absence of Descemet's membrane and endothelium in the area of the opacity), Rieger's anomaly (iris stromal hypoplasia with pseudopolycoria and iridocorneal attachments), or other combinations of iridocorneal or iridolen-ticular adhesions associated with various anterior segment anomalies. Congenital glaucoma is frequently associated with anterior segment dysgenesis syndromes.

Because most of the structures of the ocular anterior segment are of neural crest origin, it is tempting to incriminate this population of cells as being abnormal in differentiation or migration in cases of anterior segment dysgenesis. This theory has received widespread support and has resulted in labeling these conditions as "ocular neurocristopathie," particularly when other anomalies exist in tissues that are largely derived from neural crest cells (e.g., Rieger's syndrome, craniofacial connective tissue and teeth). There are several arguments in opposition to this theory. First, the neural crest is a predominant cell population of the developing craniofacial region including the eye. In fact, the number of tissues that are not neural crest derived is smaller than those which are (see Table 1-1). Thus, most malformations of this region would be expected to involve neural crest tissues, which may reflect their ubiquitous distribution rather than their common origin. The normal development of the choroid and sclera (also of neural crest origin) in anterior segment dysgenesis argues against a primary neural crest anomaly. Second, the neural crest is an actively migrating population of cells that is influenced by adjacent cell populations, and the perceived anomaly of neural crest tissue may be a secondary effect in many cases.

It is also important to recognize that, although much of the maturation of the iridocorneal angle occurs during the third trimester, much earlier events may influence anterior segment development. Anterior segment dysgenesis syndromes that are characterized primarily by axial deficits in corneal stroma and endothelium accompanied by corresponding malformations in the anterior lens capsule and epithelium (Peters' anomaly) most likely represent a manifestation of abnormal keratolenticular separation. The spectrum of malformations included in Peters' anomaly can be induced by teratogen exposure in mice at a time corresponding to the third week postfertilization in the human, just before optic sulcus invagination. Alternative theories for the pathogenic mechanism leading to Peters' anomaly, namely, intrauterine infection or anterior displacement of the lens or iris diaphragm, fail to explain the relatively localized axial defects.

Other anterior segment dysgenesis syndromes are characterized by more peripheral iridocorneal angle malformations and may represent malformations that are initiated somewhat later in gestation. These syndromes are often accompanied by absent or abnormal lining of Schlemm's canal, which is of mesodermal origin. In posterior polymorphous dystrophy and iridocorneal endothelial syndromes, the primary anomalies appear to be associated with the corneal endothelium and its basement membrane, both neural crest derivatives. Abnormal-appearing collagen within the trabecular meshwork has been identified in all these syndromes. Its significance is unknown; however, it may relate to neural crest abnormality.

Gene mutations that affect ocular neural crest cell populations and result in anterior segment dysgenesis have been identified. Of particular note is a genetic form of Rieger's syndrome caused by mutation in a homeobox transcription factor, PITX2.3 In-situ hybridization in mice has shown that mRNA encoded by this gene is localized in the periocular mesenchyme.

Congenital Glaucoma

Although glaucoma may accompany any of the anterior segment syndromes described previously, elevated intraocular pressure (IOP) is usually not present at birth, in contrast to true congenital glaucoma. Earlier theories described the gonioscopic presence of a "Barkan's membrane" covering the trabecular meshwork in eyes with congenital glaucoma. Most histological examinations of affected eyes have failed to demonstrate such a membrane. Studies have revealed anterior displacement of the ciliary body and iris base, representing the immature conformation seen in fetuses during the second trimester. In the absence of other malformations, these cases of congenital (and juvenile) glaucoma most likely represent arrested maturation and remodeling of the iridocorneal angle, which occur during the last trimester.

Pupillary Anomalies

Corectopia is defined as an eccentric location of the pupil, which may be normal or malformed (Fig. 1-29). The pupil may have an abnormal shape (dyscoria) and not be in line with the lens. Corectopia may be associated with corresponding ectopia of the lens that may or may not be in line with the ectopic pupil. Colobomas can be mistaken as eccentric pupils, but true colobo-mas lack peripheral iris whereas corectopia has an intact peripheral iris. Ectopia lentis et pupillae is the eccentric location of both the lens and pupil, which may be eccentric together and in line or, more commonly, displaced in opposite directions (Fig. 1-29).

Polycoria is a condition in which there are many openings in the iris that result from local hypoplasia of the iris stroma and pigment epithelium. True polycoria actually is a condition in which there is more than one pupil and the multiple pupils all have a sphincter and the ability to contract. Most cases of

FIGURE 1-29. Photograph of corectopia associated with iris hypoplasia and ectopia lentis. Note that the corectopia is the opposite direction to the ectopia lentis.

polycoria, however, are actually pseudopolycoria as only one of the pupils is the true pupil with an iris sphincter muscle. Therefore, in almost all clinical situations, the correct term is pseudopolycoria. Iris stromal hypoplasia, in the absence of an iris epithelium defect, represents a defect in neural crest cell migration and development.

Ectropion uvea (congenital) is iris pigment epithelium that is present at the pupillary margin and on the anterior iris stroma, most likely caused by an exuberant growth of neural ectoderm over the iris stromal mesenchyme. It can also be caused by iris stromal atrophy or congenital fibrosis of the anterior iris stroma that contracts and everts the pupillary margin to expose the pigment epithelium. This last mechanism also results in corectopia (see Fig. 1-24).

Persistent Hyperplastic Primary Vitreous

Persistent hyperplastic primary vitreous (PHPV) relates to an abnormality in the regression of the primary vitreous in the hyaloid artery and is usually associated with microphthalmia. It is also referred to as persistent fetal vasculature. A fibrovascular stalk emanates from the optic nerve and attaches to the posterior capsule. The retrolenticular vascular membrane covers the posterior half of the lens and usually extends to attach to the ciliary processes. With time, the retrolenticular membrane contracts, pulling the ciliary processes centrally. If the lens and membrane are not removed, secondary glaucoma may occur. Early surgery (lensectomy and anterior vitrectomy) is indicated to prevent amblyopia and to maintain integrity of the eye.

Retinal Dysplasia

Disorganized differentiation of the retina is often seen as a component of multiple ocular malformation syndromes. The inner optic cup may continue to proliferate in a microphthalmic eye, leading to folds and rosettes. The retina is dependent on the underlying retinal pigment epithelium for normal differentiation. Expression of cyclin-dependent kinase inhibitor protein, p27(Kip1), precedes withdrawal of retinal cells from the cell cycle, leading to terminal differentiation. Displacement of p27(Kip1)-deficient Müller glia into the photoreceptor layer is associated with experimental retinal dysplasia.66

Malformation Complexes Involving the Eye, Brain, and Face

It is not surprising, considering that the eye is an extension of the brain, that developmental abnormalities of the eye and brain frequently are concurrent. Among the most severe brain malformations are those involving abnormal closure of the neural tube or severe forebrain midline reduction abnormalities. These malformations are frequently accompanied by anophthalmia, microph-thalmia, anterior chamber cleavage abnormalities, or abnormal ocular placement (hypertelorism or hypotelorism, synophthalmia). Animal models have provided information regarding the developmental basis for a number of these malformation complexes. Because many of the relevant ocular abnormalities have been discussed earlier, the remainder of this chapter focuses on dysmorphogenesis of the brain and face.

Development of the forebrain and the midportion of the face above the oral cavity are intimately related. The olfactory (nasal) placodes become distinguishable on the frontolateral aspects of the frontonasal prominence during the fourth week of gestation. The thickened olfactory ectoderm is initially part of the antero-lateral rim of the anterior neural folds. As the frontonasal prominence develops, elevations (termed the medial and lateral nasal prominences) form around the olfactory epithelium. As their name implies, the nasal prominences develop into the nose. The lower portions of the medial nasal prominences also contribute to the upper lip and form the portion of the alveolar ridge that contains the upper four incisors as well as the associated part of the hard palate that is termed the primary palate. On each side of the developing face, fusion of the medial nasal prominence with the lateral nasal prominence and the maxillary prominence of the first visceral arch is required for normal formation of the upper lip. As previously mentioned, neural crest cells are a predominant contributor to craniofacial development and provide, among other components, the skeletal and connective tissues of the face. This function is in contrast to the majority of the skull, whose progenitor populations are mesodermal.

The maxillary prominence, the tissue of which is primarily neural crest derived, is located below the developing eye and contributes to the lower eyelid. The upper lid is associated with the lateral nasal prominence as well as other tissues of the fron-tonasal prominence. Lid colobomas might be expected to occur at sites between the various growth centers that contribute to the eyelids. In addition to its maxillary component, the first visceral arch is made up of a mandibular subunit that contributes to the lower jaw and part of the external ear. The mandibular portion of the first arch has significant mesodermal progenitor cells in addition to those of neural crest origin.

Holoprosencephaly, Synophthalmia, and Cyclopia

Formation of a single median globe (cyclopia) or two incomplete (and apparently) fused globes (synophthalmia) may occur by two different mechanisms. Experimental studies in amphibian embryos have demonstrated "fate maps" identifying the original location of the ectodermal tissue that will form the globes as a single bilobed area which crosses the midline in the anterior third of the trilaminar embryonic disc. An early failure in separation of this single field could result in formation of a single median globe or two globes that appear to be "fused" which, in reality, have failed to fully separate. Later, in gestation, loss of the midline territory in the embryo could result in fusion of the ocular fields that were previously separated. This loss of midline territory is seen in holoprosencephaly (a single cerebral hemi-sphere).96 Mutation in a number of different human genes can cause holoprosencephaly. Among the genes identified are sonic hedgehog (SHH), the protein product that is expressed at early stages of embryogenesis in the ventral midline of the forebrain and the subjacent tissue. SHH mutation results in holoprosen-cephaly type 3.90 Mutation in other genes that are conserved in the animal kingdom, including SIX3 (the Drosophila sine oculis homeobox gene) and ZIC2, a homolog of the Drosophila odd-paired gene, are also associated with holoprosencephaly (HPE).20'107

Acute exposure of rodent embryos to teratogens at gastrula-tion stages of embryogenesis can result in the spectrum of malformations associated with holoprosencephaly. Loss of progenitor populations in the median aspect of the developing forebrain epithelium or its underlying mesoderm cause the subsequent dysmorphogenesis. Selective loss of the midline-associated tissues results in abnormally close approximation of the olfactory placodes and tissue deficiencies in the medial nasal prominence derivatives. At the mild end of the spectrum is a facial phenotype characteristic of fetal alcohol syndrome (Fig. 1-30A,B). Midline deficiencies can be so severe that the nose is

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