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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.

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, synoph-thalmia). 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 hemisphere).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

FIGURE 1-30A-F. Abnormally close proximity of the nasal placodes and subsequent deficiency in medial nasal prominence development results in the development of a small nose and a long upper lip (from nose to mouth) with a deficient philtrum. Variable degrees of severity of effect in ethanol-exposed mouse fetuses results in phenotypes comparable to those in humans with fetal alcohol syndrome (A,B), cebocephaly (C,D), and premaxillary agenesis (E,F). (From Siebert JR, Cohen MM Jr, Sulik KK. Holoprosencephaly: an overview and atlas of cases. New York: Wiley-Liss, 1990, with permission.)

FIGURE 1-30A-F. Abnormally close proximity of the nasal placodes and subsequent deficiency in medial nasal prominence development results in the development of a small nose and a long upper lip (from nose to mouth) with a deficient philtrum. Variable degrees of severity of effect in ethanol-exposed mouse fetuses results in phenotypes comparable to those in humans with fetal alcohol syndrome (A,B), cebocephaly (C,D), and premaxillary agenesis (E,F). (From Siebert JR, Cohen MM Jr, Sulik KK. Holoprosencephaly: an overview and atlas of cases. New York: Wiley-Liss, 1990, with permission.)

derived from two conjoined nasal placodes, and lateral nasal prominences and hypotelorism is marked (Fig. 1-30C,D). Deficiencies that involve not only the anterior midline region but also the neural crest cells that contribute to the maxillary prominences (i.e., the crest cells derived from the mesencephalic neural folds) appear to be the basis for the premaxillary agenesis malformation complex illustrated in Figure 1-30E,F. In some rodent models, as in humans, mandibular deficiencies can also occur in conjunction with upper midface abnormalities, yielding the malformation complex termed agnathia-holoprosencephaly.

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