Ocular malformations may have genetic and nongenetic causes (e.g., environmental.) Those with genetic causes may be familial or sporadic. They may be isolated or part of a broader syndrome. In many cases, the exact cause for a given malformation is not known. Depending on the population studied, the method of ascertainment, and the definition of “ocular malformation,” various published studies have found a birth prevalence of ocular malformations of 0.04 to 6.8 per 10,000 live births.^1–7

The past decade has witnessed a tremendous increase in our understanding of the molecular and developmental causes of many important ophthalmic malformations (Table 1). Many of the mutations that cause ocular malformations are in transcription factors. Transcription factors are proteins that bind to specific DNA sequences (or to proteins that bind to DNA) to regulate expression of specific genes. A complex pattern of gene expression in different parts of the embryo during different times of gestation is required for normal organogenesis and cellular differentiation. Disruption of this process through the alteration of the function of any important transcription factor can have serious consequences. Development can also be affected by changes in cell-to-cell signaling, cell migration, cell death, and cell adhesion.

TABLE 1. Examples of Developmental Eye Diseases Caused by Mutations in Transcription Factors (transcription factors: see text for details and references)

This chapter describes malformations on an anatomic basis. However, current classifications and nosology of congenital ocular malformations are imperfect. For example, some abnormalities are difficult to classify because they affect multiple tissues (e.g., aniridia). Sometimes the same word (e.g., coloboma) is used in the literature to describe several distinct clinical and developmental entities. A primary defect in one structure may cause secondary malformations in another (e.g., the small orbits and short palpebral fissures in anophthalmic patients). A given genetic disorder may have a spectrum of presentations (phenotypic heterogeneity). Lastly, different genetic mutations can cause the same clinical phenotype (genetic heterogeneity). We attempt to clarify these sometimes confusing issues on a case-by-case basis.

Because the disorders covered in this chapter are largely developmental, we review the essential embryology behind each class of disease. A detailed discussion of ocular embryology is presented elsewhere in this text. Although we present development in a compartmentalized fashion, it is important to recognize that multiple, interdependent events are occurring simultaneously during embryogenesis. As such, insults or changes in gene expression at one time point may have multiple effects at later time points. For example, maternal alcohol use during the period of gastrulation—days before any ocular structures are visible morphologically—may result in ocular defects ranging from microphthalmia to coloboma to Peters anomaly.⁸

Throughout this chapter, we refer to “Online Mendelian Inheritance in Man” or OMIM. OMIM is a comprehensive catalog of inherited diseases available free of charge at www.ncbi.nlm.nih.gov/omim. When possible, we will provide the OMIM number for individual disorders.

DEVELOPMENTAL BIOLOGY⁹¹

Eye development becomes evident at approximately 22 days gestation, when the optic sulci appear as bilateral grooves in the neural ectoderm of the embryo. At approximately 25 days gestation, as the rostral neural tube fuses, the neural ectoderm evaginates further to form the optic vesicles. The optic vesicles are attached to the developing brain via the optic stalks. As the optic vesicles grow laterally and approach the surface ectoderm, they invaginate to form a bilayered optic cup. The inner and outer layers of the optic cup proceed to form the neural retina and the retinal pigmented epithelium, respectively. The invaginated optic cup forms a somewhat spherical structure that is open anteriorly and inferiorly. This inferior “seam” is alternatively called the optic fissure, the choroidal fissure, or the embryonic fissure, and it transmits the hyaloid vascular system beginning at approximately 5 weeks gestation. At 6 weeks gestation, the optic fissure “zippers” shut, beginning equatorially and proceeding anteriorly and posteriorly.

ANOPHTHALMIA

Anophthalmia refers to the complete absence of ocular tissue, presumably caused by abnormalities of optic vesicle formation or maturation. Patients may have unilateral or bilateral anophthalmia, and generally have short palpebral fissures and small orbits. In many cases when there is no clinically apparent ophthalmic tissue, remnants of lens epithelium, neuroretinal, and fibrovascular, choroid-like tissue can be detected on histologic sectioning. Terms such as “true anophthalmia,” “extreme microphthalmia,”¹⁰ and “clinical anophthalmia”¹¹ have been used in the literature to describe what may be, in truth, a phenotypic continuum between anophthalmia and microphthalmia (see later).

Anophthalmia may be isolated or associated with a broader syndrome (Table 2).^12–19 Isolated anophthalmia is generally an autosomal recessive condition.²⁰ Driggers et al. reported a child with isolated bilateral anophthalmia and an apparent balanced chromosomal translocation {46,XX,t(3;11)(q27;p11.2)}.²¹ Fantes et al. found that this child had, in fact, a submicroscopic deletion that eliminated the SOX2 gene on chromosome 3, and went on to show nonsense mutations in SOX2 in four of 11 subjects with bilateral anophthalmia.²² SOX2 lies within an intron of a nonexpressed gene, SOX2OT, and is expressed in neuroectoderm early in development.²³ SOX2 protein interacts cooperatively with PAX6 in the induction of lens development and delta-crystallin expression.²⁴ Hagstrom, Traboulsi et al. found a null mutation in SOX2 in a girl with bilateral clinical anophthalmia and absence of the optic nerves, chiasm, and optic tracts (unpublished data)

TABLE 2. Clinical Syndromes Associated with Anophthalmia

Reconstructive surgery can be helpful in patients with congenital anophthalmia.²⁵ Orbital expansion can be achieved with spherical implants, orbital osteotomies, bone grafts, and/or orbital expanders. Conjunctival sac reconstruction is achieved using serial expanders and buccal mucous membrane grafts. Lid reconstruction sometimes requires tissue flaps and skin grafts.

MICROPHTHALMIA

A microphthalmic eye is one with axial length less than two standard deviations below the age-adjusted mean (ie, <19 mm in a 1-year-old child and <21 mm in an adult.) Microphthalmia encompasses a range of phenotypes. Specific terms, outlined later, are applied to subgroups of microphthalmic eyes with certain characteristics. Authors of scientific communications may not use the same classification scheme or may use the more general term “microphthalmia” when a more specific term could apply. Although we will present these terms as distinct entities, remember that they likely represent points along a single, phenotypic continuum.

Simple Microphthalmia/Nanophthalmos

Simple microphthalmia refers to a small but structurally normal eye.²⁶ The term “nanophthalmos” is used synonymously, but especially when such eyes develop angle-closure glaucoma caused by crowding from the normal-size (ergo, disproportionately large) lens or uveal effusions. Weiss et al. noted that, in general, the posterior segment is proportionately shorter than the anterior segment in such patients.²⁶ Simple microphthalmia/nanophthalmos can be inherited as part of a broader syndrome (Table 3)^27–29 or as an individual trait. The sclera of nanophthalmic eyes consists of irregularly arranged collagen lamellae, absence of normal elastic fibers, and abnormal glycogen-like deposits.³⁰ These changes likely result in the increased thickness and decreased elasticity of the nanophthalmic sclera—changes that result in decreased blood flow through the vortex veins and/or decreased transscleral flow of protein. This alteration in ocular fluid dynamics increases the risk of uveal effusion and choroidal detachment, especially after surgery.^31–33

TABLE 3. Syndromes With Simple Microphthalmos/Nanophthalmos as a Phenotype

The precise embryologic mechanism for simple microphthalmia/nanophthalmos is unclear. Based on finding this phenotype in patients with fetal alcohol syndrome, achondroplasia, and myotonic dystrophy, Weiss et al. postulated that decreased size of the optic cup, altered vitreous proteoglycans, low intraocular pressure, and abnormal release of growth factors may be important in the pathogenesis of simple microphthalmos.²⁶ These authors point out that given many of these patients have normal corneal diameters and that the area primarily affected is the posterior segment, the pathogenesis in many of these conditions may be related to postnatal, rather than prenatal, changes in ocular development and growth.

In 1998, Othman et al. described a pedigree with autosomal dominant nanophthalmos that localizes to a 14.7cM region on chromosome 11 (NNO1).³⁴ Affected family members had high hyperopia (range of +7.25 to +13 D) and short axial lengths (range of 17.55–19.28 mm). Twelve of 22 affected family members had a history of angle-closure glaucoma or had occludable angles. Although OMIM lists a second nanophthalmos locus, NNO2, on 15q12-q15, the phenotype described in this pedigree is more consistent with a colobomatous, complex microphthalmia (see later).³⁵

Complex Microphthalmia

In cases in which the eye is not only small but also abnormal in other respects, the term “complex microphthalmia” is applied. Examples of associated findings are microcornea, sclerocornea, corneal opacities, aniridia, Peters anomaly and cataract. Complex microphthalmia can be associated with a syndrome (Table 4)^19,35–61 or can occur as an isolated trait. Complex microphthalmia encompasses a diversity of phenotypes. Patients in the same family with the same underlying disorder may have phenotypes of varying severity. For example, patients with the Lenz microphthalmia syndrome (OMIM 309800) may have anophthalmia, colobomatous microphthalmia, or noncolobomatous microphthalmia.⁶²

TABLE 4. Syndromes with Complex Microphthalmia as a Phenotype

Numerous chromosomal abnormalities have been associated with microphthalmia (Table 5).⁶³ Warburg and Friedrich provided a comprehensive review of these disorders in 1987.⁶⁴ Presumably, any chromosomal disorder that significantly affects telencephalon or cranial neural crest development could result in microphthalmia.

TABLE 5. Chromosomal Abnormalities Associated With Microphthalmia

Complex microphthalmia is often associated with uveal colobomas. In the most common use of the term, “coloboma” refers to a defect in the iris, retina/uvea, and/or optic nerve as a result of faulty closure of the embryonic fissure at the 7- to 20-mm stage of development. Colobomas tend to be inferonasal, which is the normal position of the embryonic fissure (Fig. 1). The term “coloboma” has also been applied to other anomalies of the optic nerve, the macula, and the uveal tract that are not related to faulty closure of the embryonic fissure. This loose use of terminology creates unnecessary confusion when describing a syndrome. Hornby et al. found in their series that 72 of 185 eyes with coloboma also were microphthalmic and 71 of those 72 had microcornea.⁶⁵ Thus, not every patient with microphthalmia has coloboma and not every patient with coloboma has microphthalmia. Microphthalmia has been postulated to arise from faulty development of the secondary vitreous and, hence, not enough pressure needed for prenatal eye growth.⁶⁶

“Microphthalmia with cyst” refers to cases of colobomatous microphthalmia with a posterior eye wall defect through which a cyst lined with neuroectodermally derived tissue protrudes into the orbit. These cysts may be small and only detected by imaging (Fig. 2); sometimes, they may be large enough to cause progressive proptosis. Most cases are isolated, but familial occurrences have been reported.^67–69 Inheritance is likely autosomal recessive. Depending on the size of the cyst, its appearance, and the visual potential of the microphthalmic eye, these cysts may be managed by observation, excision with or without enucleation, and/or aspiration.⁷⁰ Aspirated cysts tend to reaccumulate fluid. Socket expansion improves cosmesis.

Complex microphthalmia can also be seen as part of Peters anomaly and persistent hyperplastic primary vitreous (PHPV). These disorders are covered in the anterior segment and retina/vitreous sections of this chapter.

Not all cases of complex microphthalmia are genetically determined. Intrauterine infection and maternal exposure to alcohol or other teratogens can also cause complex microphthalmia.

Percin et al. described mutations in the homeobox gene CHX10 (14q24.3) in two families with autosomal recessive, nonsyndromic microphthalmia, iris abnormalities, and coloboma.⁷¹ Like other homeobox proteins, CHX10 is a transcription factor that binds to specific DNA sequences in the regulatory regions of other genes and affects their transcription during development. Chx10 mutations were previously found in the ocular retardation mouse model, which is characterized by microphthalmia, a thin hypocellular retina, and optic nerve aplasia.⁷²

One form of autosomal recessive complex microphthalmia was found by Bessant et al. to map to 14q32.⁷³ Phenotypic features included sclerocornea (8/8 patients) with secondary corneal vascularization (6/8 patients) and staphyloma formation (3/8 patients), elevated intraocular pressure (5/8 patients), and short axial length (5/5 measured).⁷⁴ These authors ruled out CHX10 and OTX2 as candidate genes in this pedigree.

Lehman et al. reported a large Mexican American pedigree with isolated X-linked recessive colobomatous microphthalmia that maps to the proximal p or q arm of the X chromosome.⁷⁵

Microphthalmia can usually be diagnosed by inspection and/or palpation of the eye through the eyelids. The presence of a bulge in the lower lid usually indicates microphthalmos with cyst (Fig. 3). Axial length measurements may aid in the diagnosis of simple microphthalmia/nanophthalmos. Refraction and amblyopia treatment may be helpful in cases in which the macula is well developed. In cases in which no useful vision is present, scleral shells may improved cosmesis. Oculoplastics procedures to enlarge the palpebral fissures and the socket are sometimes helpful.

CONGENITAL CYSTIC EYE

Congenital cystic eye results from failure of the optic vesicle to invaginate, producing a cystic structure that may contain elements of dysplastic retina or lens material.⁷⁶ These cysts do not contain an epithelial lining, may not be evident at birth, and may grow with time. Approximately 30 cases have been described in the literature. Most cases are unilateral, but bilateral developmental eye anomalies have been described.^77–80 Orbital imaging can aid in the diagnosis and preoperative planning.⁸¹

Oculocerebrocutaneous syndrome (Delleman syndrome, OMIM 164180)⁸² is a sporadic condition associated with orbital cysts, focal dermal hypoplasia, periorbital skin appendages, and cerebral malformations. Anophthalmia may also occur in patients with this syndrome.

PERSISTENT HYPERPLASIA PRIMARY VITREOUS (PHPV) AND PERSISTENCE OF FETAL VASCULATURE (PFV)

Persistent hyperplastic primary vitreous (PHPV) or persistence of fetal vasculature (PFV) is a complex malformation of the eye characterized by the presence of remnants of the hyaloid and of the tunica vasculosa lentis systems of blood vessels, together with proliferation of fibrovascular tissue behind the lens, and variable degrees of posterior pole and/or anterior retinal dysplasia.^83,84 The eye in PHPV is generally microphthalmic but can be enlarged with accompanying myopia.⁸⁵ Although PHPV primarily affects the posterior part of the eye, the ciliary body, iris, and lens are involved to a variable extent. In the typical case, ciliary processes are elongated and converge to a plaque of retrolental fibrovascular tissue that may involve the lens capsule proper (Fig. 4). The lens may be completely clear or may be cataractous. The fibrovascular plaque may adhere to the posterior lens capsule and vessels can invade the lens—a finding pathognomonic of PHPV. The retrolental membrane may contain adipose tissue, cartilage, and smooth muscle tissue. This is thought to be the result of metaplastic changes in tissues of mesenchymal origin. In a series of 47 eyes, Font et al. found adipose tissue in 10 and cartilage in one.⁸⁶ The peripheral retina may also be drawn anteriorly into the retrolental membrane. In what has been referred to as “posterior PHPV,” the retina around the disc is pulled up into the posterior vitreous and is thrown into folds that may involve the macular and lead to poor vision. The retina is generally normal in structure, but dysplastic changes have been described. Vitreoretinal traction may lead to retinal breaks and detachment. The fellow eye in PHPV is usually normal but may have a Mittendorf dot or, rarely, one of other abnormalities.

PHPV is unilateral in approximately 90% of cases. The globe varies in size from normal to moderately decreased, being slightly smaller than normal in the majority of cases. The cornea is clear. The anterior chamber is shallow in smaller eyes because of anterior displacement of the iris/lens diaphragm; this predisposes patients with PHPV to angle-closure glaucoma, which usually develops later in life. Lens extraction prevents secondary angle-closure glaucoma. The iris may be normal but frequently shows small notches at the pupillary margin, where iridohyaloidal vessels were located in the developing eye and failed to regress as the iris matures and the tunica vasculosa lentis resorbs. Patent iridohyaloidal vessels may be observed to course over the anterior iris surface, the pupillary margin, and the posterior iris surface to anastomose with vessels in the retrolental membrane. These iridohyaloidal vessels are characteristic of PHPV.

Clinically, patients with PHPV present with a small eye since birth, a white pupillary reflex from a cataract or retrolental membrane, and/or strabismus because of poor vision. Retinoblastoma should be ruled out using clinical examination, ultrasonography, and computed tomography.⁸⁷ There is no intraocular calcification in PHPV.⁸⁸ Retinoblastoma generally occurs in normal-size eyes except in patients with 13q deletions and microphthalmia. PHPV and retinoblastoma have been rarely reported together in a microphthalmic eye.⁸⁹

PHPV and its variants are not very rare. They are a common cause of unilateral congenital cataracts. PHPV has also been reported in patients with recessive oculodento-osseous dysplasia,⁴⁷ in one patient with protein C deficiency,⁹⁰ in the oculopalatocerebral syndrome, and in two generations of one family with Rieger anomaly.⁹¹

PHPV may be the result of defective formation of the secondary vitreous, which is derived from the inner retinal cells starting in the ninth week of gestation. The secondary vitreous compresses the regressing primary vitreous, which is probably derived from mesenchyme and contains the hyaloid system of blood vessels that anastomose with the tunica vasculosa lentis anteriorly. The globe remains small because its growth depends partly on the expansion of the secondary vitreous.⁹² The cause of PHPV has not been identified yet. Familial occurrences of PHPV have been reported in dizygotic twins, in two brothers, and in a mother and son.⁹³

Visual prognosis in PHPV is generally guarded. Early cataract surgery may result in relatively good visual results in selected patients.^94,95 Eyes with anterior PHPV have a better vision potential than those with posterior pole dysplasia. An anterior approach to lens extraction and retrolental membrane removal is recommended in mild anterior cases. A combined lensectomy-vitrectomy using a pars-plana surgical approach should be considered in patients with significant mid-vitreal or posterior vitreal components to the PHPV. Tractional and rhegmatogenous retinal detachments have been reported in patients with PHPV and are treated surgically as needed.

SYNOPHTHALMIA/CYCLOPIA

Cyclopia refers to a single, midline eye; synophthalmia refers to an apparent midline fusion of two eyes. These conditions are points along a phenotypic continuum. Clinical findings vary but include a proboscis above the eye(s) and forebrain malformations. Many fetuses with cyclopia or synophthalmia have chromosomal abnormalities and are spontaneously aborted.⁹⁶

Formation of a cyclopic or synophalmic globe may occur by one of two embryologic mechanism.⁹⁷ At the trilaminar embryo stage, a field of bilobed, midline ectodermal tissue is “fated” to become the eyes. Failure of this bilobed area to separate completely into two fields could result in synophthalmia or cyclopia. Alternatively, previously separated globes could fuse as a result of faulty midline development.

The latter mechanism is likely responsible for the cyclopia and synophthalmia seen in holoprosencephaly. Holoprosencephaly is a genetically and phenotypically heterogeneous group of disorders that manifest with midline abnormalities.^98,99 Classically, this includes complete (alobar) or partial (semilobar) “fusion” of the normal, bilateral cerebral hemispheres into a single hemisphere. Mutations in several genes important in forebrain development have been identified in families with holoprosencephaly, including sonic hedgehog (SHH, 7q36), ZIC2 (13q32), SIX3 (2p21), and transforming growth factor beta-induced factor (TGIF, 18p11.3).^100–103

ANIRIDIA

Classic aniridia is a sporadic or autosomal dominant, bilateral, pan-ocular condition caused by haploinsufficiency of the PAX6 homeobox gene on 11p13.^104,105 Contrary to the connotation of “aniridia,” most aniridic patients have at least some rudimentary iris tissue. “Aniridia” is also used to describe absence of iris tissue in some syndromes that are possibly unrelated to PAX6 haploinsufficiency (see later).

Aniridia affects multiple tissues in the eye and has a broad range of clinical presentations. Iris abnormalities range from almost complete absence to radial iris clefts to iris hypoplasia (Fig. 5).^106–109 Foveal hypoplasia is characteristic, but of varying severity, which include optic nerve hypoplasia, corneal pannus, and/or a superficial corneal dystrophy (Fig. 6), microcornea, Peters anomaly, congenital cataracts, ectopia lentis, and glaucoma.^{110,111–114} Visual potential varies with the severity of the aniridic phenotype. Vision-limiting factors include optic nerve and foveal hypoplasia, cataracts, and—occasionally—the keratopathy that arises in older patients with aniridia. The keratopathy/corneal pannus is presumably caused by insufficient/absent limbal stem cells. Nystagmus develops in aniridic patients, presumably caused by congenital poor visual acuity. Iris vascular anomalies and leakage have been diagnosed on fluorescein angiography of the anterior segment.¹⁰⁹

Shaw et al. estimated the prevalence of aniridia in the lower peninsula of Michigan in 1960 to be approximately 1 in 64,000.¹¹⁵ Approximately two-thirds of patients have at least one other affected family member; the remaining one-third are sporadic.

Pathologic studies of aniridic eyes are sometimes complicated by the presence of advanced glaucoma and/or a history of multiple surgical interventions. In 1983, Margo described pathologic features of seven eyes from seven children 6 months to 14 years of age.¹¹⁶ None of these eyes had advanced glaucoma or previous surgery. Congenital anomalies included iris and ciliary body hypoplasia, attenuation of Bowman membrane, and (in two eyes from children with 11p deletions) anomalous anterior chamber angles. Other abnormalities included corneal pannus, cataracts, and peripheral anterior synechiae. Resolution was insufficient to comment on retinal or optic nerve anomalies.

Elsas et al. classified aniridia into four types based on clinical criteria.¹⁰⁷ Type I aniridia—what we call classic aniridia—is autosomal-dominant and is characterized by near-absence of iris tissue, foveal hypoplasia, nystagmus, corneal pannus, optic nerve hypoplasia, secondary glaucoma, and (sometimes) dislocation of the lens. Type II aniridia patients have varying iris abnormalities, no nystagmus, and relatively preserved visual acuity. Patients with type III aniridia have classic aniridia and mental retardation. Type IV aniridia patients also have genitourinary anomalies, an increased risk of Wilmss tumor, and mental retardation (WAGR syndrome, discussed later). This system was devised before our detailed knowledge of the cytogenetic and molecular causes of aniridia. Therefore, it does not take into account more recent findings of the phenotypic, cytogenetic, and mutational heterogeneity of this disorder.

Grant and Walton noted progressive angle changes in aniridic patients.¹¹⁷ Although the trabecular meshwork of 25 aniridic patients who did not develop glaucoma appeared normal on gonioscopy, the angles of 31 aniridic patients with glaucoma showed progressive obstruction of the trabecular meshwork by iris tissue. These authors recommended prophylactic goniotomy in aniridic patients who show progressive angle changes before glaucoma develops. This recommendation has not been studied in a controlled fashion.

Cytogenetic studies have played a pivotal role in understanding the molecular basis of aniridia. WAGR syndrome (OMIM 194072)—an acronym for Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation—is associated with deletions of chromosome 11p13 (reviewed by Mannens et al.).¹¹⁸ By comparing the phenotype of patients with the size of the deletion, as determined using both cytogenetic and molecular markers, the critical region for aniridia and for Wilms tumor were identified. Other cytogenetic abnormalities such as paracentric inversions, balanced translocation, and unbalanced translocation involving 11p13 have been reported in subjects with aniridia, both with or without systemic findings.^119,120 Not all chromosomal aberrations directly disrupt the PAX6 gene, suggesting that local chromatin structure or cis-acting elements are important for PAX6 expression.¹²¹ Crolla and van Heyningen have shown that some patients with deletion of both the Wilms tumor gene (WT1) and PAX6 may not be cytogenetically visible and can only be detected with fluorescent in-situ hybridization (FISH).¹²⁰

Because the PAX6 gene and the Wilms tumor gene (WT1) are on the same 700-kilobase region of 11p13, chromosomal changes that cause aniridia may also affect the WT1 locus. In general, the increased risk of Wilms tumor occurs in sporadic aniridia cases. The exception to this rule is families in which an affected parent has a deletion of WT1 and passes his/her chromosomal abnormality onto their child. In these cases, autosomal-dominant inheritance is present. Not everyone with a WT1 deletion develops Wilms tumor. Gronskov et al. found two out of five subjects with WT1 deletions that developed Wilms tumor.¹²² Muto et al. found 13 (45%) of 29 patients with deletions in the Wilms tumor critical region developed Wilms tumor.¹²³ Therefore, cytogenetic studies focused on 11p13 are reasonable in both sporadic aniridia and familial aniridia, when the number of affected individuals in the family is small.

In 1989 Mannens et al. mapped the aniridia locus to markers on 11p13.¹²⁴ Further analysis of an aniridia pedigree originally mapping to chromosome 2 (AN1 locus)¹²⁵ showed that the true linkage in this family was also to 11p13 (the AN2 locus.) In 1991, Ton et al. discovered that a homeobox transcription factor gene, now know as PAX6, was either totally or partially deleted in two patients with aniridia.¹⁰⁴ Since then, numerous reports of mutations in PAX6 have been reported in patients with aniridia.¹⁰⁵ A detailed database of PAX6 mutations can be found online at http://pax6.hgu.mrc.ac.uk/.

The PAX6 gene covers approximately 25 kb of DNA, consists of 14 exons, and codes for a 422-amino acid transcription factor.¹⁰⁵ This 422-amino acid protein contains two distinct motifs that bind to a range of DNA target sequences—a paired domain and a homeodomain.^126,127 (The terms “paired domain” and “homeodomain” are applied to these portions of the protein because they strongly resemble similarly named genes important in body segmentation in Drosophila). DNA binding is modified by alternative splicing of one portion of the paired domain, which affects the target sequence of DNA recognized. Translation begins at exon 4 and one exon (5a) is alternatively spliced. PAX6 protein is highly conserved across vertebrates. PAX6 is expressed in all layers of the neuroectoderm that forms the developing eye, as well as in the surface ectodermal cells that become the lens.¹²⁸

Nearly all patients with classic aniridia have mutations predicted to cause loss of function of one PAX6 allele (see http://pax6.hgu.mrc.ac.uk/). In general, the ocular phenotype of these patients is indistinguishable from patients with complete deletion of the gene, implying that haploinsufficiency is the mechanism of disease. Patients with PAX6 missense mutations can have aniridia or a variety of other ocular phenotypes—corneal pannus/keratopathy, isolated foveal hypoplasia, congenital cataracts, Peters anomaly, anterior segment dysgenesis, uveal ectropion, optic nerve hypoplasia, optic nerve coloboma/morning glory discs, and persistent hyperplastic primary vitreous.^{114,129–134,135} For example, Kivlin et al. reported on what appeared to be a new, autosomal-dominant keratopathy (ADK) associated with ocular irritation and photophobia, and anterior stromal vascularization and inflammation.¹³⁶ Pearce et al. suggested that ADK was an aniridia variant based on the presence of iris abnormalities and macular hypoplasia in a four-generation family with ADK.¹¹⁰ Mirzayans et al. subsequently found splice-site mutations in PAX6 in a family with ADK.¹³⁷

The precise mechanism behind this phenotypic variability is unclear. Presumably, other gene products and environmental factors regulate or interact with PAX6 during ocular development; variations/abnormalities in these proteins lead to the variability in the aniridia phenotype. A few putative target genes activated by PAX6 have been identified, including lens crystallins, cell adhesion molecules like L1 and NCAM, glucagon, and insulin.^138–142

Heterozygous small eye (Sey) mice have disrupted expression of one allele of Pax6 and are considered a model of human aniridia.^143–145 The phenotype is variable, as in humans, and includes iris abnormalities, cataract, Peters anomaly, microphthalmia, and keratopathy.¹⁴⁶

Treatment of aniridia centers around the treatment of its individual ophthalmic manifestations. As always, aggressive treatment of amblyopia in children and optimal refraction in all patients should be pursued. Cataracts should be removed if visually significant during the amylogenic period or later in life if visual deterioration appears to be linked to cataract progression. Some success has been reported with sulcus-based intraocular lenses and with black diaphragm aniridia lenses in these patients.^147,148 Glaucoma is common and intraocular pressure should always be checked. It can be quite difficult to manage and often requires surgery. Numerous methods, including trabeculotomy, seton implantation, and ciliary body ablation, have had some success.^149–152 As previously mentioned, some advocate prophylactic goniotomy in patients with progressive angle changes.¹⁵³ No clear consensus exists on how to approach this difficult clinical problem.

The corneal pannus and ocular surface problems associated with aniridia can also cause visual deterioration. Penetrating keratoplasty is not usually successful because it does not treat the presumed, underlying limbal stem cell deficiency.^154,155 Holland et al. have reported success with keratolimbal allografts in patients with aniridia.¹⁵⁶ In their study, 74% of eyes had an improved ocular surface, mean visual acuity increased from 20/1000 to 20/165, and 70% of those undergoing secondary penetrating keratoplasty had successful grafts. However, continued use of immunosuppressive drugs appears to be required for optimal results.

Syndromes With Associated Aniridia

Warburg et al. described a girl with aniridia, mental retardation, gonadal streaks, gonadoblastoma, hearing loss, kidney malrotation, and dysmorphic facies that had an interstitial deletion between bands 11 and 13 on 11p.¹⁵⁷ As discussed previously, the constellation of Wilms tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) is caused by deletions in this region of chromosome 11. Identification of patients with such cytogenetic abnormalities was critical in the isolation of PAX6 as the gene for human aniridia.

Pupil abnormalities reminiscent of aniridia are also seen with cerebellar ataxia and mental retardation in a condition often referred to as Gillespie syndrome. (The original patients described by Gillespie, however, have some features such as congenital cataracts that are not part of what is now referred to as “Gillespie syndrome”).¹⁵⁸ The pupil in these patients appears constantly dilated and often has iris strands adherent to the lens. Unlike classic aniridia, patients with Gillespie syndrome generally do not have cataracts, corneal abnormalities, or foveal hypoplasia. Visual acuity has not been consistently recorded in the literature, but may be reduced.¹⁵⁹ The nystagmus seen in these patients appears to be more related to cerebellar and other CNS pathology than to sensory issues. Although inheritance is generally thought to be autosomal recessive, Nelson et al.. have questioned whether some autosomal dominant cases might exist.¹⁵⁹ This same group has found extensive white matter and cerebral abnormalities in one child with Gillespie syndrome, suggesting that the brain pathology may extend beyond the cerebellum. Glaser et al. did not find mutations in the PAX6 gene and the phenotype did not segregate with genetic markers on 11p in families with Gillespie syndrome.¹⁶⁰

Mirkinson and Mirkinson described a family with aniridia and hypoplastic/aplastic patellae.¹⁶¹ The proband's grandmother had glaucoma, but it is unclear if this was of childhood onset. No other stigmata of classic, PAX6-associated aniridia are mentioned. No mutations have been reported in this pedigree.

Hamming et al. reported a mother and her two children with variable iris abnormalities, ptosis, nystagmus, foveal hypoplasia, corneal pannus, and cataracts.¹⁶² The mother had unspecified cardiac anomalies, recurrent miscarriages, and alopecia. One of the children was moderately mentally retarded and both children were obese. These authors suggest that this family has a rare, autosomal-dominant aniridia variant. Although chromosomal studies were reportedly normal, PAX6 mutation testing was not performed.

Although Levin et al. reported a child with aniridia, congenital glaucoma, hydrocephalus, and a ring chromosome 6 {46 XY, r(6) (p24→q26)}, the “aniridic” iris abnormalities were unilateral.¹⁶³ The contralateral eye had findings more consistent with Axenfeld-Rieger syndrome. Ring chromosomes are formed when the long (q) and short (p) arms of a chromosome fuse together. Such joining is invariably associated with the loss of genetic material from one or both chromosomal arms. In this case, the patient was missing genetic material distal to p24 on the short arm and to q26 on the long arm of chromosome 6. This patient's ocular findings might be explained by a deletion of the FOXC1 gene on 6p25 (see discussion of Axenfeld-Rieger syndrome).

Walker and Dyson report on an association of classic aniridia with mental retardation.¹⁶⁴ Although most patients with classic aniridia are intellectually normal, PAX6 is expressed in the developing brain and it is conceivable that in some individuals it may contribute to a mental handicap.

DEVELOPMENTAL BIOLOGY

The bones, cartilage, fat, and connective tissue of the orbit arise from periocular mesenchyme in the frontonasal and maxillary processes that appear by the fourth week of gestation. The bones of the orbit are membranous, with the exception of the sphenoid, which forms from a cartilaginous precursor. Ossification begins in the fifth month and fusion of the bones occurs in the sixth month of gestation. Eyelid formation begins between the fourth and fifth weeks of gestation with the proliferation of ectodermal cells in the area of the future outer canthus. During the second month of gestation, the ectoderm of the future lids becomes invested with periocular mesenchyme, which leads to the formation of the upper and lower eyelid folds. These folds grow closer together and fuse at the eighth week of gestation, beginning nasally and proceeding temporally. The orbicularis forms from a condensation of mesenchyme at approximately 10 weeks gestation. The adnexal structures form between the third and sixth months of gestation. The eyelids reopen between the fifth month and seventh month of gestation. The lacrimal glands begin forming between the sixth and seventh weeks of gestation as cords of epithelial cells from the conjunctiva invaginate supertemporally and are surrounded by periocular mesenchyme, which becomes the lacrimal acini.

TERMINOLOGY

Several specific terms are used to describe abnormalities in the appearance or the position of the orbits, eyes, and eyelids. Hypertelorism refers to an increased distance between the orbits, often measured clinically as an increase in the interpupillary distance (IPD), although true hypertelorism refers to an increased separation between the two orbits and is a radiological term). Hypertelorism should be distinguished from telecanthus, which connotes an increased distance between the inner canthi but not an increase in the IPD or separation between the orbits. Hypertelorism occurs in a variety of craniofacial syndromes such as frontonasal dysplasia and Greig cephalopolysyndactyly (Fig. 7). Similarly, hypotelorism refers to closely set orbits, as in holoprosencephaly. Epicanthus refers to a medial fold of skin that may partially obscure the inner canthus. Epicanthus tarsalis is used to describe a fold of skin between the superior orbital rim and the nose; epicanthus palpebralis is used to describe a fold of skin equally distributed between the superior and inferior medial canthus; and epicanthus inversus refers to a fold of skin extending inferolaterally from the nose to the inferior orbital rim. Epicanthal folds are common in babies and may give the mistaken impression of esotropia (pseudoesotropia). Epicanthus inversus occurs in the blepharophimosis syndrome (see later).

CRYPTOPHTALMOS

Cryptophthalmos refers to a failure of the eyelids to form correctly during embryonic development, resulting in covering of the globe by a continuous layer of skin (Fig. 8). Although the lens and posterior structures are sometimes intact, the underlying cornea and anterior segment structures may not be present or may be malformed. Typically, no conjunctival fornices are present and microphthalmia may be present. Cryptophthalmos may be unilateral or bilateral, isolated, or syndromic. The phenotypic continuum in this disorder ranges from a complete, uninterrupted layer of skin from brow to cheek, through partial formation of lids and adnexal structures, to adherence of lids directly to the globe. Thomas et al. reviewed isolated and syndromic cryptophthalmos in 1986.¹⁶⁵ Of 127 cases in the literature at that time, 27 were isolated and 97 had other congenital malformations. The most common syndromic cause of cryptophthalmos is Fraser syndrome, an autosomal-recessive condition (see later). Some pedigrees of isolated cryptophthalmos show autosomal dominant inheritance, preservation of some adnexal structures, and microphthalmia (Fig. 9).^165,166

Fraser syndrome is an autosomal-recessive condition characterized by cryptophthalmos, cutaneous syndactyly, genitourinary abnormalities, craniofacial dysmorphism, abnormalities of the larynx, orofacial clefting, mental retardation, and musculoskeletal abnormalities.¹⁶⁷ Approximately 12% of patients with Fraser syndrome do not have cryptophthalmos. Homozygous mutations in the FRAS1 gene on 4q21 were reported in subjects with Fraser syndrome by McGregor et al..¹⁶⁸ However, not all subjects with Fraser syndrome map to 4q21, implying genetic heterogeneity. The FRAS1 gene contains 75 exons and codes for a 4007-amino acid protein that is expressed in the basement membrane of corneal, skin, kidney, and gut epithelia.¹⁶⁹ Mice homozygous for a nonsense mutation in the homologous gene, Fras1, develop hemorrhagic blistering during development, as well as postnatal cryptophthalmos, syndactyly, and renal anomalies.

The surgical management of cryptophthalmos is complex and challenging.¹⁷⁰ Reconstruction is made difficult in many cases by the absence of normal corneal and anterior segment tissue and the absence of conjunctival fornices. Before any surgery is attempted, visual potential should be determined. Diagnostic imaging, visual evoked responses, and electroretinography may be helpful. Some success has been achieved with amniotic membrane grafts in the reconstruction of conjunctival fornices in patients with partial cryptophthalmos.¹⁷¹ Advances in keratoprostheses may some day help these patients.

CONGENITAL ECTROPION

Congenital ectropion is a rare condition in which the eyelid is outwardly rotated away from the globe. Some authors make a clear distinction between congenital ectropion and congenital eversion of the eyelids, stating that the former is a surgical disease and the latter can be managed conservatively.^172–174 Other authors feel the congenital eversion of the upper lids is best managed surgically.^175–177

Congenital ectropion may be more common in blacks¹⁷⁸ and is associated with Down syndrome.^172,179,180 Dermatologic conditions that shorten the anterior lamellae—such as congenital nonbullous ichthyosiform erythroderma (OMIM 242100), harlequin ichthyosis, and lamellar ichthyosis (OMIM 242300)—may cause ectropion.^181,182,183 The relative shortage of malar and eyelid skin, coupled with eyelid abnormalities such as coloboma, may lead to ectropion in mandibulofacial dysostosis (Treacher-Collins syndrome, OMIM 154500.) The lymphedema-distichiasis syndrome (OMIM 153400) may present with congenital ectropion, probably because of tarsal abnormalities.^184,185 The blepharocheilodontic syndrome is an autosomal-dominant condition (OMIM 119580) characterized by facial clefting, ectropion, oligodontia, euryblepharon, and lagophthalmos.¹⁸⁶

Management of congenital ectropion depends on its severity, ie, the amount of corneal exposure and ocular irritation caused. Sometimes, lubrication may be sufficient. In cases in which the anterior lamella is shortened, horizontal tightening coupled with vertical lengthening (e.g., use of skin grafts) may be helpful.¹⁸⁷ Yen et al reported the use of lateral tarsal strips, lower eyelid retractor disinsertion, myocutaneous advancement of the cheek and eyelids, and lateral tarsorrhaphy in a case of blepharocheilodontic syndrome.¹⁸⁸

CONGENITAL ENTROPION

Congenital entropion is inward rotation of an eyelid toward the globe. Eyelashes directed toward the cornea can lead to irritation, epithelial defects, and secondary scarring and infection.^189,190 Congenital entropion may occur alone or in association with epiblepharon—a redundant fold of skin and orbicularis that rotates the lid inward. Congenital “kinking” of the tarsus or disinsertion of lid retractors are proposed mechanisms. Congenital entropion may be sporadic or an autosomal-dominant trait;¹⁹¹ it has been reported in trisomy 13,¹⁹² Duane retraction syndrome,¹⁹³ ectrodactyly-ectodermal dysplasia-clefting syndrome (OMIM 129900, 604292, 602077),¹⁹⁴ and the Fukuyama congenital muscular dystrophy (OMIM 607440).¹⁹⁵ In a retrospective review of 25 cases of congenital tarsal kinking, Sires found that the average age at diagnosis was 7.2 weeks, and ulcers (mostly sterile) were present in one-half of cases.¹⁹⁶ Four of 15 children developed amblyopia, but not necessarily from corneal scarring.

If corneal injury cannot be prevented with conservative measures such as lubrication or lid taping, then surgery is indicated. Advancement of eyelid retractors with excision of a small ellipse of skin is helpful in cases caused by congenital retractor disinsertion. A variety of techniques have been proposed for patients with tarsal kinking and hypoplasia, including excision of eyelid skin and orbicularis,¹⁸⁹ lid support sutures,¹⁹⁷ advancement of otherwise-normal lid retractors,¹⁹⁸ stretching of the tarsal plate followd by temporary lid sutures,¹⁹⁹ and full-thickness sutures.²⁰⁰

EYELID COLOBOMA

An eyelid coloboma is a congenital, full-thickness defect of the lid (Fig. 10). Although we prefer to reserve the term “coloboma” for defects of embryonic fissure closure, the term “eyelid coloboma” is well entrenched in the literature and is also appropriate for this condition.

Eyelid colobomas may occur in one or more lids. They may be part of a genetic syndrome or as a result of a fetal disruption of lid tissues (e.g., by an amniotic band.) They may result from a failure of the mesodermal folds of the lids to meet or from premature separation of the lids during development.

Colobomas of the upper lid are associated with Goldenhar syndrome (OMIM 164210), also known as hemifacial microsomia or oculoauriculovertebral dysplasia. Goldenhar syndrome is characterized by eyelid coloboma, epibulbar dermoids, unilateral ear anomalies and deafness with a small ipsilateral face, and vertebral anomalies. Cardiac and central nervous system anomalies have also been reported. Inheritance is usually sporadic, but some pedigrees with autosomal-dominant inheritance have been reported.^201,202 Linkage to 14q32 has been reported in one pedigree.²⁰³ Eyelid colobomas in Goldenhar syndrome tend to involve the middle and/or nasal third of the upper lid. In general, upper lid colobomas are more likely to result in corneal exposure than lower lid colobomas.

Colobomas of the lower lid are associated with Treacher Collins-Franceschetti (TCF) syndrome (OMIM 154500), also known as mandibulofacial dysostosis. TCF syndrome is autosomal-dominant with variable expressivity and is characterized by antimongoloid slant to the palpebral fissures, eyelid colobomas, micrognathia, macrostomia, microtia/other ear anomalies, hypoplastic zygomatic arches, and conductive hearing loss.²⁰⁴

The Burn-McKeown syndrome is characterized by bilateral choanal atresia, cardiac defects, abnormalities of the external ear (often with hearing deficits), and a characteristic face, which includes coloboma of the lower lids.²⁰⁵

Kinsey and Streeten reported a case of upper eyelid coloboma and symblepharon, along with corneal ectasia, microphthalmia, and other complex eye malformations in a child with median cleft syndrome/frontonasal dysplasia.²⁰⁶ In this case, it is unclear if the observed defects were genetic or teratogenic, because the mother received diazepam during her pregnancy.

Leventer et al. reported a congenital intraocular teratoma associated with eyelid coloboma.²⁰⁷ The eyelid coloboma may have been caused by interruption of eyelid development by the growing tumor.

The treatment and the timing of treatment of a congenital eyelid defect depend on the position and size of the defect. In cases in which corneal exposure and secondary infection are a concern, early closure is indicated. However, conservative management of sizable defects has been reported.²⁰⁸ Delaying surgery may reduce the risk of anesthesia and lessen the amylogenic effect of the eyelid closure that results from some repair procedures. In general, defects involving less than one-third of the lid can be closed directly.²⁰⁹ Defects up to half the lid may require a relaxing lateral cantholysis or semicircular flap to release tension on the wound. Larger defects may need more extensive use of flaps and grafts and will likely involve multiple operations. Patients with eyelid coloboma in conjunction with a syndrome (e.g., TCF) may require extensive craniofacial reconstruction as well.^210,211

BLEPHAROPHIMOSIS, EPICANTHUS IVERSUS, AND PTOSIS SYNDROME (BPES)

BPES is an autosomal-dominant disorder characterized by small horizontal palpebral fissures (blepharophimosis), folds of skin extending from a flat nasal bridge inferolaterally (epicanthus inversus), and congenital ptosis (Fig. 11). Although the distance between the medial canthi is usually increased (telecanthus), the interpupillary distance is usually normal. BPES patients have been divided into two subgroups, type I and type II, based on the presence or absence of premature ovarian failure in females, respectively. A third putative type of BPES was found to be allelic to Sathre-Chotzen syndrome, with mutations in the TWIST gene.²¹²

A series of BPES patients with chromosomal abnormalities around 3q21–23 suggested that the gene for this disorder was in that region.^213–219 In 2001, Crisponi et al. described mutations in a transcription factor gene, FOXL2, on 3q23 in several pedigrees with BPES.²²⁰ FOXL2 (like FOXC1 in Rieger syndrome and FOXC2 in lymphedema-distichiasis, discussed later), is a member of the forkhead family of transcription factors and is expressed in the periocular mesenchyme that forms the lids during development and in the follicular cells of adult ovaries. Mutations predicted to cause truncation of the FOXL2 gene are seen in families with type I BPES. In contrast, in-frame duplications or insertions that extend the FOXL2 protein are seen in families with type II BPES.²²¹ These type II alleles may be hypomorphic (ie, they retain some, but not all, of the normal function of that allele), whereas the type I alleles are likely to cause loss-of-function.

The major concern in children with BPES is amblyopia and head posture from ptosis.²²² Because the epicanthus inversus and telecanthus do not generally improve with age, corrective surgery may be undertaken in a staged fashion or as a single procedure.²²³

The term blepharophimosis can also be used as a descriptive term to describe small palpebral fissures. This trait can be seen in a variety of syndromes such as Ohdo syndrome (OMIM 249620, blepharophimosis, ptosis, cardiac malformations, mental retardation, and hypoplastic teeth) and van den Ende-Gupta syndrome (OMIM 600920, blepharophimosis, arachnodactyly, congenital contractures). A more extensive list is available on OMIM and is beyond the scope of this chapter.

DISTICHIASIS

Distichiasis refers to the presence of a second row of eyelashes that arise from the meibomian glands (Fig. 12). (This is in distinction to trichiasis in which eyelashes arise from their normal location but are misdirected). Distichiasis can be inherited either alone (OMIM 12630) or, more commonly, as part of the lymphedema-distichiasis (LD) syndrome (OMIM 153400).^184,224 The aberrant lashes in distichiasis may cause ocular irritation and photophobia.

The LD syndrome is an autosomal-dominant disorder characterized by congenital distichiasis and peripheral lymphedema that usually begins at approximately the age of puberty. Other reported associated features include lower eyelid ectropion, congenital ptosis, photophobia, cleft palate, webbing of the neck, vertebral anomalies, extradural cysts, varicose veins, renal abnormalities, and congenital heart disease.^225–230 Fang et al. recently described mutations in the forkhead transcription factor, FOXC2, in families with LD.²³¹ Numerous additional mutation—all predicted to cause haploinsufficiency of FOXC2—have been reported in LD families.^{185,232–235} Brooks et al. recently reported a family presenting with distichiasis and no lymphedema who had a truncating mutation in FOXC2.²³⁶ This pedigree suggests that LD syndrome and simple distichiasis may be points along a phenotypic continuum, rather than separate genetic defects. Ophthalmologists should also be aware that LD syndrome might present as distichiasis alone and should counsel their patients accordingly.

Ocular irritation and photophobia may be treated conservatively with lubrication. Severe cases may cause corneal scarring and may be treated with cryotherapy, lid-splitting procedures, and/or tarsal excision.^237–241

CHORISTOMAS

Choristomas are benign, congenital tumors consisting of normal tissue in an abnormal location.²⁴² Epibulbar and orbital choristomas are the most common epibulbar and orbital tumors in children. Choristomas are divided into four histologic types: (1) dermoids, which contain collagenous connective tissue surrounded by epidermis; (2) lipodermoids, which are similar to dermoids but also contain fatty tissue; (3) single-tissue choristomas, which contain either dermis-like or meso/ectodermal tissue of one type; and (4) complex choristomas, which contain tissues of several types. A teratoma is a choristoma that contains tissue from all three embryonic layers, ie, ectoderm, mesoderm, and endoderm. A teratoid tumor contains tissue from two embryonic layers. Dermoid cysts frequently contain a keratinized epithelium with adnexal structures.

Epibulbar choristomas vary in appearance and visual significance. Their color may be white, yellow, or pink (Fig. 13). They may be unilateral or bilateral and range in size from relatively small and flat lesions to large, bulky masses that fill the interpalpebral space and displace the globe. Epibulbar choristomas can cause astigmatism that, if untreated, can lead to amblyopia. The appearance of the tumor may be a cosmetic problem that affects a child's psychosocial development. Treatment involves dissection and excision, along with treatment of refractive error and amblyopia.²⁴³ Excision of any choristoma that involves the cornea will leave a residual opacity. It is therefore important to warn parents that surgery will not completely remove the opacity but will remove the mass. Occasionally, if the choristoma creates an opacity that extends into the visual axis, a lamellar keratoplasty may be indicated.²⁴⁴

Conjunctival or episcleral osseous choristomas contain compact bone.²⁴⁵ They may be freely mobile or may adhere to sclera or other extraocular muscles. In one case, an osseous choristoma mimicked extraocular extension of retinoblastoma.²⁴⁶

Choristomas may also occur in the orbit, with a predilection for the supratemporal quadrant and the nasal area above the lacrimal sac. Orbital choristomas may present as a bulging mass or as proptosis in childhood. Sometimes they are asymptomatic and present, after years of growth, in adulthood. The spontaneous rupture of an orbital choristoma may cause acute proptosis and inflammation, mimicking an orbital cellulitis. Orbital imaging with CT or MRI is helpful in diagnosis and surgical excision.

Choristomas may be associated with other ophthalmic abnormalities, especially in syndromic children. As previously mentioned, epibulbar dermoids may be seen in Goldenhar syndrome (OMIM 164210). Epibulbar choristomas are also seen in nevus sebaceous of Jadassohn (OMIM 163200), a sporadic disorder characterizes by seizures, multiple skin lesions with malignant potential, arachnoid cysts, and mental retardation. These patients may also have posterior choristomas that contain cartilage and appear as flat, yellow lesions in the fundus.^247–249 Encephalocraniocutaneous lipomatosis (ECCL) is characterized by multiple systemic choristomas and hamartomas (abnormal tissue found in its normal location), mental retardation, and seizures. Epibulbar choristomas are common in ECCL.²⁵⁰

Pedigrees primarily involving ocular or periocular choristomas have been reported. Plewes and Jacobson described a family with presumably dominant frontonasal dermoids that extended into the intracranial cavity.²⁵¹ Mattos et al. reported a three-generation Peruvian family with dominant limbal choristomas in a ring configuration and no other systemic abnormalities.²⁵² X-linked recessive corneal dermoids were observed in a Puerto Rican family and tentatively mapped to Xq24-qter.^253,254

DEVELOPMENTAL BIOLOGY

At approximately day 27 of gestation, the surface ectoderm over the developing optic vesicle begins to thicken in response to inductive signals from the optic vesicle and anterior neuroectoderm.⁹⁷ This thickening, called the lens placode, is facilitated by adhesions, but not direct cell-to-cell contact, between the optic vesicle and the surface ectoderm. As the surface ectoderm in this area is mitotically active, these adhesions cause crowding of the surface ectoderm cells, which elongate and begin to invaginate to form a lens vesicle. PAX6 expression in the optic vesicle and the surface ectoderm is required for proper lens formation.²⁵⁵ Bone morphogenetic protein–4 (BMP–4) is also important in lens induction.²⁵⁶ The area of contact between the optic vesicle and the surface epithelium determines the size of the lens.

As the lens vesicle continues to expand, it begins to “pinch off” from the surface ectoderm, with complete separation at approximately 33 days gestation. The presence of a somewhat spherical lens vesicle separates the eye into future anterior and posterior segments. Failure of the lens vesicle to completely separate from the surface ectoderm can lead to anomalies such as anterior lenticonus (seen in Alport syndrome, OMIM 301050, 203780, 104200), anterior polar cataracts, and Peters anomaly. The lens vesicle initially consists of a monolayer of epithelial cells with their apices directed inward. The basement membrane of this epithelium forms the lens capsule. The surface ectoderm, which reforms a continuous layer after the separation of the lens vesicle, becomes the future corneal epithelium.

At 37 days of gestation, the posterior lens epithelial cells elongate to fill the lens vesicle, lose their nuclei and most organelles, and form the primary lens fibers. The primitive lens filled with primary lens fibers forms the embryonic lens nucleus. The posterior portions of the primary lens fibers detach from the posterior capsule, leaving room for migration of anterior, mitotically active epithelial cells. As these cells pass the equator of the lens, they become more elongated and eventually lose their nuclei and most organelles. These cells form the secondary lens fibers that migrate anteriorly and posteriorly around the embryonic nucleus and form interdigitations visible as the two Y-sutures of the lens.

After lens vesicle separation, the anterior margins of the optic cup advance beneath the ectoderm. Neural crest cells migrate between the surface ectoderm and optic cup, filling the anterior chamber. This neural crest will form the future corneal stroma, corneal stroma, iris stroma, ciliary body, and iridocorneal angle structures. By the sixth month of gestation, Descemet membrane and the corneal endothelium are functioning and the cornea is transparent. Mesenchymal tissue around the lens forms the tunica vasculosa lentis, which anastomoses with the hyaloid artery system.

The anterior and posterior iris epithelium as well as the bilayered ciliary body epithelium form from the nonpigmented and pigmented cells of the optic cup. These cells are arranged apex-to-apex. The iris stroma and ciliary muscles form from neural crest.

The iridocorneal angle begins to form during week 15 of gestation. The iris and ciliary body move posteriorly and the mesenchyme in the anterior segment undergoes rearrangement, including significant atrophy. Spaces continuous with the anterior chamber appear in the mesenchyme, forming an early trabecular meshwork. Schlemm canal is present by week 16 of gestation. Abnormalities in the remodeling of the mesenchyme of the anterior segment are postulated to be the cause of congenital glaucoma and of iridogoniodysgenesis. The trabecular meshwork continues to mature postnatally.

ANTERIOR SEGMENT DYSGENESIS

Abnormalities during development of the anterior segment can result in a variety of phenotypes. Historically, these have been given descriptive names (e.g., iridogoniodysgenesis, iris hypoplasia) or eponyms (e.g., Axenfeld-Rieger anomaly, Peters anomaly) Molecular genetic discoveries have shown that phenotypes that were considered separate disorders were, in fact, caused by mutations in the same gene. Similarly, mutations in distinct classes of genes were found to cause identical phenotypes. The phenotype in any individual is clearly influenced by a variety of heretofore-uncharacterized genetic and environmental factors during development.

Peters Anomaly

Peters anomaly (OMIM 604229, 603807) refers to a central corneal opacity related to a congenital absence of Descemet membrane and endothelium sometimes accompanied by iridocorneal adhesions and/or lenticulo-corneal adhesions. Peters anomaly may be unilateral or bilateral, and, although most often sporadic, autosomal-recessive and autosomal-dominant pedigrees have been reported.^257–262 The severity of Peters anomaly ranges from a mild central corneal opacity to dense opacification with extensive irido-corneal and lenticulo-corneal adhesions and cataract formation (Fig. 14). Glaucoma may be present at birth or develop later in childhood in some cases.^263,264 Peters anomaly may occur in the presence of other eye malformations such as sclerocornea (which may also include areas where Descemet membrane is absent), microphthalmia, uveal coloboma, and persistent fetal vasculature (PFV.)^265–268 The developmental mechanisms leading to Peters anomaly may include incomplete separation of the lens vesicle from the surface ectoderm and/or abnormal migration and differentiation of neural crest in the anterior segment.

The genetics of Peters anomaly are complex. Although mutations in genes such as PAX6,^114,269 PITX2,²⁷⁰ CYP1B1,²⁷¹ and FOXC1²⁷² have been reported in some pedigrees, the underlying genetic cause is unclear in many cases.²⁷³ Approximately 40% of mice lacking on active copy of the forkhead transcription factor FoxE3 have Peters anomaly.²⁷⁴ Patients with Peters anomaly and several different chromosomal abnormalities (e.g., interstitial deletion 2q14q21,²⁷⁵ 4p- [Wolf-Hirschorn syndrome],²⁷⁵ partial trisomy 5p,²⁷⁶ trisomy 9,²⁷⁷ 11q-,²⁷⁸ and 21 ring²⁷⁹) have been reported. David et al. reported a family with an apparent balanced chromosomal translocation, t(1;7) (q41;p21), and Peters anomaly.²⁸⁰ This translocation disrupts the histone deacetylase 9 (HDAC9) and transforming growth factor beta 2 (TGFβ2) genes, which they suggest may be involved in the pathogenesis of Peters. Teratogens such as alcohol and isotretinoin and intrauterine infections may also produce Peters anomaly.^281–283

Up to 60% of patients with Peters anomaly have some form of systemic abnormalities or developmental delay.^266,284 Traboulsi and Maumenee define the “Peters plus” syndrome as one that includes midline defects, cleft lip and/or palate, ear abnormalities, midline abnormalities, mental retardation/developmental delay, cardiac abnormalities, and/or genitourinary abnormalities. The “Peters plus” syndrome is likely caused by a host of different genetic mutations and environmental teratogenic agents.

The Krause-Kivlin syndrome (OMIM 261540)—sometimes also referred to as “Peters plus” syndrome²⁸⁵—consists of Peters anomaly, short-limb dwarfism, with variable mental retardation, a “cupid-bow” upper lip, and frequent cleft lip with or without cleft palate.²⁸⁶ It likely represents a distinct, autosomal-recessive syndrome.^287–289

The visual prognosis for patients with Peters anomaly depends on the severity of opacification in the visual axis. Mild cases may require little or no treatment. Unilateral cases are often accompanied by amblyopia in the affected eye. More severe cases may require cataract extraction, lysis of iridocorneal adhesions, and corneal transplantation. However, the risk of corneal transplant rejection in children is substantial.^{290–292,293} Signs of glaucoma should be monitored and treated appropriately.

Axenfeld-Rieger Syndrome

Axenfeld-Rieger syndrome (ARS) is a multisystem genetic disorder inherited in an autosomal-dominant fashion.^294,295 It includes several prominent eye findings, including posterior embryotoxon, iris strands adherent to Schwalbe line, and iris hypoplasia that can lead to corectopia, polycoria, or pseudopolycoria (Fig. 15). More importantly, approximately half of ARS patients develop glaucoma.^295–297 These abnormalities are likely caused by abnormalities in neural crest migration and differentiation during anterior segment development.²⁹⁸ Patients with the full-blown ARS—as opposed to the Axenfeld-Reiger anomaly that is limited to eye findings—can also have dental anomalies (microdontia, hypodontia) (Fig. 16), a flattened midface, and umbilical ring anomalies (Fig. 17). In some cases of ARS, patients have abnormalities in pituitary, cardiac, and limb development.

In 1996 Semina et al. reported mutations in PITX2(RIEG1), a gene on 4q25-q26 that codes for a homeobox transcription factor, in subjects with ARS.²⁹⁹ The mutations that were initially reported clustered around the homeobox region. Subsequently, additional mutations throughout the PITX2 sequence have been observed in subjects with various forms of anterior segment dysgenesis (ARS, iris hypoplasia, iridogoniodysgenesis, and Peters anomaly).^300–307 These mutations include nonsense, missense, frameshift, and splicing mutations, as well as an in-frame duplication.²⁹⁸ Such mutations interfere with protein stability, protein–DNA interaction, nuclear localization, and/or transactivation.^308–310 Mutations that eliminate PITX2 transactivation in vitro appear more likely to produce an ARS phenotype, whereas others that retain some transactivation ability appear more likely to produce a milder, iris hypoplasia phenotype.³¹⁰ Although most mutations likely result in a loss of protein function and PITX2 haploinsufficiency, Priston et al report a V45L mutation in a syndromic ARS family that enhances in vitro transactivation.³⁰³ This observation suggests that either too much or too little PITX2 activity can produce an ARS phenotype. Lastly, Saadi et al demonstrated that mutation of the bicoid-specific lysine to glutamic acid in the PITX2 homeobox (K88E) produces a dominant-negative effect on wild-type PITX2 protein.³⁰⁴ PITX2 expresses multiple protein isoforms as a result of alternative splicing.^311,312 A great deal of interfamilial and intrafamilial phenotypic variability exists in patients with PITX2 mutations.

ARS can also be caused by mutations in the FOXC1 gene on 6p25, a member of the forkhead family of transcription factors.^{272,313–318} These mutations are predicted to cause a loss of FOXC1 function and functional experiments support a variety of molecular mechanisms, including reduced protein expression, decreased DNA binding, and decreased transactivation.³¹⁹ Nishimura et al have also reported pedigrees with duplications of 6p25 and an ARS-like phenotype, suggesting that either too much or too little FOXC1 activity may lead to anterior segment dysgenesis.³²⁰ As with subjects with PITX2 mutations, subjects with FOXC1 mutations have a great deal of phenotypical variability. At least two other ARS loci await cloning on 13q14 and 16q24.

The management of ARS centers on monitoring for and treatment of glaucoma. Ophthalmologists should be aware of the systemic manifestations of ARS and should refer patients appropriately.

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