Abnormalities of Structure
Anterior Segment Dysgenesis
Anterior segment dysgenesis (ASD) was formerly called mesodermal dysgenesis (anterior chamber cleavage syndrome), but evidence indicates that the affected embryonic tissues probably originate from the neuroectoderm of the neural crest rather than from the mesoderm (26
). These problems may be thought of as a spectrum in which any of several abnormalities may exist alone or in various combinations (1
). Some of the more frequently
occurring combinations are given eponymic designations such as Rieger’s anomaly, Peters’ anomaly, and others.
In trying to understand this subject, it is helpful to review some of the embryology of the anterior segment of the eye (3
). After separation of the lens vesicle, the surface ectoderm forms a layer that becomes corneal epithelium. Three waves of tissue then invade the primary mesenchyme that lies behind the surface ectoderm: the first wave gives rise to corneal endothelium, the second forms corneal stroma, and the third becomes the iris stroma. These waves of tissue (secondary mesenchyme) were once thought to be mesodermal, thus giving rise to the concept of mesodermal dysgenesis, but are now widely held to be of neural crest origin and the term most commonly used now is that of anterior segment dysgenesis.
During early development, there is no anterior chamber, the entire area being filled with primary or secondary mesenchyme. This gradually recedes, and its remnant in the form of the pupillary membrane begins to undergo atrophy at about the seventh month. The angle recess does not become fully opened until sometime during the first year after birth.
Three hypotheses have been proposed to explain the disappearance of mesenchyme and the consequent formation of the anterior chamber (25
). The first idea was that the mesenchyme disappears by means of atrophy and absorption. The next explanation was that it is pulled apart passively as a result of different growth rates of the anterior tissues; there is no evidence to support this idea and so the term anterior segment cleavage syndrome
is rarely used. The latest, and most plausible, explanation for the abnormalities that occur in conjunction with the development of the anterior chamber is that they represent abnormal migration, proliferation, or final differentiation of secondary mesenchymal cells that originate from the neural crest (26
). This concept accounts also for the fact that associated abnormalities of the head and face are often present.
The various ASDs are now classified as follows: (a) abnormalities of neural crest cell migration (congenital glaucoma, posterior embryotoxon, Axenfeld’s anomaly and syndrome, Rieger’s anomaly and syndrome, Peters’ anomaly, and sclerocornea); (b) abnormalities of neural crest cell proliferation (essential iris atrophy, Chandler’s syndrome, and Cogan-Reese iris nevus syndrome); and (c) abnormalities of neural crest cell final differentiation (congenital hereditary endothelial dystrophy, posterior polymorphous corneal dystrophy, congenital cornea guttata, and Fuchs’ corneal dystrophy). Other abnormalities such as prominent iris processes, dysgenesis of the iris, circumscribed posterior keratoconus (and, perhaps, generalized posterior keratoconus), goniodysgenesis with glaucoma, and iridogoniodysgenesis with cataract are probably also abnormalities of neural crest cell migration or differentiation.
Posterior embryotoxon is an exaggeration of the normal Schwalbe’s ring. This structure is a collagenous band that encircles the periphery of the cornea on its posterior surface (34
). The collagen fibers of Schwalbe’s ring course circumferentially (parallel to the limbus), whereas the fibers elsewhere in the cornea run radially. Schwalbe’s ring is bounded anteriorly by the termination of Descemet’s membrane and posteriorly by the trabecular meshwork. Gonioscopically, it is seen just above the meshwork and is then referred to as Schwalbe’s line. It may be flat and indistinct, or elevated and ridgelike.
In most persons, Schwalbe’s ring is not visible biomicroscopically because it lies behind the opaque portion of the limbus; if it is sufficiently prominent and anteriorly displaced as to be visible, it is called a posterior embryotoxon and is present in 15% to 30% of normal eyes. It appears clinically as an arcuate or scalloped translucent membrane on the posterior surface of the cornea just inside the limbus. It is usually seen in the horizontal meridian, nasally and temporally, but may encircle the entire cornea.
Posterior embryotoxon is inherited as a dominant trait. The eye is usually otherwise normal unless Axenfeld’s anomaly or syndrome (discussed below) is present. A prominent Schwalbe’s line may be associated with other disorders, including primary congenital glaucoma, Alagille’s syndrome (arteriohepatic dysplasia), megalocornea, aniridia, corectopia, and Noonan’s syndrome.
Even a Schwalbe’s ring that is not anteriorly displaced may be visible without gonioscopy if there is a sectoral deficiency of the normal extension of sclera into the superficial tissues of the limbus. This extremely rare anomaly is called the partial limbal coloboma of Ascher
and exposes Schwalbe’s ring and the meshwork to direct view (1
Axenfeld’s Anomaly and Syndrome
is the combination of posterior embryotoxon with prominent iris processes. The iris processes extend across the angle and insert into the prominent Schwalbe’s line. Axenfeld syndrome
is the name given to Axenfeld anomaly occurring along with glaucoma (30
). Both the anomaly and the syndrome are dominantly inherited. Hypertelorism is occasionally present. Systemic abnormalities are rare (10
Rieger’s Anomaly and Syndrome
consists of the changes found in Axenfeld anomaly plus hypoplasia of the anterior iris stroma (28
). Peripheral anterior synechiae, corectopia, and pseudopolycoria are often present also, as is glaucoma in 50% to 60% of cases. Reiger’s syndrome is present when the Reiger’s anomaly is accompanied by skeletal abnormalities,
such as maxillary hypoplasia, microdontia, and other limb and spine malformations (35
). Some patients are mentally retarded.
Rieger’s anomaly and syndrome are usually dominant but are occasionally sporadic. One case showed a presumptive isochromosome of the long arm of chromosome 6 (36
), and another had a pericentric inversion of chromosome 6 (37
). Various systemic associations have been described, such as Down syndrome, Ehlers-Danlos syndrome, Franceschetti’s syndrome, Noonan’s syndrome, Marfan’s syndrome, oculodentodigital dysplasia, and osteogenesis imperfecta.
Examination of these patients must include gonioscopy and tonometry: this not only helps make the differential diagnosis, it also helps direct treatment (especially if intraocular pressure is elevated). The pneumotonometer or Tonopen is preferable to the Perkins, or Schiötz tonometers because the presence of associated corneal abnormalities or small radius of corneal curvature may give false intraocular pressure readings. Also, a thorough assessment of the optic nerve is critical in determining the overall visual prognosis and deciding on the course of future treatment.
Medical therapy can be useful when intraocular pressure is high and needs to be decreased in an urgent manner. However, this disorder generally has a relatively poor surgical prognosis, both for glaucoma control and for corneal opacities, if present. Deciding on the correct balance between chronic administration of medications and performing surgery is difficult. The advent of effective use of antimetabolites for filtration in children may tip the balance in favor of surgery when the optic nerve is threatened significantly. However, this type of treatment in the maturing eye of a child is, itself, embryonic.
Goniodysgenesis with Glaucoma
Goniodysgenesis with glaucoma is probably just a minor form of Rieger’s anomaly, lacking only posterior embryotoxon (30
). Transmission is dominant.
Iridogoniodysgenesis with Cataract
Iridogoniodysgenesis with cataract differs from Rieger’s anomaly in that cataract is present, posterior embryotoxon is absent, and the heredity is autosomal recessive (30
). Iridogoniodysgenesis is not associated with systemic abnormalities, but Conradi’s syndrome (congenital stippled epiphyses) sometimes manifests other forms of ASD in association with cataract.
Peters’ anomaly is characterized by a central corneal opacity with corresponding defects in the stroma, Descemet’s, and endothelium. Two variants of Peters’ anomaly have been described: in the so-called mesodermal form
(or, probably more properly, the neuroectodermal form
) or type I Peter’s anomaly, the central cornea has a congenital leukoma with strands of iris adherent to it (1
). The adhesions usually, but not invariably, arise from the iris collarette and represent persisting remnants of the pupillary membrane. The lens, which is ectodermal in origin, is clear in the classic and purely mesodermal (neuroectodermal) form of the anomaly. It is most often sporadic but may be transmitted recessively or as an irregularly dominant trait (39
). Approximately 80% of cases are bilateral, and about half include glaucoma. Other associated abnormalities such as microcornea and sclerocornea may be present, although they usually are not. This form of Peters’ anomaly is caused by abnormal development of the tissues associated with the central portions of the iris, anterior chamber, and cornea. Descemet’s membrane and endothelium are generally absent at the site of the leukoma, as is true also of the other two forms of the anomaly that are discussed below.
Peters’ anomaly type II, or the surface ectodermal form of the anomaly, is the result of faulty separation of the lens vesicle from surface ectoderm. In addition to the features of the mesodermal (neuroectodermal) type, anterior cataract (polar, subcapsular, or reduplication) is present. This form is usually bilateral and is almost always associated with other more severe manifestations, both ocular and systemic. Fifty percent to 70% of patients have concomitant glaucoma, and other associated abnormalities include microcornea, microphthalmos, cornea plana, sclerocornea, colobomas, aniridia, and dysgenesis of the angle and iris.
The inflammatory form follows intrauterine inflammation and so is nonhereditary. The inflammation can interfere with surface ectodermal or neuroectodermal development or both. There is no definitive way to make the diagnosis, although signs of inflammation may still be present after birth, and the iris adhesions are extensive and do not arise only from the vicinity of the collarette. Cases of inflammatory Peters’ anomaly nearly always fulfill the criteria for use of the term von Hippel’s posterior corneal ulcer, namely inflammatory signs in association with congenital defects of Descemet’s membrane and endothelium. We have already seen that some examples of circumscribed posterior keratoconus have these same features and so may also be referred to as cases of von Hippel’s ulcer; in fact, there seems to be little, if any, difference between the inflammatory form of Peters’ anomaly and the inflammatory form of circumscribed posterior keratoconus.
The management of patients with Peters’ anomaly is complex, and the outcome of a keratoplasty depends on the ability to control the associated glaucoma.
Prominent Iris Processes
Although prominent iris processes are not corneal anomalies, they should be mentioned because they are part of
the spectrum of ASD and because it is necessary to determine their relationship to the peripheral cornea in order to evaluate their pathologic importance (14
It is normal for some slender processes (usually fewer than 100) to extend from the peripheral iris to the scleral roll (also known as the scleral spur) at the posterior edge of the trabecular meshwork or, occasionally, even to the central portion of the meshwork itself. Extensions to or beyond Schwalbe’s ring are abnormal and are referred to as prominent iris processes. Abnormal processes are often more numerous, in addition to being more prominent and anteriorly displaced, than are normal processes.
Prominent iris processes can occur with any of the other manifestations of ASD. They are also seen in many cases of primary congenital glaucoma and in several systemic disorders that are associated with congenital glaucoma: phakomatosis; homocystinuria; rubella; and Marfan’s, Lowe’s, Pierre Robin, Hallermann-Streiff, Rubenstein-Taybi, and Turner’s syndromes (14
Anterior Segment Dysgenesis of the Iris
In addition to prominent iris processes, ASD may be associated with congenital peripheral anterior synechiae and a variety of abnormalities of the iris itself, including atrophy of the iris stroma, corectopia, pseudopolycoria, and congenital ectropion uveae.
Posterior Polymorphous Dystrophy
Posterior polymorphous dystrophy may be classified either as a dystrophy or as a congenital anomaly. Its histopathologic features suggest a relationship to ASD, and it not infrequently occurs with other forms of ASD (22
). This entity is described in detail elsewhere in this book.
Congenital Cornea Guttata
Cornea guttata can occur, rarely, as a congenital anomaly. It is sometimes familial. A dominant pedigree with associated anterior polar cataract has been described, which suggests an abnormality in the secondary mesenchyme that helps to separate the lens from the surface ectoderm at about the sixth to eighth week of embryonic life (45
). Congenital cornea guttata is also described elsewhere in this book.
Congenital Hereditary Endothelial Dystrophy
Congenital hereditary endothelial dystrophy (CHED) is now classified as an ASD. It is characterized by the presence, at birth or soon thereafter, of bilateral corneal edema that is often slightly worse centrally and that is not associated with vascularization or inflammation (44
). Epithelial edema is not prominent, but the stroma may be swollen to two or three times its normal thickness. Descemet’s membrane, when visible, is seen to be thick and opaque, but guttate changes are not present. Intraocular pressures are normal. The corneas are not enlarged.
Two types of CHED with different modes of transmission are recognized (46
). The recessive form is more common, and is usually more severe, than the dominant form. In the recessive disease, the corneas are cloudy at birth, and nystagmus is common. The condition is essentially nonprogressive and is asymptomatic except for severely decreased vision. Deafness is sometimes present; otherwise, there are no related systemic abnormalities (51
Corneal edema in dominant CHED may not become apparent until sometime during the first or second year after birth (44
). Nystagmus is absent. The edema is likely to progress slowly, and some patients develop pain, photophobia, and tearing.
Histopathologically, the anterior (“banded”) portion of Descemet’s membrane is normal, but the posterior nonbanded layer (which is formed later during development) is abnormal and consists of a variably thickened, or occasionally thinned, layer of aberrant collagen (47
). Guttate excrescences do not form. Endothelial cells are absent or atrophic. The primary abnormality is presumed to be with the endothelial cells and must manifest itself during or after the fifth month of gestation, at which time the endothelial cells begin to form the posterior nonbanded portion of Descemet’s membrane.
Asymptomatic relatives of patients with CHED may show corneal changes resembling posterior polymorphous dystrophy (54
). An attempt should be made to identify such persons because their children seem to run a greater risk of having CHED.
Circumscribed Posterior Keratoconus
Circumscribed posterior keratoconus may be a localized form of Peter’s anomaly. It is characterized by the presence of a localized, crater-like defect (convex toward the stroma) in the posterior surface of the cornea (22
). Contrary to former belief, Descemet’s membrane and endothelium are usually present in the area of the defect, although the collagen of Descemet’s membrane may be thinned and abnormal in structure and configuration (22
). More than one pit may be present. The overlying stroma often has nonspecific opacities. Most cases are in females, unilateral and sporadic, although familial examples have occurred. It is probably the result of abnormal migration or terminal induction of cells of neural crest origin in the area of involvement, perhaps secondary to some problem with separation of the lens vesicle. Some cases show evidence of being related to intrauterine inflammation: corneal infiltrates and vascularization, keratic precipitates, anterior synechiae, and uveitis; these cases often have defects in Descemet’s membrane and endothelium and are
sometimes referred to as von Hippel’s posterior
) corneal ulcer.
TABLE 39-5. ABNORMALITIES ASSOCIATED WITH CIRCUMSCRIBED POSTERIOR KERATOCONUS
Anterior segment dysgenesis
Poorly developed nasal bridge
The characteristics of circumscribed posterior keratoconus, as compared with generalized posterior keratoconus, anterior keratoconus, and keratoglobus, are summarized in Table 39-4
. Associated ocular and systemic abnormalities are listed in Table 39-5
The anterior surface of the cornea is usually normal in these individuals, unless there is enough thinning to cause ectasia. Thus, although the posterior corneal surface may degrade vision to some extent, this is usually not enough to warrant a surgical procedure.
Sclerocornea is an abnormality in which the margins of the cornea are not well defined because scleral tissue with conjunctival vessels extends to the margins (56
). The scleralization may be only peripheral or virtually complete. Even when it is complete, the central cornea is apt to be slightly less opaque than the periphery. Affected areas have fine, superficial vessels that are direct extensions of normal scleral, episcleral, and conjunctival vessels. Sclerocornea is usually bilateral (57
Histopathologic studies reveal elastic fibers and collagen fibers of increased and variable diameter in the anterior corneal stroma. The deeper collagen fibers have smaller diameters than do the more anterior ones, as is typical of sclera; the reverse is true of normal cornea (58
About 50% of cases of sclerocornea are sporadic, and the remainder can be dominant or recessive (57
). The dominant forms are less severe than the recessive ones (58
). Sclerocornea is occasionally caused by chromosomal aberrations. There is no sex predilection. The most common associated finding is cornea plana. Other ocular and systemic associations are given in Table 39-6
). In brief, sclerocornea is associated with cornea plana in about 80% of patients. Other associated ocular abnormalities include microphthalmos, iridocorneal synechiae, persistent pupillary membrane, dysgenesis of angle and iris, congenital glaucoma, coloboma, and posterior embryotoxon of the fellow eye. Somatic abnormalities sometimes occur along with associated chromosomal abnormalities; they include mental retardation, deafness, and craniofacial, digital, and skin abnormalities.
TABLE 39-6. ABNORMALITIES ASSOCIATED WITH SCLEROCORNEA
High refractive errors
Horizontally oval cornea
Anterior segment dysgenesis
Uveal and retinal coloboma
Anomalies of skull and facial bones
Deformities of the external ear
Others (numerous and variable)
Other Combined Forms of Anterior Segment Dysgenesis
Although the foregoing disorders are the most frequently encountered combined forms of ASD, it is worth reemphasizing that any combination of features is possible. This is illustrated well by the family reported by Grayson (43
), in which some members had all of the following findings: cornea guttata, posterior polymorphous dystrophy, posterior embryotoxon, circumscribed posterior keratoconus, iris atrophy, peripheral anterior synechiae, prominent iris processes, and glaucoma. These patients also developed corneal edema and fibrocalcific band keratopathy.