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INTRODUCTIONCorneal anomalies are often present at birth. The cause can be genetic, the result of a teratogen, or idiopathic. At the fifth week of gestation, the lens vesicle separates from the surface ectoderm. Mesenchymal neural crest cells migrate between the surface ectoderm and the optic cup in what will become the anterior chamber.1 The first wave of mes-enchyme becomes the corneal endothelium and trabecular meshwork, the second becomes the corneal stromal keratocytes, and the third becomes the anterior iris stroma. Separation of these mesenchyme lay-ers forms the anterior chamber. Alterations in this process result in the anomalies of corneal size, shape, and clarity, as described below.

Recent studies from large corneal referral practices have shown the most common conditions requiring surgical intervention were: poste-rior polymorphous dystrophy, Peters’ anomaly, congenital glaucoma, and sclerocornea. After a mean follow-up of 40 months, 78% of corneal grafts remained clear.2 However, medical management accounted for the majority (52.7%) of eyes with congenital corneal opacities.3

SIZE AND SHAPE ANOMALIES

MICROCORNEAThe cornea’s horizontal diameter is normally 9.5–10 mm at birth and 10–12.5 mm in adulthood. An adult cornea less than 10 mm in hori-zontal diameter is called microcornea and may occur in conjunction with microphthalmos, which is a small disorganized eye often associ-ated with anomalies such as coloboma of the iris, retina, choroid, and even the optic nerve (Fig. 4-3-1). In contrast, nanophthalmos is a small functional eye that has normal internal organization and proportions.

Epidemiology, Pathogenesis, and Ocular ManifestationsMost cases are sporadic, although autosomal recessive and autosomal dominant pedigrees have been reported.4 Microphthalmos in associa-tion with dermal aplasia and sclerocornea is known as MIDAS syn-drome (caused by deletion in Xp22).5 In microcornea, because the remainder of the eye is normal in size, angle-closure glaucoma may occur as the lens enlarges. An autosomal dominant variant of micro-cornea associated with cataract and other anterior segment anomalies has been described.6 Microcornea has been associated with numerous syndromes, including the “micro” syndrome of microcornea, congenital cataract, mental retardation, retinal dystrophy, optic atrophy, hypogeni-talism, and microcephaly.7

TreatmentTreatment involves spectacle correction for hyperopia resulting from the flat cornea. Other ocular pathology such as cataract and glaucoma may require separate treatment.

MEGALOCORNEAEpidemiology, Pathogenesis, and Ocular ManifestationsMegalocornea is characterized by bilateral anterior segment enlarge-ment with a corneal horizontal diameter of 12 mm or greater at birth and 13 mm or greater after 2 years of age (Fig. 4-3-2). It is distinct from buphthalmos, which manifests as elevated intraocular pressure and an enlarged globe (which includes an enlarged cornea). The cause appears to be related to defective growth of the optic cup, which leaves a larger space for development of the cornea. In utero, elevated intraocular pres-sure, which spontaneously arrests, may result in similar changes, but presumably the endothelial cell density decreases and the entire globe enlarges.

A number of variants of this disorder have been described. Auto-somal dominant megalocornea without other ocular abnormalities is the least common. X-linked recessive megalocornea is reported more frequently and is associated with iris transillumination, pigment dis-persion, lens subluxation, arcus, and central crocodile shagreen.8,9 Endothelial cell density is normal, which confirms that the enlarge-ment does not arise from corneal stretching, and corneal clarity and thickness are usually normal.10 The genetic locus for X-linked megalo-cornea appears to be in the region Xq21–q22.6. Megalocornea has been reported in association with congenital miosis,11 ectopia lentis, ectopia pupillae, and mental retardation.12

Megalophthalmos is an enlarged cornea in an overall enlarged eye that does not have glaucoma. This is most likely autosomal recessive with findings similar to X-linked megalocornea, in addition to increased axial length (often > 30 mm), juvenile cataract, and high myopia.8

TreatmentTreatment is not necessary except for spectacle correction for myopic refractive error.

Joel Sugar, Hormuz P. Wadia, Roshni A. Vasaiwala 4.3Congenital Corneal Anomalies

SECTION 2 Congenital Abnormailities

PART 4 CORNEA AND OCULAR SURFACE DISEASES

Definition: Developmental abnormalities of the cornea present at birth.

Key features■ Not acquired■ Generally involve defects in the migration of mesenchyme in the

anterior segment of the eye■ Often associated with iris and lens anomalies

Fig. 4-3-1 Colobomatous microphthalmos. Right eye; note the small cornea and typical coloboma.

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Fig. 4-3-2 Megalocornea. (A) This patient has corneal diameters of 14 mm bilaterally. (B) Gross specimen shows appearance of enlarged cornea and heavily pigmented trabecular meshwork. (B, Courtesy of Dr. M. Yanoff)

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Fig. 4-3-3 Posterior embryotoxon. Schwalbe’s line is evident nasally, superiorly, and temporally in the eye of this patient.

CORNEAL ABSENCEIsolated absence of the cornea does not occur. Concomitant and severe developmental anomalies of the anterior segment or the entire eye are seen because of the intimate relationship between the ocular structures in the development of the cornea. Anophthalmos is the extreme; absence of the cornea and other ocular structures may occur as part of more extreme genetic developmental disorders. Cryptophthalmos involves partial or complete failure of eyelid formation, dermoid trans-formation of the cornea, an undeveloped anterior segment, or a rudimentary cyst-like globe with an absent anterior segment. Cryp-tophthalmos also may be associated with systemic anomalies such as syndactyly and genitourinary anomalies. This syndrome, known as Fraser syndrome, is inherited as an autosomal recessive trait. Pseudocryptophthalmos occurs when the lids fail to separate and the underlying globe is intact.

CONGENITAL CORNEAL ECTASIAKeratoglobus (discussed in Chapter 4.18) is not congenital, but corneal ectasia may be present at birth as part of a congenital anterior staphy-loma, which is often seen with Peters’ anomaly. Congenital corneal ectasia includes significantly more corneal thinning and bulging com-pared to Peters’ anomaly (see Fig. 4-3-6), presumably as a consequence of the same developmental abnormalities in the migration of mesen-chyme. This anomaly is usually unilateral and is often associated with iris developmental defects. Anterior staphyloma may also occur as a result of inflammatory or infectious corneal thinning in utero.

ANOMALIES OF CORNEAL CLARITYChanges in the first wave of neural crest mesenchyme migration result in anomalies of the corneal endothelium and anterior chamber angle, while those in the second wave lead to corneal stromal alterations, and those in the third wave affect iris development. The factors that com-monly result in maldevelopment impact more than just one phase in this process of neural crest differentiation.

ANTERIOR EMBRYOTOXONAnterior embryotoxon refers to a congenital broad limbus superiorly with an otherwise normal anterior segment, representing merely a broad transition from sclera to cornea. The term also is used to describe an appearance similar to arcus senilis (arcus juvenilis) present at birth. Though it is often sporadic, autosomal dominant and autosomal reces-sive pedigrees have been described.

POSTERIOR EMBRYOTOXONPosterior embryotoxon is likely the most frequently seen anomaly, with the prevalence being reported as high as 24% in a random population.13 It consists of thickening and anterior displacement of Schwalbe’s line, which is seen most readily at the slit lamp in the temporal cornea (Fig. 4-3-3). The term toxon is derived from the Greek word for bow, in refer-ence to the crescent of Schwalbe’s line; when present alone, this has no functional significance.

CORNEAL KELOIDSKeloids are white, glistening, protuberant lesions that involve all or part of the cornea. Although usually resulting from trauma or ocular inflam-mation, they may be present at birth. Histopathologically, they repre-sent an irregular array of collagen bundles, fibroblasts, and capillaries arising in the corneal stroma. They are sometimes progressive and may be associated with disorders that involve oculodigital manipulation, as in Lowe’s syndrome. In otherwise healthy eyes, keratoplasty is appro-priate.14 For lesions in which progressive growth causes discomfort, dissection of the lesion from the cornea followed by covering with a conjunctival flap may halt progression.

DERMOIDSDermoids (choristomas, or growths of tissue not normally present) may be found on the cornea, usually at the inferotemporal limbus. At times they may involve larger areas of the cornea, the entire limbus, the entire cornea, or the interior of the eye. They usually are round, domed, and pink to white to yellow in color. They may have hair, or in the lipoder-moid variant, globules of lipid, as evident on slit-lamp examination. Induced astigmatism, even amblyopia, may be present. Limbal dermoids may be associated with other malformations, e.g., Goldenhar’s syn-drome, which involves lid colobomas, hemifacial microsomia,

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iridocorneal endothelial (ICE) syndrome (which is acquired and usually unilateral), posterior polymorphous dystrophy with iridocorneal adhe-sions, and the iridogoniodysgenesis syndrome.20

PETERS’ ANOMALYOcular ManifestationsPeters’ anomaly includes a variety of findings, not all of which need to be present to make the diagnosis. Most cases are sporadic, but Peters’ anomaly can be recessively or occasionally dominantly inherited. Eighty percent of cases are bilateral. The pathogenesis involves altera-tion of the migration of neural crest cells. Type I consists of a central or paracentral corneal opacity with iris strands that arise from the collar-ette and attach to the periphery of the opacity. Initially, a defect in corneal endothelium and Descemet’s membrane is present, often with marked corneal edema, which may extend well beyond the defect (Fig. 4-3-6). Over time, the surrounding endothelium covers the defect and produces new basement membrane, and the edema regresses leaving the corneal opacity only.21 Posterior keratoconus and posterior ulcer of von Hippel may be thought of as Peters’ anomaly without iris adhe-sions. Peters’ anomaly type II has lens adherence to the posterior cor-nea, failure of complete separation of the lens from the cornea, and/or cataract. Type I usually is unilateral, while type II frequently is bilateral. Peters’ anomaly may be associated with other ocular anomalies (Fig. 4-3-7), including microcornea, cornea plana, sclerocornea, chorioreti-nal coloboma, iris coloboma, dysgenesis of the angle and iris, persistent hyperplastic primary vitreous, microphthalmos, optic nerve hypoplasia and foveal hypoplasia.22 The most frequent associated ocular abnormal-ity is glaucoma in over 50% of cases.

Systemic AssociationsThe systemic associations of Peters’ anomaly include short stature, facial dysmorphism, developmental delay, and delayed skeletal maturation,

preauricular skin tags, and other ear anomalies. Limbal dermoids also may be associated with mandibular and other facial anomalies.

Histopathology confirms the presence of skin-like collagen with skin adnexal appendages, which include hair follicles, sweat and sebaceous glands, and fat. Treatment consists of simple excision, since a plane can be developed between the lesion and normal sclera, limbus, and cornea, and the dermoid can be readily removed. Infrequently, the lesion is of sufficient depth to warrant concurrent lamellar keratoplasty to fill the defect15 and very rarely may penetrate into the anterior of the eye. The depth can be ascertained by ultrasound biomicroscopy.16 A rare case of spontaneous partial regression of a congenital corneal dermoid has been reported.17

AXENFELD’S ANOMALY AND RIEGER’S SYNDROMEAxenfeld’s anomaly consists of bilateral posterior embryotoxon with iris strands adherent to Schwalbe’s line (Fig. 4-3-4). Rieger’s syndrome includes the changes of Axenfeld’s anomaly along with iris atrophy, corectopia, and polycoria. Dental anomalies and a flattened midface and nasal bridge are associated with the Axenfeld–Rieger syndrome (Fig. 4-3-5). The term anomaly refers to the localized anatomical changes seen, while the term syndrome refers to the more widespread ocular and sys-temic findings. Glaucoma occurs in about half of the patients who have Axenfeld–Rieger syndrome. It appears that Axenfeld’s anomaly and Rieger’s syndrome arise from retention of neural crest remnants and primordial endothelium on the iris and chamber angle.18 Defects in the PITX 2 gene on chromosome 4q25 and in the FKHL7 gene on 6p25, as well as other defects, have been found in different families with the Axenfeld–Rieger phenotype.19 Differential diagnosis includes the

Fig. 4-3-4 Axenfeld’s anomaly (posterior embryotoxon). Histological section shows an iris process attached to the anteriorly displaced Schwalbe’s ring. (Courtesy of Dr R. Y. Foos.)

Fig. 4-3-5 Axenfeld–Rieger syndrome. This patient has bilateral glaucoma as well as dental and facial anomalies.

Fig. 4-3-6 Peters’ anomaly in a neonate. (A) Typical Peters’ anomaly type I. (B) Severe Peters’ involvement with corneal thinning and ectasia. This is called a congenital anterior staphyloma.

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Fig. 4-3-7 Severe Peters’ anomaly. This infant has bilateral glaucoma, Peters’ anomaly type II, and features of sclerocornea.

Fig. 4-3-8 Peters’ anomaly. Lens material is attached to the posterior cornea (LM). Centrally, the endothelium, Descemet’s membrane, and Bowman’s membrane are not present . The large space (arrow) is an artifact caused by fixation shrinkage. (Courtesy of Dr. M. Yanoff)

LM

TABLE 4-3-1 RELATIONSHIP OF EMBRYONIC NEURAL CREST MIGRATORY “WAVES” TO VARIOUS ANOMALIES

Anomaly Mesenchymal wave abnormality

1st 2nd 3rd

Posterior embryotoxon xAxenfeld–Rieger syndrome x xPeters’ anomaly x xPosterior keratoconus xSclerocornea x

which form the Krause–Kivlin syndrome (inheritance is autosomal reces-sive). The Peters’-plus syndrome consists of Peters’ anomaly with syn-dactyly, genitourinary anomalies, brachycephaly, central nervous system anomalies, cardiac disease, or deafness.23,24 Peters’ anomaly also has been reported as part of the fetal alcohol syndrome.25 Most interesting is the finding of mutations at the PAX 6 locus on chromosome 11p13 in some Peters’ anomaly patients.26 The PAX 6 gene appears to play a regu-latory role in embryogenesis and also has been found to be abnormal in aniridia and autosomal dominant keratitis.27 PAX 6 is normal, however, in most patients with Peters’ anomaly.28 Increasing molecular evidence has also been found with mutations in the CYP1B1 gene as a possible causative role in Peters’ anomaly.29 This gene defect along with other defects (such as in Axenfeld–Rieger, 4q25) have thus been implicated in ocular development as well as glaucoma.30

PathologyPathology of Peters’ anomaly shows absence of Descemet’s membrane and endothelium in the area of opacity initially (Fig. 4-3-8). As men-tioned earlier, over time, the endothelial and Descemet’s membrane defects are repaired by surrounding cells. Except for residual fibrosis in the posterior stroma, the remainder of the cornea, except for a usually absent central Bowman’s membrane, is normal.

Treatment and OutcomeTreatment of Peters’ anomaly includes treatment of the associated glau-coma. Typically, penetrating keratoplasty is considered when corneal opacification is bilateral. A recent study, however, examined results of penetrating keratoplasty for unilateral corneal opacification in Peters’ anomaly.31 Of 14 eyes, 11 (78.6%) had clear grafts at 30 months’ follow-up. Ten of 14 children gained seemingly useful vision after strict amblyopia therapy. The Boston Keratoprosthesis has become an alter-native to penetrating keratoplasty in children with Peters’ anomaly who are at high risk for graft failure.22 Although visual outcomes often are not ideal, the establishment of useful vision is worthwhile.32

SCLEROCORNEASclerocornea refers to a non-progressive, non-inflammatory scleral-like clouding of the cornea, which may be peripheral or diffuse. It results from a disorder of the second wave mesenchyme migration and may be associated with corneal flattening or cornea plana because of the par-ticipation in the formation of the limbus. Peripheral forms need to be differentiated from a congenital broad limbus or anterior embryotoxon. Sclerocornea may be associated with other anomalies of anterior seg-ment development, such as Peters’ anomaly; indeed, the entire anterior segment developmental abnormalities discussed here may be consid-ered part of a spectrum and often have many overlapping findings. Glaucoma is common. Associations with systemic anomalies and other ocular anomalies may occur, as noted earlier. Inheritance may be

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autosomal dominant, recessive, or X-linked. Most cases, however, are sporadic and usually bilateral. Treatment consists of keratoplasty, or most recently the Boston Keratoprosthesis, once the glaucoma has been controlled. Outcomes are poor, usually because of the difficulty in con-trolling glaucoma or secondary to optic nerve anomalies.

A review of the relationship of the embryonic neural crest migratory waves to the anomalies discussed is given in Table 4-3-1.

KEY REFERENCESAlward WL. Axenfeld–Rieger syndrome in the age of molecular genetics. Am J Ophthalmol

2000;130:107–15.Churchill AJ, Booth AP, Anwar R, et al. PAX 6 is normal in most cases of Peters’ anomaly.

Eye 1998;12:299–303.Cook CS. Experimental models of anterior segment dysgenesis. Ophthalmic Pediatr Genet

1989;10:33–46.Dana MR, Schaumberg DA, Moyes AL, et al. Corneal transplantation in children with Peters’

anomaly and mesenchymal dysgenesis. Multicenter Pediatric Keratoplasty Study. Ophthalmology 1997;104:1580–6.

Hanson IM, Fletcher JM, Jordan T, et al. Mutations at the PAX 6 locus are found in heterogeneous anterior segment malformations including Peters’ anomaly. Nat Genet 1994;6:168–73.

Harissi-Dagher M, Colby K. Anterior segment dysgenesis: Peters anomaly and sclerocornea. Int Ophthalmol Clin 2008;48:35–42.

Heon E, Barsoum-Homsy M, Cevrette L, et al. Peters’ anomaly, the spectrum of associated ocular malformations. Ophthalmic Pediatr Genet 1992;13:137–43.

Mader TH, Stulting D. Technique for the removal of limbal dermoids. Cornea 1998;17:66–7.Mayer UM. Peters’ anomaly and combination with other malformations. Ophthalmic Pediatr

Genet 1992;13:131–5.Meire FM. Megalocornea, clinical and genetic aspects. Doc Ophthalmol 1994;87:1–1121.Mejia LF, Acosta C, Santamaria JP. Clinical, surgical, and histopathologic characteristics of corneal

keloid. Cornea 2001;20:421–4.Michaeli A, Markovich A, Rootman DS. Corneal transplants for the treatment of congenital

corneal opacities. J Pediatr Ophthalmol Strabismus 2005;42:34–44.Miller MT, Epstein RJ, Sugar J, et al. Anterior segment anomalies associated with the fetal alcohol

syndrome. J Pediatr Ophthalmol Strabismus 1984;21:8–18.Rezende RA, Uchoa UB, Uchoa R, et al. Congenital corneal opacities in a cornea referral practice.

Cornea 2004;23:565–70.Shields MB, Buckley E, Klintworth GK, et al. Axenfeld–Rieger syndrome: a spectrum of

developmental disorders. Surv Ophthalmol 1985;29:387–409.

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REFERENCES1. Cook CS. Experimental models of anterior segment dysgenesis. Ophthalmic Pediatr Genet

1989;10:33–46.2. Michaeli A, Markovich A, Rootman DS. Corneal transplants for the treatment of congenital

corneal opacities. J Pediatr Ophthalmol Strabismus 2005;42:34–44.3. Rezende RA, Uchoa UB, Uchoa R, et al. Congenital corneal opacities in a cornea referral

practice. Cornea 2004;23:565–70.4. Vingolo EM, Steindl K, Forte R, et al. Autosomal dominant simple microphthalmos. J Med

Genet 1994;31:721–5.5. Zvulunov A, Kachko L, Manor E, et al. Reticulolinear aplasia cutis congenita of the face and

neck: a distinctive cutaneous manifestation in several syndromes linked to Xp22. Br J Dermatol 1998;138:104–52.

6. Salmon JF, Wallis CE, Murray ADN. Variable expressivity of autosomal dominant microcornea with cataract. Arch Ophthalmol 1988;106:505–10.

7. Warburg M, Sjo O, Fledelius HC, et al. Autosomal recessive microcephaly, microcornea, congenital cataract, mental retardation, optic atrophy and hypogenitalism. Am J Dis Child 1993;147:1309–12.

8. Meire FM. Megalocornea, clinical and genetic aspects. Doc Ophthalmol 1994;87:1–1121.9. Pletz C, Hentsch R. Hereditary anterior megalophthalmos – a genealogical study of 12

patients in 4 generations. Klin Monatsbl Augenheilkd 2000;217:284–8.10. Skuta GL, Sugar J, Ericson ES. Corneal endothelial cell measurements in megalocornea.

Arch Ophthalmol 1983;101:51–3.11. Meire FM, Delleman JW. Autosomal dominant congenital miosis with megalocornea.

Ophthalmic Paediatr Genet 1992;13:123–9.12. Antinolo G, Rufo M, Borrego S, et al. Megalocornea–mental retardation syndrome: an

additional case. Am J Med Genet 1994;52:196–7.13. Ozeki H, Shirai S, Majima A, et al. Clinical evaluation of posterior embryotoxon in one

institution. Jpn J Ophthalmol 1997;41:422–5.14. Mejia LF, Acosta C, Santamaria JP. Clinical, surgical, and histopathologic characteristics of

corneal keloid. Cornea 2001;20:421–4.15. Mader TH, Stulting D. Technique for the removal of limbal dermoids. Cornea 1998;17:66–7.16. Lanzl M, Augsburger JJ, Hertle RW, et al. The role of ultrasound biomicroscopy in surgical

planning for limbal dermoids. Cornea 1998;17:604–6.

17. Roncevic MB, Doresic JP, Md LD. Large congenital corneal dermoid with spontaneous partial regression: the first report. Cornea 2011;30:219–21.

18. Shields MB, Buckley E, Klintworth GK, et al. Axenfeld–Rieger syndrome: a spectrum of developmental disorders. Surv Ophthalmol 1985;29:387–409.

19. Alward WL. Axenfeld–Rieger syndrome in the age of molecular genetics. Am J Ophthalmol 2000;130:107–15.

20. Walter MA, Mirzayans F, Means AJ, et al. Autosomal-dominant iridogoniodysgenesis and Axenfeld–Rieger syndrome are genetically distinct. Ophthalmology 1996;103:1907–15.

21. Townsend WM, Font RL, Zimmerman LE. Congenital corneal leukomas II. Histopathologic findings in 19 eyes with central defect in Descemet’s membrane. Am J Ophthalmol 1974;77:192–206.

22. Harissi-Dagher M, Colby K. Anterior segment dysgenesis: Peters anomaly and sclerocornea. Int Ophthalmol Clin 2008;48:35–42.

23. Heon E, Barsoum-Homsy M, Cevrette L, et al. Peters’ anomaly, the spectrum of associated ocular malformations. Ophthalmic Pediatr Genet 1992;13:137–43.

24. Mayer UM. Peters’ anomaly and combination with other malformations. Ophthalmic Pediatr Genet 1992;13:131–5.

25. Miller MT, Epstein RJ, Sugar J, et al. Anterior segment anomalies associated with the fetal alcohol syndrome. J Pediatr Ophthalmol Strabismus 1984;21:8–18.

26. Hanson IM, Fletcher JM, Jordan T, et al. Mutations at the PAX 6 locus are found in heterogeneous anterior segment malformations including Peters’ anomaly. Nat Genet 1994;6:168–73.

27. Mirzayans F, Pearce WG, MacDonald IM, et al. Mutation of the PAX 6 gene in patients with autosomal dominant keratitis. Am J Hum Genet 1995;57:539–48.

28. Churchill AJ, Booth AP, Anwar R, et al. PAX 6 is normal in most cases of Peters’ anomaly. Eye 1998;12:299–303.

29. Vincent A, Billingsley G, Priston M, et al. Further support of the role of CYP1B1 in patients with Peters’ anomaly. Mol Vis 2006;12:506–10.

30. Doward W, Periseen R, Lloyd GC. A mutation in the RIEG 1 gene associated with Peters’ anomaly. J Med Genet 1999;36:152–5.

31. Basdekidou C, Dureau P, Edelson C, et al. Should unilateral congenital corneal opacities in Peters’ anomaly be grafted? Eur J Ophthalmol 2011;21:695–9.

32. Dana MR, Schaumberg DA, Moyes AL, et al. Corneal transplantation in children with Peters’ anomaly and mesenchymal dysgenesis. Multicenter Pediatric Keratoplasty Study. Ophthalmology 1997;104:1580–6.