Anomalies of Corneal and Associated Anterior Segment Structures
Beginning around the sixth week of gestation, anterior ocular structures are formed by 3 waves of neural crest migration that differentiate into corneal endothelium, corneal stroma, and iris stroma. Disruption at any point in this process can hinder subsequent development and differentiation of anterior segment structures. Anterior segment dysgenesis is the term used to describe a spectrum of congenital anomalies that arise from miscues during anterior segment embryogenesis and affect any or all of the anterior segment structures, including the cornea, anterior chamber angle, iris, and lens. Historically, this mixed group of anomalies was categorized by phenotypic, clinical, and anatomical presentation. Updated reclassification of anterior segment dysgenesis disorders is based on underlying genetic factors and the recognition that widely variable phenotypes may share common genotypes. For further discussion, see the chapter on ocular development in BCSC Section 2, Fundamentals and Principles of Ophthalmology.
Mihelec M, St Heaps L, Flaherty M, et al. Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma. Twin Res Hum Genet. 2008;11(4): 412–421.
Nischal KK. Genetics of congenital corneal opacification–impact on diagnosis and treatment. Cornea. 2015;34(10 Suppl):S24–S34.
Reis LM, Semina EV. Genetics of anterior segment dysgenesis disorders. Curr Opin Ophthalmol. 2011;22(5):314–324.
Smith JEH, Traboulsi EI. Malformations of the anterior segment of the eye. In: Traboulsi EI, ed. Genetic Diseases of the Eye. 2nd ed. Cary, NC: Oxford University Press; 2011:92–108.
Posterior embryotoxon involves a thickened and anteriorly displaced Schwalbe line (Fig 5-2). The Schwalbe line, which represents the junction of the trabecular meshwork and the termination of Descemet membrane, is visible in 8%–30% of normal eyes as an irregular, opaque ridge 0.5–2.0 mm central to the limbus. The term posterior embryotoxon is used when the Schwalbe line is visible on external examination. Posterior embryotoxon is usually bilateral and inherited as a dominant trait. Posterior embryotoxon may occur as an isolated finding or with other anterior segment anomalies that are part of ocular or systemic syndromes, such as Axenfeld-Rieger syndrome, arteriohepatic dysplasia (Alagille syndrome), X-linked ichthyosis, and familial aniridia.
Figure 5-2 Posterior embryotoxon displaying a prominent and anteriorly displaced Schwalbe line (arrows).
The conditions previously referred to as Axenfeld anomaly or syndrome and Rieger anomaly or syndrome overlap genotypically and phenotypically and are now considered a single entity, Axenfeld-Rieger syndrome. This syndrome represents a spectrum of disorders characterized by an anteriorly displaced Schwalbe line (posterior embryotoxon) with attached iris strands, iris hypoplasia, corectopia, and glaucoma (in 50% of the cases occurring in late childhood or in adulthood) (Fig 5-3). Associated craniofacial, dental, skeletal, and umbilical abnormalities are often present.
Autosomal dominant inheritance is most common (75% of cases) for the Axenfeld-Rieger group, but transmission can be sporadic. The syndrome can be caused by mutations in the forkhead box C1 gene (FOXC1), the pituitary homeobox 2 gene (PITX2), or PAX6.
Nishimura DY, Searby CC, Alward WL, et al. A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet. 2001;68(2):364–372.
Peters anomaly is characterized by the presence, at birth, of a central or paracentral corneal opacity, which is due to the localized absence of the corneal endothelium and Descemet membrane beneath the area of opacity. Eighty percent of cases are bilateral. Most cases occur sporadically, but autosomal recessive and dominant modes of inheritance have been reported.
Figure 5-3 Axenfeld-Rieger syndrome exhibiting iris atrophy, corectopia, and pseudopolycoria.
(Courtesy of Vincent P. deLuise, MD.)
Peters anomaly type I is characterized by iridocorneal adhesions and a corneal opacity that is usually avascular and may be central, eccentric, or less commonly total. The syndrome is associated with mutations in PITX2, FOXC1, CYP1B1, PAX6, and other genes. Peters anomaly type II is characterized by corneolenticular adhesions and/or cataract, along with a central or total corneal opacity that is usually vascularized (Fig 5-4). Peters anomaly type II is presumed to be due to a developmental failure in separation of the invaginating lens vesicle from the overlying surface ectoderm. Mutations in the gene FOXE3 have been implicated in lens malformation in Peters anomaly type II. The same genetic mutation can cause Peters type I to occur in one eye and type II in the contralateral eye. High-frequency ultrasonography can be very useful in differentiating Peters types I and II, and sclerocornea.
Figure 5-4 Peters anomaly type II.
Glaucoma is present in 50% of Peters anomaly cases. Additional associated ocular abnormalities include microcornea, aniridia, retinal detachment, and PFV. The prognosis for vision rehabilitation with corneal transplantation is better for patients with Peters anomaly type I than for those with type II (see Chapter 15).
Peters plus syndrome refers to Peters anomaly associated with systemic abnormalities. Systemic involvement is variable and may include cleft lip/palate, short stature, external ear abnormalities, hearing loss, intellectual disability, heart defects, central nervous system deficits, spinal defects, gastrointestinal and genitourinary defects, and skeletal anomalies. Although the systemic malformations in this syndrome may be associated with genetically transmitted syndromes (trisomy 13–15, Kivlin syndrome, Pfeiffer syndrome), these associations are the exception rather than the rule.
See also BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors, Section 6, Pediatric Ophthalmology and Strabismus, and Section 10, Glaucoma.
Bhandari R, Ferri S, Whittaker B, Liu M, Lazzaro DR. Peters anomaly: review of the literature. Cornea. 2011;30(8):939–944.
Nischal KK. Genetics of congenital corneal opacification—impact on diagnosis and treatment. Cornea. 2015;34(10 Suppl):S24–S34.
Traboulsi EI, Maumenee IH. Peters anomaly and associated congenital malformations. Arch Ophthalmol. 1992;110(12):1739–1742.
Posterior keratoconus is characterized by a usually localized central or paracentral indentation of the posterior cornea without protrusion of the anterior corneal surface, as is seen in typical keratoconus. Posterior excavation can occur in multiple areas; there is also a generalized form of this disease that can involve much of the cornea. Classification of posterior keratoconus as a congenital anomaly is supported by its association with abnormal anterior banding of Descemet membrane and its presence at birth. Loss of stromal substance can lead to corneal thinning that approaches one-third of normal (Fig 5-5). The ectasia is usually stable but can gradually progress. Focal deposits of pigment and guttae are often present at the involved margins. Subtle anterior corneal irregularities overlying the area of posterior involvement can contribute to irregular astigmatism and amblyopia, which should be identified and treated appropriately. Corneal tomography can confirm the corneal thinning and posterior elevation.
Most cases of posterior keratoconus are unilateral and sporadic. An autosomal recessive form of disease is associated with bilateral corneal changes, short stature, intellectual disability, cleft lip and palate, and vertebral anomalies. Acquired posterior keratoconus can also occur, usually following trauma.
Charles N, Charles M, Croxatto JO, Charles DE, Wertheimer D. Surface and Orbscan II slitscanning elevation topography in circumscribed posterior keratoconus. J Cataract Refract Surg. 2005;31(3):636–639.
Krachmer JH, Rodrigues MM. Posterior keratoconus. Arch Ophthalmol. 1976;96:1867–1873.
Zare MA, Mehrjardi HZ, Zare F, Oskoie J. Visante in atypical posterior keratoconus. Iran J Ophthalmol. 2011;23(4):61–64.
Figure 5-5 Posterior keratoconus. A, Scanning-slit corneal topography shows a nasally displaced anterior corneal apex (top left), temporal paracentral posterior corneal vaulting (top right), normal anterior keratometry reading (bottom left), and significant loss of stromal thickness (bottom right).B, This slit-lamp photograph shows loss of stromal thickness, stromal haze, and a craterlike depression in the posterior cornea (arrow).
(Courtesy of Kenneth M. Goins, MD.)
Sclerocornea is a nonprogressive, noninflammatory scleralization of the cornea. The scleralization may be limited to the corneal periphery, or the entire cornea may be involved. The limbus is usually ill defined, and superficial vessels that are extensions of normal scleral, episcleral, and conjunctival vessels cross the cornea (Fig 5-6). Sclerocornea is usually sporadic, but both autosomal dominant and recessive patterns of inheritance have been reported. No sex predilection is evident, and 90% of cases are bilateral.
The most common associated ocular finding is cornea plana, which occurs in 80% of cases. Angle structures are also commonly malformed. Multiple systemic anomalies have been reported in association with sclerocornea.
Ali M, Buentello-Volante B, McKibbin M, et al. Homozygous FOXE3 mutations cause non-syndromic, bilateral, total sclerocornea, aphakia, microphthalmia and optic disc coloboma. Mol Vis. 2010;16:1162–1168.
Congenital anterior staphyloma and keratectasia
Congenital anterior staphyloma is a rare developmental anomaly characterized by an opaque cornea protruding between the eyelids and partial or complete absence of Descemet membrane and endothelium (Fig 5-7). A thin layer of uveal tissue lines the posterior cornea. The anterior segment is usually markedly abnormal, often with iridocorneal adhesions, iris hypoplasia, and lens opacity. Exposure may promote corneal scarring and keratinization. Inflammation is markedly absent. Unlike Peters anomaly, congenital anterior staphyloma is usually unilateral, but the contralateral eye frequently has some form of anterior segment abnormality. Typically, cases are sporadic, with no familial or systemic association.
Keratectasia differs from congenital anterior staphyloma histologically in that there is no thin layer of uveal tissue lining the posterior cornea. Keratectasia is possibly the result not of abnormal development but rather of intrauterine keratitis or vitamin deficiency and subsequent corneal perforation.
Figure 5-7 Congenital anterior staphyloma.
(Courtesy of Denise de Freitas, MD.)
Except in very mild cases, the visual prognosis for both congenital anterior staphyloma and keratectasia is poor because of associated severe damage to the anterior segment. Penetrating keratoplasty and sclerokeratoplasty may be useful to preserve the globe and improve cosmesis; however, enucleation may be required for a painful, blind glaucomatous eye.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.