scarring, and soft distensibility. See Chapter 11 for further discussion of Ehlers-Danlos syndrome. These syndromes may share similar manifestations of fractures from minor trauma in childhood, kyphoscoliosis, joint extensibility, and elastic skin. Decreased hearing and tinnitus may also occur.
Regular hearing evaluations after adolescence are recommended. Oral bisphosphonate therapy may be specifically indicated for these patients. Postmenopausal women should engage in a long-term physical therapy program to strengthen the paraspinal muscles. Estrogen and progesterone replacement and adequate calcium and vitamin D intake are indicated. Fractures are treated with standard methods. Future therapies may include stem cell transplantation and gene therapy.
Developmental Anomalies of the Anterior Segment
See Table 9-1 for a summary of developmental anomalies of the anterior segment.
Anomalies of Size and Shape of the Cornea
Microcornea
Microcornea refers to a clear cornea of normal thickness whose diameter is less than 10 mm (or <9 mm in a newborn). If the whole anterior segment is small, the term anterior microphthalmos applies. If the entire eye is small and malformed, the term microphthalmos is used in contrast to nanophthalmos, in which the eye is small but otherwise relatively normal.
The cause is unknown and may be related to fetal arrest of growth of the cornea in the fifth month. Alternatively, it may be related to overgrowth of the anterior tips of the optic cup, which leaves less space for the cornea to develop.
Microcornea may be transmitted as an autosomal dominant (most commonly) or recessive trait with equal sex predilection. Because their corneas are relatively flat, patients with microcornea are usually hyperopic and have a higher incidence of angle-closure glaucoma. Of patients who do not develop angle-closure glaucoma, 20% develop open-angle glaucoma later in life. Important ocular anomalies often associated with microcornea include PFV, congenital cataracts, anterior segment dysgenesis, and optic nerve hypoplasia. Significant systemic associations include myotonic dystrophy, fetal alcohol syndrome, achondroplasia, and Ehlers-Danlos syndrome.
If microcornea occurs as an isolated finding, the patient has an excellent visual prognosis with spectacles to treat the hyperopia resulting from the flat cornea. Concurrent ocular pathologic conditions such as cataract, PFV, and glaucoma may require treatment following the usual procedures for those conditions.
Megalocornea
Megalocornea is a bilateral, nonprogressive corneal enlargement with an X-linked recessive inheritance pattern (see Table 9-1). Rare cases of autosomal recessive inheritance have been reported. Affected persons have histologically normal corneas measuring 13.0–16.5 mm in diameter (Fig 9-3). Males are more typically affected, but heterozygous women may demonstrate a slight increase in corneal diameter.
Figure 9-3 Megalocornea.
The etiology may be related to failure of the optic cup to grow and of its anterior tips to close, leaving a larger space for the cornea to fill. Alternatively, megalocornea may represent arrested buphthalmos and exaggerated growth of the cornea in relation to the rest of the eye. An abnormality in collagen production is suggested by the association of megalocornea with systemic disorders of collagen synthesis (eg, Marfan syndrome).
Megalocornea may be associated with iris translucency (diaphany), miosis, goniodysgenesis, cataract, ectopia lentis, arcus juvenilis, and glaucoma (but not congenital glaucoma). Systemic associations include craniosynostosis, frontal bossing, hypertelorism, facial anomalies, dwarfism, facial hemiatrophy, intellectual disability, hypotonia, Down syndrome, Marfan syndrome, Alport syndrome, osteogenesis imperfecta, mucolipidosis type II, or occasionally other genetic syndromes.
Congenital glaucoma must be ruled out by intraocular pressure measurement and careful biomicroscopy. Ultrasonography may be of value in determining the short vitreous length, deep lens and iris position, and normal axial length that distinguish megalocornea from buphthalmos caused by congenital glaucoma. Myopia and with-the-rule astigmatism are managed as in unaffected patients. Care must be taken during cataract surgery to implant the intraocular lens into the lens capsular bag. Standard-sized posterior chamber lenses are typically too short to be fixated in the ciliary sulcus, and anterior chamber lenses are similarly problematic in the enlarged anterior chamber.
Mackey DA, Buttery RG, Wise GM, Denton MJ. Description of X-linked megalocornea with identification of the gene locus. Arch Ophthalmol. 1991;109(6):829–833.
Traboulsi EI, ed. Genetic Diseases of the Eye. 2nd ed. Cary, NC: Oxford University Press; 2011.
Cornea plana
Cornea plana refers to a flat cornea, where the radius of curvature is less than 43 D, and readings of 30–35 D are common. Corneal curvature that is the same as that of the adjacent sclera is pathognomonic of this rare condition. Sclerocornea also features flat corneas, but it is distinguished by the loss of transparency as well (see Fig 9-8).
Both autosomal recessive and dominant forms of cornea plana have been associated with
mutations of the KERA gene (12q22), which codes for keratan sulfate proteoglycans (keratocan, lumican, and mimecan). These proteins are thought to play an important role in the regular spacing of corneal collagen fibrils. Investigators have speculated that mutations in the KERA gene cause an alteration of the tertiary structure of the keratan sulfate proteoglycans that leads to the cornea plana phenotype.
Cornea plana is often seen in association with sclerocornea or microcornea. Other associated ocular or systemic abnormalities include cataracts, anterior and posterior colobomas, and EhlersDanlos syndrome. Cornea plana usually produces hyperopia, but any type of refractive error may be present because of variations in globe size. Angle-closure glaucoma occurs because of a morphologically shallow anterior chamber, and open-angle glaucoma occurs because of angle abnormalities. The majority of isolated cases appear in patients of Finnish ancestry.
Refractive errors are corrected, and glaucoma must be controlled either medically or surgically. Loss of central clarity may require penetrating keratoplasty (PK), but cornea plana increases the risk of graft rejection and postkeratoplasty glaucoma.
Lehmann OJ, El-Ashry MF, Ebenezer ND, et al. A novel keratocan mutation causing autosomal recessive cornea plana. Invest Ophthalmol Vis Sci. 2001;42(13):3118–3122.
Tahvanainen E, Villanueva AS, Forsius H, Salo P, and de la Chapelle A. Dominantly and recessively inherited cornea plana congenita map to same small region of chromosome 12. Genome Res. 1996;6(4):249–254.
Traboulsi EI, ed. Genetic Diseases of the Eye. 2nd ed. Cary, NC: Oxford University Press; 2011.
Abnormalities of Corneal Structure and/or Clarity
The following group of conditions is associated with various congenital and/or developmental anomalies of the cornea and anterior segment. Previously called anterior chamber cleavage syndrome, this spectrum of developmental abnormalities is now referred to as anterior segment dysgenesis.
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.
Traboulsi EI, ed. Genetic Diseases of the Eye. 2nd ed. Cary, NC: Oxford University Press; 2011.
Posterior embryotoxon
Posterior embryotoxon involves a thickened and anteriorly displaced Schwalbe line (Fig 9-4). The Schwalbe line represents the junction of the trabecular meshwork with the termination of Descemet membrane, and it 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 by external examination. Posterior embryotoxon is usually bilateral and inherited as a dominant trait. The eye is usually normal but can manifest a number of other anterior segment anomalies that are part of ocular or systemic syndromes, such as arteriohepatic dysplasia (Alagille syndrome), X-linked ichthyosis, and familial aniridia.
Figure 9-4 Posterior embryotoxon displaying a prominent and anteriorly displaced Schwalbe line.
Axenfeld-Rieger syndrome
The conditions previously referred to as Axenfeld anomaly and syndrome and Rieger anomaly and syndrome have overlapping findings and have now been grouped into a single entity known as 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, and glaucoma in 50% of the cases occurring in late childhood or in adulthood (Fig 9-5). Associated skeletal, cranial, facial, and dental abnormalities are often present.
Figure 9-5 Axenfeld-Rieger syndrome exhibiting iris atrophy, corectopia, and pseudopolycoria. (Courtesy of Vincent P. deLuise,
MD.)
Transmission is usually dominant (75%) for the Axenfeld-Rieger group, but it can be sporadic. Evidence suggests that a spectrum of mutations of transcription factors located in chromosome region 6p25, known as forkhead genes, are responsible for many developmental defects of the anterior segment of the eye.
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
Peters anomaly is characterized by the presence, at birth, of a central corneal opacity, which is due to the localized absence of the corneal endothelium and Descemet membrane beneath the area of opacity. Peters anomaly has recently been divided into type I, characterized by iridocorneal adhesions, and type II, characterized by a cataractous lens or corneolenticular adhesions (Fig 9-6). Most cases are
bilateral, and the bilateral cases are typically associated with systemic malformations. Additional associated ocular abnormalities include congenital glaucoma, microcornea, aniridia, 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.)
Figure 9-6 Type II Peters anomaly.
Systemic involvement with Peters anomaly can vary. In the new classification of this condition, the term Peters plus syndrome refers to Peters anomaly associated with cleft lip/palate, short stature, external ear abnormalities, and intellectual disability. Other systemic malformations seen with Peters anomaly include heart defects, hearing loss, central nervous system deficits, spinal defects, gastrointestinal and genitourinary defects, and skeletal anomalies. Although systemic malformations may be associated with genetically transmitted syndromes (trisomy 13–15, Peters plus syndrome, Kivlin syndrome, Pfeiffer syndrome), these associations are the exception rather than the rule.
Most cases of Peters anomaly occur sporadically; however, both autosomal recessive and dominant modes of inheritance have been reported. Peters anomaly can be caused by mutations in the PAX6 gene (11p13), the PITX2 gene (4q25-26), the CYP1B1 gene (2p22-21), and the FOXC1 gene (6p25). See also BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors, BCSC Section 6,
Pediatric Ophthalmology and Strabismus, and BCSC 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. Traboulsi EI, Maumenee IH. Peters anomaly and associated congenital malformations. Arch Ophthalmol. 1992;110(12):1739–
1742.
Circumscribed posterior keratoconus
The presence of a localized central or paracentral indentation of the posterior cornea without any protrusion of the anterior surface, as is seen in typical keratoconus, characterizes circumscribed posterior keratoconus. A variable amount of overlying stromal haze is also usually present. Loss of stromal substance can lead to corneal thinning approaching one-third of normal (Fig 9-7). Descemet membrane and endothelium are usually present in the area of the defect. Focal deposits of pigmentation and guttae are often present at the margins of the opacity. Most cases are unilateral, nonprogressive, and sporadic. Irregular astigmatism and/or amblyopia may occur. An autosomal recessive form of disease is associated with bilateral corneal changes, short stature, intellectual disability, cleft lip and palate, and vertebral anomalies.
Charles N, Charles M, Croxatto JO, Charles DE, Wertheimer D. Surface and Orbscan II slit-scanning elevation topography in circumscribed posterior keratoconus. J Cataract Refract Surg. 2005;31(3):636–639.
Zare MA, Mehrjardi HZ, Zare F, Oskoie J. Visante in atypical posterior keratoconus. Iranian J Ophthalmol. 2011;23(4):61–64.
Figure 9-7 Circumscribed 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, A slit-lamp photograph shows loss of stromal thickness, stromal haze, and posterior corneal crater (arrow). (Courtesy of Kenneth M. Goins, MD.)
Sclerocornea
Sclerocornea, a nonprogressive, noninflammatory scleralization of the cornea, 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 9-8). The most common associated ocular finding is cornea plana, which occurs in 80% of cases. Angle structures are also commonly malformed. No sex predilection is evident, and 90% of cases are bilateral. Multiple systemic anomalies have been reported in association with sclerocornea.
Figure 9-8 Sclerocornea.
Sclerocornea is usually sporadic, but both autosomal dominant and recessive patterns of inheritance have been reported.
Ali M, Buentello-Volante B, McKibbin M, et al. Homozygous FOXE3 mutations cause nonsyndromic, bilateral, total
sclerocornea, aphakia, microphthalmia and optic disc coloboma. Mol Vis. 2010;16:1162–1168.
Keratectasia and congenital anterior staphyloma
Keratectasia and congenital anterior staphyloma are very rare unilateral conditions that are both characterized by protrusion of the opaque cornea (Fig 9-9) between the eyelids at birth and accompanied by a deep anterior segment. They differ only in the presence of a uveal lining of the cornea in congenital anterior staphyloma. These cases are typically unilateral, and all are sporadic, with no familial or systemic association.
Figure 9-9 Congenital anterior staphyloma in Peters anomaly. (Courtesy of Wallace L. Alward, MD.)
Intrauterine perforation from an infection or from thinning following secondary failure of neural crest cell migration results in dermoid transformation of the cornea to stratified squamous epithelium, sparing the eyelids and conjunctiva. Keratectasia is probably the result not of abnormal development but rather of intrauterine keratitis or vitamin deficiency and subsequent corneal perforation. Histologically, Descemet membrane and endothelium are absent, and a uveal lining is present (except in keratectasia). The cornea is variably thinned and scarred and the anterior segment disorganized, with the lens occasionally adherent to the posterior cornea, resembling unilateral Peters anomaly.
Except in very mild cases, the visual prognosis is poor because of associated severe damage to the anterior segment. Penetrating keratoplasty and sclerokeratoplasty techniques may be useful to preserve the globe and improve cosmesis; however, enucleation may be required for a blind, glaucomatous, painful eye.