Absent Red Reflexes and Cloudy Corneas.

Abstract

A 2.56-kg female infant is born via spontaneous vaginal delivery to a 27-year-old gravida 5, para 3 woman at 38 6/7 weeks’ gestation. The pregnancy is complicated by maternal type 2 diabetes, chronic hypertension, and fetal intrauterine growth restriction. Maternal blood type is A positive, with a negative antibody screen. Other prenatal laboratory results were as follows: rapid plasma reagin—nonreactive, rubella—immune, HIV—negative, gonorrhea—negative, Chlamydia—negative, and hepatitis B surface antigen—negative. Culture for group B Streptococcus is positive and adequate intrapartum antibiotic prophylaxis is provided. The membranes are ruptured at the time of delivery, and the infant appears well, requiring no intervention. Apgar scores are 8 and 9 at 1 and 5 minutes, respectively. Physical examination in the nursery reveals bilateral gray and opaque corneas (Figs 1 and 2). The red reflexes are not seen. The remainder of the physical examination findings are normal. The mother states that a 2-year-old sibling required eye surgery and is visually impaired. Echocardiography and renal ultrasonography findings are normal. Further examination and genetic testing reveal the diagnosis.The differential diagnosis includes birth trauma, infectious or inflammatory processes (eg, rubella keratitis), primary congenital glaucoma, Axenfeld-Rieger syndrome, congenital hereditary endothelial dystrophy, Peters anomaly, aniridia, sclerocornea, mucopolysaccharidoses, and chromosomal anomalies.Ophthalmology consultation confirms the diagnosis of glaucoma with bilateral anterior segment dysgenesis and bilateral staphylomas (thinning of the anterior sclera). The patient is started on carbonic anhydrase inhibitors (including oral acetazolamide and dorzolamide ophthalmic drops), a prostaglandin analogue (latanoprost), and a β-blocker (timolol), to reduce intraocular pressure preoperatively. Optical coherence tomography (OCT) shows marked central corneal edema, central leukoma (corneal opacity), anterior staphyloma, and anterior synechiae between the iris and cornea (Fig 3). B-scan ultrasonography demonstrates that the abnormalities are limited to the iridocorneal structures and do not extend to the lens or posterior segment of either eye.Intraoperatively, the infant is confirmed to have elevated intraocular pressures bilaterally. Full-thickness penetrating keratoplasty with overlying amniotic membrane transplantation is performed in the right eye. An external trabeculotomy procedure is performed for elevated intraocular pressure. The infant tolerates the surgery well and is discharged from the hospital 4 days later.Microscopic examination of the surgically removed corneal tissue shows dense fibroblastic proliferation partially covered by conjunctival-type epithelium with partial detachment of the epithelium from a very densely hyalinized Bowman membrane (Fig 4). The underlying stroma is thickened and contains prominent fibroblastic proliferation, hyaline fibrosis, and diffuse edema with a mild chronic inflammatory cellular infiltrate consisting of histiocytes and rare lymphocytes. The stroma has a loose myxoid appearance with disorganized cellular orientation with absence of corneal endothelium and Descemet layer.The infant’s newborn screening results are within normal limits. Genetic testing reveals the patient to be heterozygous for 2 pathogenic variants in the CYP1B1 gene (c.1200-1209dup, p.Thr404Serfs*30 and c.868del, p.Arg290Alafs*3), both resulting in frameshift changes and subsequent premature protein termination. The CYP1B1 gene is involved in the production of the largest known enzyme of the human P450 pathway and is expressed in the trabecular meshwork, iris, retina, and ciliary body. This biallelic mutation has been reported in patients with congenital glaucoma and Peters anomaly. (1)Congenital corneal opacities occur in 2 to 3 per 100,000 newborns each year and are associated with early visual deprivation, amblyopia, and vision loss. (2) The pathogenesis of corneal opacities can be infectious (rubella keratitis), metabolic (mucopolysaccharidoses), traumatic, genetic, developmental, glaucomatous, or multifactorial. (3) Congenital glaucoma develops from an increase in intraocular pressure because of a developmental defect affecting the outflow of aqueous fluid. Malformations affecting either the outflow mechanisms or the trabecular meshwork prevent the egress of aqueous humor from the anterior chamber, leading to increased pressure, bulging and thickening of the cornea, and increased corneal opacity. Congenital glaucoma may be the result of abnormal differentiation of embryonic neural crest cells, resulting in altered development of the cornea, iris, and trabecular meshwork. This is referred to as anterior segment dysgenesis. Pathogenic variants have been identified in patients with various forms of anterior segment dysgenesis involving abnormal transcription factors expressed during neural crest cell migration (CYP1B1, PAX6, PITX2, FOXC1, FOXE3, PITX3), abnormal structural components called crystallins (CRYAA, CRYAB, CRYBA1, CRYBB1, CRYBB2, CRYBB3, CRYBB4, CRYGS, CRYGC, CRYGD) and lens-specific connexins (GJA3, GJA8), membrane proteins (aquaporin-0, AGP0, MIP), and cytoskeletal structural proteins (FYCO1, GCNT2, HSF4, LIM2, SIL1, FOXC1). (1) Phenotypic expressions of these genetic variants include aniridia, congenital cataracts, microcornea, Axenfeld-Rieger syndrome, and Peters anomaly. Axenfeld-Rieger syndrome (MIM 180500, 602482) is an autosomal dominant disorder (PITX2, FOXC1 pathogenic variants) manifesting as slit or duplicated pupils, atrophy of the iris, posterior embryotoxon (a distinct posterior corneal arcuate ring), microdontia, abnormal facial structure, cardiac defects, and umbilical abnormalities.Peters anomaly includes defects in Descemet membrane (the thick elastic basement membrane of the inner cornea) and the corneal epithelium, both of which are involved in pumping fluid out of the corneal substantia propria into the anterior chamber. A functional endothelium is necessary for maintaining corneal clarity. In the case of Peters anomaly, a shallow anterior chamber, iridocorneal synechiae (adhesions), and corneal leukoma (opacity) may develop. Peters anomaly is associated with homeobox gene mutations FOXC1, PAX6, PITX2, CYP1B1, the last of which is found in this infant. OCT can be helpful in assessing corneal thickness and diagnosing iridocorneal synechiae. In addition to the aforementioned features, Peters-plus syndrome (MIM 261540) includes short stature, cleft lip with or without cleft palate, distinctive facial features (prominent forehead, small ears, elongated philtrum), rhizomelia, brachydactyly, cardiac defects, hearing loss, kidney abnormalities, genital abnormalities, and intellectual disability.