The right corneal graft had significant corneal edema since the first postoperative day. Topical corticosteroid (Maxidex, Alcon, Puurs, Belgium) was commenced every hour. The graft never became clear after 4 weeks. After surgery, graft edema persisted, and a second penetrating keratoplasty for primary graft failure was performed in July 1997, when the child was 7 months old. The quality of the second cornea was good. Horizontal corneal diameter in the right eye was 12 mm, and intraocular pressure was 20 mm Hg. Examination of the left eye showed features similar to those noted in May 1997. During surgery, inflammatory fibrin membranes on the intraocular lens, segmental iris bombé, exposed iris vessels, and peripheral anterior synechiae were noted in the right eye. The pupillary membranes were excised and peripheral anterior synechiae were released. An 8 × 7 mm penetrating keratoplasty was performed. Histopathologic examination of the excised graft showed features consistent with a failed graft. Immediately after surgery, a persistent epithelial defect developed in the corneal graft and led to graft failure and ectasia.
When the child was 1 year old, in January 1998, examination under anesthesia showed a horizontal corneal diameter of 14 mm in the right eye. A recurrence of the fleshy, vascularized corneal mass was noted. The anterior chamber was shallow and the intraocular lens was in contact with the corneal endothelium. Removal of the corneal mass, 7 × 6.5 mm penetrating keratoplasty, intraocular lens removal, and glaucoma implant surgery with an Ahmed valve were performed. Histopathologic examination of the excised corneal lesion showed benign stratified squamous epithelium with hyperkeratosis. Fibrosis and interstitial hemorrhage were noted in the stroma. There was no evidence of dysplastic changes. The corneal button showed stromal fibrosis with detachment of basement membrane, and adhesion of iris tissue to the cornea. In March 1998, the child was 14 months old. The IOP was 28 mm Hg, and multiple punctures were performed in the fibrous capsule surrounding the glaucoma implant, with subconjunctival injection of mitomycin-C (0.02% × 0.01 mL). Lateral tarsorrhaphy was also performed for a persisting epithelial defect. In March 1999, when the child was 2 years and 2 months old, the mass lesion had recurred in the right eye. The mass in the left eye had regressed spontaneously. However, the left cornea was hazy. In April 1999, at the age of 2 years and 3 months, limbal stem cell transplantation and penetrating keratoplasty were performed in the left eye, in another center. Postoperative trauma by the child's finger resulted in wound dehiscence, necessitating resuturing of the graft–host junction. Final examination in August 1999 at the age of 2 years and 7 months old showed a large, brown mass protruding from the right cornea and preventing closure of the eyelids (Fig. 6). The left eye showed a failed graft.
PAX6 gene mutation analysis using a standardized method, same as that in our previous publication, 11 was also performed for the patient.
The pathogenesis of corneal keloids remains obscure. Earlier theories suggested that they originated from the stromal cells of the iris or from proliferating fibrovascular tissue during the healing stage of corneal perforation. 4 Because corneal perforation is unlikely in congenital corneal keloids, failure of normal differentiation of corneal tissue during embryogenesis, rather than an abnormal reparative process, has been proposed as the mechanism in a recent report. 7
The clinical appearance of a protuberant, firm, white or brownish, vascularized corneal mass in an infant suggests a differential diagnosis of a keloid or corneal dermoid. A corneal dermoid is a choristoma composed of displaced epithelial and dermislike elements interspersed with hair follicles and sebaceous glands. 12 None of the above features were present in our patient. Histopathologic examination of the excised corneal mass in the right eye did not show the characteristic features of juvenile xanthogranuloma 13 or fibrous histiocytoma 14 of the cornea. Although the lesion recurred after multiple excisions, neither the clinical appearance nor the histopathologic features suggested a malignant lesion.
The histopathologic features described in our patient—thickened, keratinized epithelium, absence of Bowman's layer, fibrovascular hyperplasia, and absence of displaced dermal elements—have been considered pathognomonic of a corneal keloid. 1–7 The tendency of a corneal keloid to recur and grow larger after each excision has also been described. 15
Management of the lesion by multiple penetrating keratoplasties in the right eye proved unsatisfactory. Repeated epithelial breakdown leading to graft failure suggested a possible limbal stem cell deficiency. This is possible considering the extensive anterior segment malformations seen in our patient. Although he underwent limbal stem cell transplantation in the left eye at the time of penetrating keratoplasty, ocular trauma in the postoperative period resulted in graft failure and did not allow evaluation of the efficacy of this approach. An earlier report 16 2 described encouraging results with sclerokeratoplasty in tectonic reconstruction of such eyes, although the visual prognosis remains guarded because of associated ocular abnormalities and amblyopia. Failure of the keloid to recur after this surgical approach may be the result of complete excision of the lesion. In contrast, penetrating keratoplasty in the initial few months after birth may result in a recurrence of the keloid, as seen in the right eye of our patient. It is interesting that the keloid in the left eye, which did not undergo surgery, regressed spontaneously.
An increased frequency of ocular complications in RTS has led authorities to recommend routine ophthalmologic examination in all patients with RTS. 17 A recent comprehensive review of clinical findings in 614 patients with RTS showed the presence of glaucoma in 32 cases and corneal opacities in 25 cases. 10 The authors concluded that the incidence of glaucoma in RTS exceeds that of the general population and is often congenital or develops in infancy. However, they did not report the occurrence of ASMD in these patients. In this and other reports of congenital 18 and juvenile glaucoma 13,19 in RTS, authors describe a well-formed anterior chamber with a high, flat iris insertion. Features of ASMD were noted in both eyes of our patient on ultrasound biomicroscopic examination. These findings were confirmed by intraoperative visualization of the iris, lens, and corneal relationships during penetrating keratoplasty in the right eye. The role of ultrasound biomicroscopy in characterizing anterior segment changes in patients with dense corneal opacities has been described. 14 ASMD is thought to result from faulty migration of neural crest cells during embryogenesis. 20 Although a number of distinct entities, Axenfeld, Peter, and Reiger anomalies, have been described in ASMD, there is often considerable overlap in the clinical features. 21 The findings in our patient suggested a diagnosis of Peter anomaly in both eyes.
There have been three reports of patients with ASMD who were reported to have small deletions in the short arm of chromosome 11. 22–24PAX6 mutation analysis, however, was performed in only one study. 23 The PAX genes are thought to function as major controllers in development by switching on and off expression of other genes. Nine PAX genes have been identified in humans, and PAX6 is thought to be located on the short arm of chromosome 11. 21 Other evidence from studies in mice also suggests that Peter anomaly, and possibly Reiger anomaly, may result from loss of function of PAX6. 23 Thus, although the genetics of ASMD are still being worked out, existing evidence suggests a role for PAX6 in the cause of this disorder. 21 We looked for, but did not detect, PAX6 mutation in our patient. Genetic changes in RTS have been localized to the short arm of chromosome 16. 25,26 We are unable to offer a satisfactory explanation for the co-occurrence of these lesions with RTS.
In conclusion, we report hitherto undescribed anterior segment changes in RTS. The clinical course in our patient confirms earlier reports 6 that children with RTS undergo hospitalization and surgery 10 times more often than other children. Our experience also indicates that subtotal excision of a corneal keloid, especially in infants, can result in aggressive recurrence of the corneal lesion.
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Keywords:© 2002 Lippincott Williams & Wilkins, Inc.
Anterior segment mesenchymal dysgenesis; Corneal keloid; Rubinstein-Taybi syndrome; Ultrasound biomicroscopy