Forme fruste anterior segmentdysgenesis

A 38-year-old woman with a history of poor vision in her lefteye was referred for evaluation of closed-angle glaucoma.Best corrected visual acuity was 20/25 in the right eye witha manifest refraction of �2.00+2.503180 and 20/400 in the left

eye with +1.00+0.753090. The anterior chamber was deepcentrally with clear lenses bilaterally. The intraocular pressurewas 15 mmHg in both eyes.Slit lamp examination revealed prominent posterior embryo-

toxon in both eyes and a central disc-shaped posterior cornealstromal haze more prominent in the left eye than in theright eye (figure 1AeF). Gonioscopy demonstrated posteriorembryotoxon bilaterally and anomalous appearing open angleswith fine areas of peripheral anterior synechiae (figure 1G,H) and

Figure 1 Photograph of the right eye demonstrating mild central corneal opacity (white arrow) and posterior embryotoxon (black arrows) of the right(A) and left (B) eyes. Slit lamp photograph demonstrating deep central corneal opacity in the right (C) and left (D) eyes and by retroillumination of theright (E) and left (F) eyes. Gonioscopy photographs of the peripheral iris processes to Schwalbe’s line in the right (G) and left (H) eyes.

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high iris processes in both eyes. The posterior segment exami-nation was unremarkable with a normal-appearing 0.3 verticalcup to disc ratio bilaterally. Central corneal thickness was626 mm and 601 mm in the right and left eyes, respectively.

Both eyes of the patient were assessed using in vivo confocalmicroscopy (Nidek, Inc., Fremont, California, USA). In vivoscanning laser confocal microscopy is an imaging modality thatvisualises thin serial sections of the cornea without disruptingthe living tissue often referred to as optical sectioning. Theobjective of the microscope is an immersion lens with 603magnification, and coupling gel was used on the cornea forcontact with the microscope objective.

QUESTIONS1. What is the differential diagnosis of the patient?2. Describe the confocal corneal findings.3. What insight can be learned regarding anterior segment

dysgenesis?

See page 1763 for answers

M R Banitt,1 A Romano,1,2 S Iragavarapu,1 D L Budenz,1 R K Lee1

1Bascom Palmer Eye Institute, University of Miami Miller School of Medicine,Miami, Florida, USA; 2Vision Institute, Federal University of Sao Paulo, Sao Paulo,Brazil

Correspondence to RK Lee, Bascom Palmer Eye Institute, University of Miami MillerSchool of Medicine, 900 NW 17th Street, Miami, FL 33136, USA;rlee@med.miami.edu

Funding NIH grant EY016775, Research to Prevent Blindness, and the NIH Core Grantto the University of Miami. The authors have no proprietary or financial interest in anyof the work discussed in this manuscript. RK Lee is supported by NIH grant EY016775.The Bascom Palmer Eye Institute is supported by an unrestricted grant from theResearch to Prevent Blindness (New York, New York) and the NIH Center grantP30-EY014801.

Competing interests None.

Patient consent Obtained.

Provenance and peer review Not commissioned; externally peer reviewed.

Published Online First 30 August 2010

Br J Ophthalmol 2011;95:1756e1757. doi:10.1136/bjo.2009.177535

Br J Ophthalmol December 2011 Vol 95 No 12 1757

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ANSWERSFrom questions on page 1756

1. Axenfeld anomaly, posterior keratoconus, Peters’ anomaly,posterior polymorphousdystrophy, anterior segmentdysgenesis.Other considerations were macular dystrophy, granulardystrophy, congenital hereditary endothelial dystrophy,congenital stromal corneal dystrophy, infections, andiridocorneal endothelial syndrome.

Posterior polymorphous dystrophy is typically bilateralwith lesions affecting the endothelium and posterior corneaappearing as vesicles. The endothelium can have a glassymembrane appearance that covers the entire corneal surfaceand even extend to cover the surface of the iris, leading to irisatrophy and corectopia with resulting glaucoma and cornealoedema. Our patient had large bilateral posterior cornealopacities but appeared to be limited to the central cornea anddid not have a multiple vesicular appearance. Maculardystrophy affects the mid- to anterior stroma and extends tothe periphery. Granular dystrophy also affects the mid- to

anterior stromawith clear areas in between the opacified areas.Congenital hereditary endothelial dystrophy is bilateral buttypically has an onset at birth or in the first years of life and hascorneal oedema affecting the entire cornea without opacity.Congenital stromal corneal dystrophy affects the entire corneaand does not fit this patient’s corneal appearance. Infections(either congenital infection or herpetic endothelitis) were alsoconsidered, but this is less likely as the patient had bilateral andsymmetric opacification. Chandler ’s syndrome (iridocornealendothelial syndrome) was also considered but no cornealoedema was present and the patient had a bilateral diseaseprocess. Corneal opacity from Chandler ’s syndrome is usuallysecondary to oedema with a mild diffuse endothelial opacitycovering the entire cornea (not isolated to the central cornea)and typically is not bilateral.

2. Central epithelial cells have nuclei brighter than thesurrounding cytoplasm and a perinuclear hyporeflectivedark ring, indicating a loss of contact inhibition anddesquamation (figure 2A,B). The corneal basal layer appearednormal. However, the corneal nerves in this region appeared

Figure 2 In vivo confocal microscopy (Nidek, Inc., Fremont, California, USA, 603 magnification) of the epithelial cells of the right (A) and left (B)eyes demonstrating brighter nuclei than the surrounding cytoplasm with a perinuclear hyporeflective dark ring; normal basal layer with distorted andirregular branching nerves highlighted with red circle (C); indistinguishable keratocytes with abnormal morphology are seen in the left eye (D);endothelial layer with cell density approximately 1000 cells/mm2 with associated polymegathism and pleomorphism (E); diffuse hyperreflective areanear Descemet’s membrane prevented clear visualisation of the endothelial layer in the left eye (F).

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distorted and irregular with significant branching (figure 2C).The posterior corneal stroma of the right eye and the anteriorto middle corneal stroma of the left eye demonstratedindistinguishable keratocytes with an abnormal morphology(figure 2D). In the right eye, the endothelial cell layerexhibited polymegathism and pleomorphism with a markedlydecreased cell density of approximately 1000 cells/mm2

(figure 2E). In the left eye, a diffuse hyperreflective areanear Descemet’s membrane prevented clear visualisation ofthe endothelial layer (figure 2F), which was consistent withthe hazy slit lamp view of the central circular opacity in theposterior cornea (figure 1AeF).

3. Our patient has clear evidence of Axenfeld anomaly with thefine iris processes and a prominent Schwalbe’s line. Inaddition, the presence of bilateral, posterior, central, disc-shaped, corneal opacities with reduced endothelial celldensity is suggestive of Peters’ anomaly except for theabsence of iris adhesions to the cornea. Overlap existsbetween Axenfeld anomaly, Peters’ anomaly, as well ascongenital glaucoma and aniridia with defects in theCYP1B1, LTBP2, PAX6, PITX2, PITX3, FOXC1, and FOXE3genes. The overlap in genetic defects between these oculardisease entities led us to identify our patient as a case offorme fruste anterior segment dysgenesis, which we assertillustrates the importance of considering the diseases ofanterior segment dysgenesis as a spectrum of findings andconditions and not as distinct ocular entities.

DISCUSSIONPeters’ anomaly is typified by a central posterior corneal defectwith an overlying opacity and a variable degree of synechiaeextending from the iris collarette to the edge of the defect.Peripheral areas of clear cornea are typically observed. The lensmay be adherent to the posterior corneal defect. A diagnosis ofAxenfeldeRieger syndrome is made by the presence of posteriorembryotoxon and iridocorneal angle and iris abnormalities.

At the time these ocular entities were described by Peters andAxenfeld, the embryologic origin of the affected tissues was notknown.1 2 However, Johnston’s avian experiments revealed thatthe corneal endothelium, stroma, and trabecular meshwork areall derived from migrating neural crest cells and referred to asanterior segment dysgenesis.3

The genetic inheritance of Peters’ anomaly is usually sporadic,but several genetic mutations have been reported in literature.These genes include CYP1B1, LTBP2, PAX6, PITX2, PITX3,FOXC1, and FOXE3.4e7 Interestingly, two of the genes linked toAxenfeldeRieger anomaly, the PITX2 and FOXC1 genes, havealso been linked to Peters’ anomaly.6 8e12 Both conditions shareiris abnormalities and glaucoma. Congenital glaucoma has beenmapped to the genetic mutation CYP1B1, which has also beenreported in Peters’ anomaly.7 13 Mutations in PAX6 have beenlinked to aniridia and several cases of Peters’ anomaly.5 10 Takencollectively, the disorders of anterior segment dysgenesis appearto share genetic abnormalities.

We believe the clinical findings of this patient offer insightinto developmental aspects of these diseases. We postulate thatthe marked reduction in central endothelial cell density is froma congenital lack of cells as is observed in cases of Peters’

anomaly. Without attached iris collarettes to act as a barrier tomigration, a redistribution of cells from the periphery may haveoccurred. This may explain why our patient’s corneal opacitywas mild and isolated to the central posterior stroma, instead ofthe opacity typically seen in Peters’ anomaly. Additionally, ourpatient had normal intraocular pressures, again pointingtowards a forme fruste version of anterior segment dysgenesis.Confocal microscopy is not possible in most cases of Peters’

anomaly due to the severe nature of the corneal opacities.However, in our case, we were able to image the cornea from theepithelium to the endothelium characterising corneal features ofanterior segment dysgenesis. The unique abnormalities of thecorneal epithelial cells may be the result of abnormal stromal-epithelial interactions.14 The diffuse hyperreflective area nearDescemet’s membrane clearly correlates with the posteriorcorneal opacity. Taken together with the endothelial cellabnormalities and morphologically abnormal keratocytes, thesesymmetric corneal findings suggest an early disturbance in thedevelopment of the anterior segment.We believe this to be a forme fruste case of anterior segment

dysgenesis with mild posterior disc-shaped central corneal opac-ities, reduced endothelial cell density, and fine iris processesconnecting to a prominent Schwalbe’s line. We feel this case to beunique in reporting findings from corneal confocal microscopythat characterise the corneal changes associated with a mildanterior segment dysgenesis similar to Peters’ anomaly. Finally,we assert that this case illustrates the importance of consideringthe diseases of anterior segment dysgenesis as a spectrum offindings and conditions and not as distinct entities.

Br J Ophthalmol 2011;95:1763e1764. doi:10.1136/bjo.2009.177535

REFERENCES1. Axenfeld T. Embryotoxon cornea posterius. Berichte der Deutschen

ophthalmologischen Gesellschaft 1920;42:301.2. Peters A. Uber angeborene defektbildung der descemet’schen membran. Klinische

Monatsblatter fur Augenheilkunde 1906;44:27e40, 105e119.3. Johnston MC, Noden DM, Hazelton RD, et al. Origins of avian ocular and periocular

tissues. Exp Eye Res 1979;29:27e43.4. Doward W, Perveen R, Lloyd IC, et al. A mutation in the RIEG1 gene associated with

Peters’ anomaly. J Med Genet 1999;36:152e5.5. Hanson IM, Fletcher JM, Jordan T, et al. Mutations at the PAX6 locus are found in

heterogeneous anterior segment malformations including Peters’ anomaly. Nat Genet1994;6:168e73.

6. Honkanen RA, Nishimura DY, Swiderski RE, et al. A family with AxenfeldeRiegersyndrome and Peters anomaly caused by a point mutation (Phe112Ser) in the FOXC1gene. Am J Ophthalmol 2003;135:368e75.

7. Vincent A, Billingsley G, Priston M, et al. Phenotypic heterogeneity of CYP1B1:mutations in a patient with Peters’ anomaly. J Med Genet 2001;38:324e6.

8. Bateman JB, Maumenee IH, Sparkes RS. Peters’ anomaly associated with partialdeletion of the long arm of chromosome 11. Am J Ophthalmol 1984;97:11e15.

9. Chavarria-Soley G, Michels-Rautenstrauss K, Caliebe A, et al. Novel CYP1B1 andknown PAX6 mutations in anterior segment dysgenesis (ASD). J Glaucoma2006;15:499e504.

10. Ciralsky J, Colby K. Congenital corneal opacities: a review with a focus on genetics.Semin Ophthalmol 2007;22:241e6.

11. Murray JC, Bennett SR, Kwitek AE, et al. Linkage of Rieger syndrome to the regionof the epidermal growth factor gene on chromosome 4. Nat Genet 1992;2:46e9.

12. Semina EV, Reiter R, Leysens NJ, et al. Cloning and characterization of a novelbicoid-related homeobox transcription factor gene, RIEG, involved in Riegersyndrome. Nat Genet 1996;14:392e9.

13. Churchill AJ, Yeung A. A compound heterozygous change found in Peters’ anomaly.Mol Vis 2005;11:66e70.

14. Wilson SE, Liu JJ, Mohan RR. Stromaleepithelial interactions in the cornea. ProgRetin Eye Res 1999;18:293e309.

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doi: 10.1136/bjo.2009.17753530, 2010

2011 95: 1756-1757 originally published online AugustBr J Ophthalmol M R Banitt, A Romano, S Iragavarapu, et al. Forme fruste anterior segment dysgenesis

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