Dr. Kanwal Nischal, better known as Ken Nischal is the Division Chief, Pediatric Ophthalmology, Strabismus, and Adult Motility Professor of Ophthalmology at the University of Pittsburgh, School of Medicine. He is also the Vice Chair, Department of Ophthalmology in addition to being the Associate Director of International Business – Ophthalmology & the Director of the Pediatric Program Development at the UPMC Eye Center.

Dr. Nischal attended King’s College Hospital Medical School, University of London and completed his Ophthalmology residency at the Oxford Eye Hospital in the United Kingdom. He completed his fellowship at The Hospital for Sick Children in Toronto, and prior to joining Children’s in 2011, he was at Great Ormond Street Hospital for Children, London in the United Kingdom.

Dr. Nischal is a pioneer in Pediatric Anterior Segment disease and surgery. He has described innovative surgical techniques, disease classification and management algorithms. He is evidence based and protocol driven in terms of clinical practice, and uses clinical audit to define management outcomes.

1) Which of these genes do you expect to be mutated in this case?
a) PAX6, PITX2, CYP1B1, FOXC1 The term Peters anomaly was coined by Peters in the late 1800’s and he described central congenital corneal opacity due to either iridocorneal adhesions or keratolenticular adhesion. This case shows neither. The term Peters anomaly is a SIGN and not as diagnosis; looking for genetic causes of a sign is not logical. In order to decide what genetic testing should be done, the accompanying ocular and systemic features should be looked for. E.g. if the child has maxillary hypoplasia and an umbilical hernia, then I would expect FOXC1 or PITX2 (if the child is small for age and has the above two features then PITX2 is more likely and an MRI of the pituitary should be done. If the child had aniridia (she does not) then I would look for PAX6 but before then I would do a renal USS to ensure no kidney masses. There is a condition called CYP1B1 cytopathy where the child gets congenital glaucoma and corneal opacity BUT the UBM does not look like this. The lens in options b and c are most commonly associated with corneal dystrophies and this is not a dystrophy. Note: it is ALWAYS important in children like this to get a cardiac and renal evaluation. 1.

2) Which of these would you consider as differential diagnosis in this case?
NONE OF THESE. Sclerocornea is a non-entity and only means total corneal opacification which this child does not have (see: Nischal KK, Naor J, Jay V, MacKeen LD, Rootman DS. Clinicopathological correlation of congenital corneal opacification using ultrasound biomicroscopy. Br J Ophthalmol. 2002 Jan;86(1):62-9.). Endothelial dystrophies that present at birth are CHED, PPMD and XL-ECD. NONE of them look like this (see: Weiss JS, Møller HU, Aldave AJ, Seitz B, Bredrup C, Kivelä T, Munier FL, Rapuano CJ, Nischal KK, Kim EK, Sutphin J, Busin M, Labbé A, Kenyon KR, Kinoshita S, Lisch W. IC3D classification of corneal dystrophies-edition 2. Cornea. 2015 Feb;34(2):117-59.) This is NOT a dermoid and rubella keratopathy never looks like this.

3) Would you recommend surgery for visual rehabilitation (cornea/lens) now, age 7 months?
This would depend entirely on a number of factors, especially the results of visual electrophysiology which will give a measure of the child’s visual potential – see below. However, if VEP is not available based on the clinical description we would recommend bilateral PKP but not at the same sitting.

4) Would you proceed in a different way in this case?
Yes. While Peters anomaly is a popular terminology many papers and studies have shown it to be used too erroneously. Describing a developmental corneal opacity as being “Peters’ anomaly” is akin to diagnosing someone with a respiratory problem as having a cough. It is a sign and not a diagnosis (see: Nischal KK. A new approach to the classification of neonatal corneal opacities. Curr Opin Ophthalmol. 2012 Sep;23(5):344-54.) The intraocular pressure is reported as elevated at 31-35mmHg, however the method of measurement is critical in these cases. Rebound tonometry over an area of corneal opacity or thickening will be falsely elevated. How was the IOP measured? Was the child awake or under anesthesia? Are there any other signs to support a diagnosis of glaucoma? An axial length of 17mm is normal at 7 weeks of age, so there is no axial elongation. What is the horizontal corneal diameter? What is the pachymetry? Are there other clinical signs to suggest iridotrabecular dysgenesis? Was medical therapy trialled to control the IOP prior to trabeculectomy? Was cyclodiode laser considered? On the other hand, at 6 months of age, an axial length of 21mm and 22mm, growing from 17mm at birth, suggests uncontrolled glaucoma despite a measured IOP of 17mmHg (again, how this was measured is important). Is there any view of the optic disc?

5) Would you consider Cyclo-G-6 to control IOP in this patient?
Yes. Cyclodiode laser is an excellent method of controlling raised IOP in infants, it provides temporary control and can be repeated multiple times. It should be performed under UBM guidance to definitively identify the location of the ciliary body, which may be challenging in cases of anterior segment dysgenesis using transillumination alone. (see: Way AL, Nischal KK. High-frequency ultrasound-guided transscleral diode laser cyclophotocoagulation. Br J Ophthalmol. 2014 Jul;98(7):992-4.)

6) UBM findings
The UBM shows that the lens is formed and there is no keratolenticular or iridocorneal attachment, suggesting that the congenital corneal opacity is primary and not secondary. It is not possible to comment on corneal thickening without pachymetry measurement or calipers on the image. It appears that the cornea is in fact thin centrally in the area of the opacity, and the peripheral cornea (which is clinically clear) may be of normal thickness.
The anterior lens reflectivity may be normal for age and not necessarily indicate the presence of cataract.

7) What would you do with the corneal opacity?
a) Corneal graft (PK) at this age; Possibly, depending on visual potential. Visual electrophysiology would help to guide further visual rehabilitation. If there is severe macular pathway dysfunction on the VEP, further surgery would be unlikely to improve visual function. b) Rotational autokeratoplasty. No – the corneal opacities are large and in the central cornea, therefore rotational keratoplasty is not a feasible option. Furthermore, the anterior chamber is shallow, so one would want to oversize a donor graft by 1mm to ‘create space’ in the anterior chamber. c) Limbal stem cell transplantation. No – the child does not have limbal stem cell failure. Furthermore, our group has specifically studied this and we found that almost all children with the phenotype shown in this case had limbal stem cell function (see: Nischal KK, Lathrop KL. The Palisades of Vogt in Congenital Corneal Opacification (An American Ophthalmological Society Thesis). Trans Am Ophthalmol Soc. 2016 Aug;114:T8.) d) Wait (In this case, until when?) No – if surgical intervention were to be considered, it would have to be now. The child is now 7 months old and has a large exotropia with nystagmus, therefore the visual outcome is likely to be poor in any case. e) Other: Consider a large surgical iridectomy in one or both eyes.