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Summary: Congenital primary aphakia (CPA) is rare developmental abnormality presents with an absence of lens, micro cornea, ill-defined limbus, variable corneal thinning, distorted anterior segment architecture and atypical silvery white corneal sheen. Embryonic lens plays a crucial role in the anterior segment development in turn maintaining their structural integrity and normal corneal architecture. The efficacy of corneal transplantation in the setting of a diffusely thinned corneal bed, hypoplastic ciliary body and immature vitreous is abysmally poor. Most patients lose vision owing to irreversible hypotony and consequent retinal detachment. This is a short case report on a child with a CPA, who presented with a secondary glaucoma in both eyes, who underwent glaucoma filtering surgery (GFS) in right eye and trans-scleral cyclophotocoagulation (TSPC) in the left eye, and the successful outcomes of the same. This entity was clinically confirmed by ultrasound imaging and prompt corrective measures were instituted. Introduction:Congenital primary aphakia (CPA; OMIM 610256) is a rare autosomal recessive developmental abnormality of the lens. CPA can have some associated ocular co-morbidities comprising microphthalmia, absence of the iris, anterior segment aplasia, and/or sclerocornea (when the cornea blends with the sclera).

This condition is thought to result from an aberration during the 4th or 5th week of fetal development, which prevents the formation of crystalline lens structure in the eye. This original failure leads, in turn, to complete aplasia of the anterior segment of the eye, which is the diagnostic histological criterion for CPAADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1006/dbio.2000.

9638″, “author” : { “dropping-particle” : “”, “family” : “Beebe”, “given” : “David C”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Coats”, “given” : “J Michael”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2000” }, “page” : “424-431”, “title” : “The Lens Organizes the Anterior Segment : Specification of Neural Crest Cell Differentiation in the Avian Eye”, “type” : “article-journal”, “volume” : “431” }, “uris” : “http://www.mendeley.com/documents/?uuid=69cd78d9-60ac-40c8-88b6-0bc4285fa88a” } , “mendeley” : { “formattedCitation” : “¹”, “plainTextFormattedCitation” : “1”, “previouslyFormattedCitation” : “(1)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.

com/citation-style-language/schema/raw/master/csl-citation.json” }1. Mutations in the FOXE3 gene have been implicated with this condition.ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Valleix, S Niel, F Nedelec, B Algros, MP Schwartz, C Delbosc”, “given” : “B”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Al”, “given” : “Et”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “American Journal of Human Genetics”, “id” : “ITEM-1”, “issued” : { “date-parts” : “2006” }, “page” : “358-64”, “title” : “Homozygous nonsense mutation in the FOXE3 gene as a cause of congenital primary aphakia in humans.”, “type” : “article-journal”, “volume” : “79” }, “uris” : “http://www.mendeley.

com/documents/?uuid=da149f2a-2f97-4388-b5bc-d20060c771a6″ } , “mendeley” : { “formattedCitation” : “²”, “plainTextFormattedCitation” : “2”, “previouslyFormattedCitation” : “(2)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }2In disparity, congenital secondary aphakia (CSA); where in lens induction ensues and the lens vesicle develops to some degree but is progressively reabsorbed perinatally, leading to less severe ocular defects.

Valleix et alADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Valleix, S Niel, F Nedelec, B Algros, MP Schwartz, C Delbosc”, “given” : “B”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Al”, “given” : “Et”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “American Journal of Human Genetics”, “id” : “ITEM-1”, “issued” : { “date-parts” : “2006” }, “page” : “358-64”, “title” : “Homozygous nonsense mutation in the FOXE3 gene as a cause of congenital primary aphakia in humans.”, “type” : “article-journal”, “volume” : “79” }, “uris” : “http://www.mendeley.com/documents/?uuid=da149f2a-2f97-4388-b5bc-d20060c771a6” } , “mendeley” : { “formattedCitation” : “²”, “plainTextFormattedCitation” : “2”, “previouslyFormattedCitation” : “(2)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }2 analyzed a consanguineous family in which 3 siblings had bilateral aphakia, microphthalmia, and complete agenesis of the ocular anterior segment. Two siblings exhibited sclerocornea, and one had megalocornea with secondary glaucoma.Posterior segment involvement is also inevitable in these eyes.

There is presence of hypoplastic ciliary processes and abnormal vitreous as reported Maschot ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Manschot”, “given” : “W A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Archives of Ophthalmology”, “id” : “ITEM-1”, “issue” : “5”, “issued” : { “date-parts” : “1963” }, “page” : “571-577”, “title” : “Congenital Aphakia”, “type” : “article-journal”, “volume” : “69” }, “uris” : “http://www.mendeley.com/documents/?uuid=ae455bf4-d97a-4aa0-92c8-97b17971ad2d” } , “mendeley” : { “formattedCitation” : “³”, “plainTextFormattedCitation” : “3”, “previouslyFormattedCitation” : “(3)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }3. Thus these eyes are prone to develop complications, either spontaneously or following a surgical intervention. Mainstay of management include the prevention of gouging by providing protective polycarbonate goggles, watchful monitoring of visual function, and assessment for complications such as hypotony, retinal detachment and or rarely secondary glaucoma. Herein, we describe a child who presented with a CPA with a secondary developmental glaucoma which was managed appropriately.

Methods: A retrospective chart review was conducted of a child diagnosed with CPA at our institute. The clinical history, systemic and ocular findings were assessed. Case description:A 5-year-old male child was brought to us by his parents with complaints of whitish discoloration of the eye and subnormal vision since birth. This child was a product of an uncomplicated full term cesarean delivery. Family history was negative for known genetic disorders. There was no history of parental consanguinity.On examination in the clinic, visual acuity in both eyes was recorded as fixing and following objects close to face. The corneas were obviously prominent with a significant greyish white corneal discoloration (Fig 1 A-C).

Ocular movements were full. On finger tension test, the intraocular pressure was found to be high. The anterior segment examination under general anesthesia revealed marked corneal opacification, with distorted anterior segment architecture, ill-defined limbus, steeper corneal contour, and both corneas had a typical silvery white sheen. A 3×3 mm of ciliary staphyloma was noted at 2 o’ clock in the right eye.

The sclera was thinned out with underlying uveal show from 11 to 1 o’ clock in the left eye. The tangential illumination reveled absence of lens which was corroborated using ultrasound sound imaging (Fig 1 D-E). The intraocular pressure measured by Perkins tonometer was 22 mm Hg in the right eye and 20 mm Hg in the left eye. Fundus was hazily seen and retina appeared attached though disc details were indiscernible. Corneal pachymetry was 250 and 348 microns in right and left eyes respectively. B scan of both eyes confirmed the absence of crystalline lens and did not show any disc excavation.

Based on the corroborative evidence a diagnosis of bilateral primary congenital aphakia with a secondary developmental glaucoma was made. A trabeculectomy with trabeculotomy was performed in the right eye and a trans-scleral photocoagulation was performed in the left eye owing to the superior scleral show. The post-operative course was uneventful. At post-operative 6 weeks, an examination under anesthesia was repeated. The right eye showed a diffuse bleb. The rest of the findings were as before.

Using Perkin’s tonometer IOP was recorded as 14 and 26 mmHg in right and left eye respectively. In view of the consistently raised IOP in the left eye, Dorzolamide 2% eye drops thrice daily was started.The parents were counseled about the child’s eye condition and encouraged to get the other healthy siblings for a genetic analysis. They were also referred for visual rehabilitation where the vision was assessed and child was able to point out 16M Lea symbols from 30cm distance. Parents were taught visual stimulation exercises to be done at home. In the next follow up, the child was stable with good navigational vision. The elder siblings were also examined and ocular examination was within normal limits.

Re-examination occurred in April 2018. Developmental milestones were normal and child had decent navigational visual functions. Slit lamp examination under general anesthesia showed dense corneal opacification as compared to previous visit. The remainder of the anterior segment and posterior segment was hazily seen. Parents were advised to continue the protective goggles and the importance of the eye protection was re-emphasized. Parents were advised that there is a 1/4th risk of having another affected child and a 2/3rd risk of subsequent children being a carrier for either point mutation or the gene deletion.

DISCUSSION: CPA is rare autosomal recessive condition associated with severe anterior segment dysgenesis. Frequently, absence of lens is overlooked in these cases. Invariably surgical intervention such as full thickening corneal grafting carries abysmal outcomes. Therefore, it is crucial to recognize this distinct clinical entity to undertake the necessary preventive measures to reduce the risk of consequent complications of spontaneous phthisis bulbi and retinal detachment and thus reduce the rate of irreversible morbidity associated with this disease. Features that differentiate CPA from primary congenital glaucoma (PCG) are the presence of discernible and characteristic ocular signs in children with CPA namely the typical silvery white corneal sheen, alongside absence of crystalline lens as revealed on imaging. Development of the lens begins at 4 weeks of gestation after the lens placode forms at surface ectoderm adjacent to the developing optic vesicle.

Sequentially the lens placode invaginates and forms the lens vesicle after separation from the surface ectoderm. The lens vesicle gets surrounded by the optic cup. The space between the lens vesicle and the surface ectoderm is filled with migrating neural crest cells and give rise to structures of the anterior segment namely the corneal endothelium, corneal stroma, iris stroma, trabecular meshwork.ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Beebe, DC, Coats”, “given” : “JM”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Developmental Biology”, “id” : “ITEM-1”, “issued” : { “date-parts” : “2000” }, “page” : “424-31”, “title” : “The lens organizes the anterior segment: specification of neural crest cell differentiation in the avian eye”, “type” : “article-journal”, “volume” : “220” }, “uris” : “http://www.

mendeley.com/documents/?uuid=426aeea4-8703-4a37-a6c5-bd6a787bc676″ } , “mendeley” : { “formattedCitation” : “⁴”, “plainTextFormattedCitation” : “4”, “previouslyFormattedCitation” : “(4)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.

json” }4 Several studies have shown that absence of the lens leads to aplasia of the anterior segment, abnormal ciliary bodyADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “al”, “family” : “Trabucchi, G Piantanida, A Bandello, F Freschi, M Nucci, P Brancato”, “given” : “R et”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Acta Ophthalmologica”, “id” : “ITEM-1”, “issued” : { “date-parts” : “1997” }, “page” : “595-597”, “title” : “Congenital aphakia in Peters u2019 anomaly syndrome”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=1f8bbe13-76a8-4b2f-a3a8-ebc9a4a0a7e9” } , “mendeley” : { “formattedCitation” : “⁵”, “plainTextFormattedCitation” : “5”, “previouslyFormattedCitation” : “(5)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }5. Not only does the developing lens effect anterior segment development, but also differentiation of the optic vesicle into the optic cup, which will give rise to the future posterior segment. Absence of secondary and tertiary vitreous is evident, and choroidal and optic disc coloboma has also been reported in literatureADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Johnson, BL Cheng”, “given” : “KP”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Pediatric Ophthalmology and Strabismus”, “id” : “ITEM-1”, “issued” : { “date-parts” : “1997” }, “page” : “35-39”, “title” : “Congenital aphakia: a clinicopathologic report of three cases”, “type” : “article-journal”, “volume” : “34” }, “uris” : “http://www.mendeley.

com/documents/?uuid=daea7cad-e48e-4dfa-89cd-3c3d6e8643d7″ } , “mendeley” : { “formattedCitation” : “⁶”, “plainTextFormattedCitation” : “6”, “previouslyFormattedCitation” : “(6)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }6. This kind of affection of the anterior segment and posterior segment is seen in CPA. Genetic analysis has revealed that mutations in the fork head transcription factor gene, FOXE3, present on chromosome 1p32, is responsible of the phenotype of congenital primary aphakiaADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Valleix, S Niel, F Nedelec, B Algros, MP Schwartz, C Delbosc”, “given” : “B”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Al”, “given” : “Et”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “American Journal of Human Genetics”, “id” : “ITEM-1”, “issued” : { “date-parts” : “2006” }, “page” : “358-64”, “title” : “Homozygous nonsense mutation in the FOXE3 gene as a cause of congenital primary aphakia in humans.”, “type” : “article-journal”, “volume” : “79” }, “uris” : “http://www.

mendeley.com/documents/?uuid=da149f2a-2f97-4388-b5bc-d20060c771a6″ } , “mendeley” : { “formattedCitation” : “²”, “plainTextFormattedCitation” : “2”, “previouslyFormattedCitation” : “(2)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }2. It is expressed in the developing lens, and its absence results in abnormal development of anterior segment structures. Along with features of anterior segment dysgenesis, it is not uncommon to find raised intra ocular pressures in the affected individualsADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Semina, EV, Brownell, I Mintz-Hittner, HA Murray, JC Jamrich”, “given” : “M”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Human Molecular Genetics”, “id” : “ITEM-1”, “issue” : “3”, “issued” : { “date-parts” : “2001” }, “page” : “231-236”, “title” : “Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts”, “type” : “article-journal”, “volume” : “10” }, “uris” : “http://www.

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json” }7. However, due to the altered anatomy of the cornea, the accuracy of IOP measurement is questionable. The corneal opacity precludes visualization of the posterior segment, though disc excavation can be looked for on B scan as corroborative evidence. Valleix(2) et al have reported 3 siblings with CPA, one of which was developed secondary glaucoma and underwent trabeculectomy.

Apart from this, extensive literature search did not reveal other such case reports.Our case presented with typical ocular findings of CPA, associated with raised IOP and enlarged eyes, suggestive of secondary developmental glaucoma. The child underwent uneventful trabeculectomy with trabeculotomy in the right eye and TSCPC in the left eye. Managing a case of CPA with secondary glaucoma can be very challenging. Firstly, the intraocular pressure measurement may not be accurate owing to the thin, scarred and ectatic cornea. Secondly, performing a successful trabeculotomy technically may be difficult owing to the disorganized anterior segment, unreliable external limbal landmarks, or obscured anatomy of the Schlemm’s canal. Post-operatively the child was doing well with a well-formed bleb and controlled IOP in right eye.

There were no signs suggestive of hypotony. The left eye had persistently raised IOP and thus was started on anti glaucoma medication. In contrast to the published reports, secondary developmental glaucoma can be a rare part of CPA. The management of corneal opacification in setting of CPA is quite challenging. The efficacy of corneal transplantation in the setting of a poorly developed anterior segment is abysmally poor. Our experience has shown that out of the 71 eyes of primary congenital aphakia seen in our institute, 5 had undergone penetrating keratoplasty and eventually had poor anatomical outcomes. The grafts were clear in the immediate post-operative period, however, the eyes subsequently had persistent low IOP despite intense steroids and cycloplegic medication.

Perhaps the ciliary body hypoplasia resulted in low IOP, and eventually phthisis ensued within 3 months in most cases. It was inferred that any penetrating procedures in these eyes would ultimately lead to poor anatomical outcomes ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Muralidhar, Ramappa Sunita, Chaurasia Subhadra”, “given” : “Jalali”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Indian Journal of Ophthalmology2”, “id” : “ITEM-1”, “issue” : “2”, “issued” : { “date-parts” : “2018” }, “page” : “341-342”, “title” : “Keratoplasty in congenital primary aphakia”, “type” : “article-journal”, “volume” : “66” }, “uris” : “http://www.mendeley.

com/documents/?uuid=f5fce400-299d-4fb7-a250-c8d612f33e03″ } , “mendeley” : { “formattedCitation” : “⁸”, “plainTextFormattedCitation” : “8”, “previouslyFormattedCitation” : “(8)” }, “properties” : { “noteIndex” : 0 }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }8.

.In this context, the key challenge in the management of CPA is the prevention of ocular hypotony, which relies on early diagnosis to allow for targeted measures aimed at preventing ocular trauma or inadvertent surgical intervention. Therefore, in context of poor penetrating keratoplasty outcomes, no further intervention was advised for the child, and regular follow up, along with visual rehabilitation was advised.In conclusion: We believe it possible that CPA remains an under-diagnosed rare genetic condition of the anterior segment.

Timely recognition of the secondary developmental glaucoma is crucial in minimizing the sight threatening sequelae. A multidisciplinary approach is necessary, with prompt IOP control, visual stimulation, avoiding eye poking, and close monitoring to pick up post-operative complications. Definitive molecular diagnosis allows for appropriate preventive management strategy including advice and aids to preclude future ocular complications.BIBLIOGRAPHY ADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Beebe DC, Coats JM. The Lens Organizes the Anterior Segment?: Specification of Neural Crest Cell Differentiation in the Avian Eye. 2000;431:424-431.

doi:10.1006/dbio.2000.9638.2. Valleix, S Niel, F Nedelec, B Algros, MP Schwartz, C Delbosc B, Al E.

Homozygous nonsense mutation in the FOXE3 gene as a cause of congenital primary aphakia in humans. Am J Hum Genet. 2006;79:358-364.3. Manschot WA. Congenital Aphakia.

Arch Ophthalmol. 1963;69(5):571-577.4. Beebe, DC, Coats J. The lens organizes the anterior segment: specification of neural crest cell differentiation in the avian eye. Dev Biol. 2000;220:424-431.

5. Trabucchi, G Piantanida, A Bandello, F Freschi, M Nucci, P Brancato R et al. Congenital aphakia in Peters ‘ anomaly syndrome. Acta Ophthalmol. 1997:595-597.6. Johnson, BL Cheng K. Congenital aphakia: a clinicopathologic report of three cases.

J Pediatr Ophthalmol Strabismus. 1997;34:35-39.7.

Semina, EV, Brownell, I Mintz-Hittner, HA Murray, JC Jamrich M. Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. Hum Mol Genet. 2001;10(3):231-236.8. Muralidhar, Ramappa Sunita, Chaurasia Subhadra J.

Keratoplasty in congenital primary aphakia. Indian J Ophthalmol. 2018;66(2):341-342.

Legends:Fig 1. Digital images depicting phenotype and B scan. A: Frontal view of face showing bilateral corneal opacification. B-C: Grayish white corneal discoloration with classic silvery white corneal sheen. D-E: B Scan images showing absent lens echo (star) and normal posterior segment and optic nerve shadow in both eyes. Inset showing A scan with absent lens spike.