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Genetics of congenital corneal opacification affect diagnosis and treatment

A novel classification helps not only with genotyping but also with decision making for surgical intervention and management.

Traditionally, the causes of congenital corneal opacities have been recalled using the pneumonic “STUMPED,” but as our understanding of phenotype has improved with better anterior segment imaging, it has become increasingly clear that the early genotype-phenotype correlations were largely misled by inaccurate phenotyping.

Recently, a novel classification for neonatal corneal opacification was published from our group (Table). Using this, corneal opacification can be considered to be primary or secondary. Secondary corneal disease may be developmental or acquired.

Ken K. Nischal

Genetic analysis using this phenotypic classification becomes easier to navigate.

Primary corneal disease

Primary corneal disease includes congenital hereditary endothelial dystrophy (CHED), posterior polymorphous corneal dystrophy (PPCD), X-linked endothelial corneal dystrophy, corneal dermoids, cornea plana and CYP1B1 cytopathy. Genotyping for all of these conditions is reasonably advanced. CHED is caused by mutations in SLC4A11 and is associated with hearing loss. (CHED 1 is no longer considered a separate entity, and all cases of CHED 1 are now thought to have been cases of PPCD.) PPCD is caused by mutations in ZEB1, VISX1 and COL8A1.

CYP1B1 cytopathy is a condition in which there is glaucoma. The corneal opacity is not due to stromal edema, but due to absence of Descemet’s, endothelium and Bowman’s layers only centrally. These are the cases in which glaucoma is controlled but the opacity remains, and grafting fails to show the features expected for CHED. In these cases, there are no Haab striae, and the corneal diameter is usually no bigger than 11.5 mm. The corneal graft remains clear, but the glaucoma can be difficult to treat.

Secondary corneal disease

Source: Nishal KK

 

Secondary developmental corneal disease includes the entities that are the least well understood genotypically. These are kerato-irido-lenticular dysgenesis (KILD), which may be better known as Peters’ anomaly type 1 and 2. The genotyping literature of these conditions is littered with confusion. Iridocorneal adhesions (Peters’ anomaly 1) are often avascular, while keratolenticular adhesions (Peters’ anomaly 2) are usually vascularized. Children with a known molecular diagnosis can have iridocorneal adhesion in one eye and keratolenticular adhesion in the other. This further supports the notion that Peters’ anomaly 1 and 2 are signs and not a diagnosis. Further types of KILD are those in which the lens fails to form or forms and then degenerates. Genotyping in these cases has been somewhat more fruitful but, as always, not comprehensive. If the lens fails to form or forms partially, the gene involved is FOXE3, which is a lens gene. Not surprisingly, if the lens forms partially or fails to form, this has an effect on the vitreous and the drainage angle. These cases are often associated with severe glaucoma.

Other secondary developmental corneal disease may include Axenfeld-Rieger syndrome, aniridia and primary congenital glaucoma, all of which have specific genotypic characterization. Axenfeld-Rieger syndrome is due to mutations in FOXC1 and PITX2. If a child has Axenfeld-Rieger syndrome and is short for his or her age, the likely gene is PITX2 and the child needs an MRI to exclude pituitary axis problems, which have been reported in cases of PITX2 mutations. Aniridia may be associated with keratolenticular adhesions (Peters’ anomaly 2), but in spontaneous cases once the diagnosis of aniridia is made, then a microarray must be done to exclude the possibility of a deletion knocking out not only PAX6 but also WT1 (Wilms tumor gene) and predisposing the child to nephroblastoma. Until this is done, two to three monthly renal ultrasounds must be performed. CYP1B1 is the most common cause of congenital glaucoma, but FOXC1 can also cause glaucoma at birth. The presence of posterior embryotoxon helps differentiate between the two causes, with posterior embryotoxon only being seen in cases of FOXC1 mutation.

Purpose of classification

The purpose of using a novel classification is to help with not only genotyping but also with decision making with respect to our current understanding of surgical intervention and management. In cases of FOXE3 mutations causing primary aphakia, glaucoma control is the only safe option because cornea transplant often leads to a phthisical eye.

However, all of this is only beneficial if we understand the unique nature of a developing biological system (the infant’s brain) and the effect small improvements in vision can have on global development in such infants. While corneal clarity after keratoplasty is the gold standard, it should not supersede the need for sufficient vision to allow an infant to develop globally as well as visually.

Understanding the genetics of congenital corneal opacities has an effect not only on diagnosis but also treatment.

Take-home messages Peters’ anomaly and sclerocornea are unhelpful terms in phenotyping congenital corneal opacities in 2015. Primary corneal disease and secondary corneal disease are better ways to consider such opacities. Accurate phenotyping is essential for accurate genotyping, and anterior segment imaging should always be used. Global development of a child is paramount when assessing success of a cornea transplant, not just corneal clarity.

Visit UPMCPhysicianResources.com/Ocular to submit clinical questions or read the most recent questions asked of the UPMC Eye Center’s ophthalmology experts.

References:
Castinetti F, et al. Mol Endocrinol. 2011;doi:10.1210/me.2010-0388.
Kelberman D, et al. Ophthalmology. 2011;doi:10.1016/j.ophtha.2011.01.044.
Nischal KK. Curr Opin Ophthalmol. 2012;doi:10.1097/ICU.0b013e328356893d.
Sonksen PM, et al. Dev Med Child Neurol. 2002;doi:10.1111/j.1469-8749.2002.tb00287.x.
Weiss JS, et al. Cornea. 2015;doi:10.1097/ICO.0000000000000307.
For more information:
Ken K. Nischal, MD, FRCOphth, is a professor of ophthalmology at UPMC and the University of Pittsburgh. He can be reached at Children’s Hospital of Pittsburgh, Children’s Hospital Drive, 45th and Penn Avenue, CHP Faculty Pavilion, Suite 5000, Pittsburgh, PA 15201; email: nischalkk@upmc.edu.
Disclosure: Nischal reports no relevant financial disclosures.

Traditionally, the causes of congenital corneal opacities have been recalled using the pneumonic “STUMPED,” but as our understanding of phenotype has improved with better anterior segment imaging, it has become increasingly clear that the early genotype-phenotype correlations were largely misled by inaccurate phenotyping.

Recently, a novel classification for neonatal corneal opacification was published from our group (Table). Using this, corneal opacification can be considered to be primary or secondary. Secondary corneal disease may be developmental or acquired.

Ken K. Nischal

Genetic analysis using this phenotypic classification becomes easier to navigate.

Primary corneal disease

Primary corneal disease includes congenital hereditary endothelial dystrophy (CHED), posterior polymorphous corneal dystrophy (PPCD), X-linked endothelial corneal dystrophy, corneal dermoids, cornea plana and CYP1B1 cytopathy. Genotyping for all of these conditions is reasonably advanced. CHED is caused by mutations in SLC4A11 and is associated with hearing loss. (CHED 1 is no longer considered a separate entity, and all cases of CHED 1 are now thought to have been cases of PPCD.) PPCD is caused by mutations in ZEB1, VISX1 and COL8A1.

CYP1B1 cytopathy is a condition in which there is glaucoma. The corneal opacity is not due to stromal edema, but due to absence of Descemet’s, endothelium and Bowman’s layers only centrally. These are the cases in which glaucoma is controlled but the opacity remains, and grafting fails to show the features expected for CHED. In these cases, there are no Haab striae, and the corneal diameter is usually no bigger than 11.5 mm. The corneal graft remains clear, but the glaucoma can be difficult to treat.

Secondary corneal disease

Source: Nishal KK

 

Secondary developmental corneal disease includes the entities that are the least well understood genotypically. These are kerato-irido-lenticular dysgenesis (KILD), which may be better known as Peters’ anomaly type 1 and 2. The genotyping literature of these conditions is littered with confusion. Iridocorneal adhesions (Peters’ anomaly 1) are often avascular, while keratolenticular adhesions (Peters’ anomaly 2) are usually vascularized. Children with a known molecular diagnosis can have iridocorneal adhesion in one eye and keratolenticular adhesion in the other. This further supports the notion that Peters’ anomaly 1 and 2 are signs and not a diagnosis. Further types of KILD are those in which the lens fails to form or forms and then degenerates. Genotyping in these cases has been somewhat more fruitful but, as always, not comprehensive. If the lens fails to form or forms partially, the gene involved is FOXE3, which is a lens gene. Not surprisingly, if the lens forms partially or fails to form, this has an effect on the vitreous and the drainage angle. These cases are often associated with severe glaucoma.

Other secondary developmental corneal disease may include Axenfeld-Rieger syndrome, aniridia and primary congenital glaucoma, all of which have specific genotypic characterization. Axenfeld-Rieger syndrome is due to mutations in FOXC1 and PITX2. If a child has Axenfeld-Rieger syndrome and is short for his or her age, the likely gene is PITX2 and the child needs an MRI to exclude pituitary axis problems, which have been reported in cases of PITX2 mutations. Aniridia may be associated with keratolenticular adhesions (Peters’ anomaly 2), but in spontaneous cases once the diagnosis of aniridia is made, then a microarray must be done to exclude the possibility of a deletion knocking out not only PAX6 but also WT1 (Wilms tumor gene) and predisposing the child to nephroblastoma. Until this is done, two to three monthly renal ultrasounds must be performed. CYP1B1 is the most common cause of congenital glaucoma, but FOXC1 can also cause glaucoma at birth. The presence of posterior embryotoxon helps differentiate between the two causes, with posterior embryotoxon only being seen in cases of FOXC1 mutation.

Purpose of classification

The purpose of using a novel classification is to help with not only genotyping but also with decision making with respect to our current understanding of surgical intervention and management. In cases of FOXE3 mutations causing primary aphakia, glaucoma control is the only safe option because cornea transplant often leads to a phthisical eye.

However, all of this is only beneficial if we understand the unique nature of a developing biological system (the infant’s brain) and the effect small improvements in vision can have on global development in such infants. While corneal clarity after keratoplasty is the gold standard, it should not supersede the need for sufficient vision to allow an infant to develop globally as well as visually.

Understanding the genetics of congenital corneal opacities has an effect not only on diagnosis but also treatment.

Take-home messages Peters’ anomaly and sclerocornea are unhelpful terms in phenotyping congenital corneal opacities in 2015. Primary corneal disease and secondary corneal disease are better ways to consider such opacities. Accurate phenotyping is essential for accurate genotyping, and anterior segment imaging should always be used. Global development of a child is paramount when assessing success of a cornea transplant, not just corneal clarity.

Visit UPMCPhysicianResources.com/Ocular to submit clinical questions or read the most recent questions asked of the UPMC Eye Center’s ophthalmology experts.

References:
Castinetti F, et al. Mol Endocrinol. 2011;doi:10.1210/me.2010-0388.
Kelberman D, et al. Ophthalmology. 2011;doi:10.1016/j.ophtha.2011.01.044.
Nischal KK. Curr Opin Ophthalmol. 2012;doi:10.1097/ICU.0b013e328356893d.
Sonksen PM, et al. Dev Med Child Neurol. 2002;doi:10.1111/j.1469-8749.2002.tb00287.x.
Weiss JS, et al. Cornea. 2015;doi:10.1097/ICO.0000000000000307.
For more information:
Ken K. Nischal, MD, FRCOphth, is a professor of ophthalmology at UPMC and the University of Pittsburgh. He can be reached at Children’s Hospital of Pittsburgh, Children’s Hospital Drive, 45th and Penn Avenue, CHP Faculty Pavilion, Suite 5000, Pittsburgh, PA 15201; email: nischalkk@upmc.edu.
Disclosure: Nischal reports no relevant financial disclosures.