Abstract
Purpose: Primary congenital glaucoma is a common disorder in the Middle East mainly caused by mutations in the the CYP1Bl gene. We report a family with three siblings that presented with recalcitrant childhood glaucoma, aniridia in two siblings with a novel CYP1B1 gene mutation.
Materials and methods: Review of pedigree, clinical history and clinical course of the family. Genetic testing in the affected family members.
Results: Three sisters presented with clinical findings of severe congenital glaucoma and a positive family history. Clinical examination of two of sisters revealed corneal scarring, bilateral aniridia with severe glaucoma that required multiple surgical procedures to control intraocular pressure. The third sibling presented with garden-variety primary congenital glaucoma. Genetic analysis revealed a novel CYP1B1 gene mutation (g.8291 C > T; p.S485F).
Conclusion: CYP1B1 mutation related congenital glaucoma can present with an extreme form of anterior segment dysgenesis that includes recalcitrant glaucoma, corneal opacification and aniridia.
Primary congenital glaucoma is caused by anterior chamber angle abnormalities that lead to obstruction of aqueous outflow, elevated intraocular pressure and its sequelae.Citation1 In the Middle East, the most common phenotype of congenital glaucoma is caused by mutations in the CYP1B1 gene. CYP1B1 mutations result in ocular disorders with a variable phenotype that include abnormalities in the cornea, anterior chamber and iris.
This case series reports on three sisters with primary congenital glaucoma with a positive family history of glaucoma and a novel CYP1B1 gene mutation. Two sisters presented with bilateral aniridia and severe glaucoma whereas the third sibling presented with garden-variety primary congenital glaucoma. The clinical findings on presentation, course of intractable glaucoma requiring multiple surgical procedures, and other findings are summarized in and illustrated in .
FIGURE 1. Top. Case one: Note the diffuse corneal haze, aniridia and lens edge (arrow). Middle. Case two: Photograph showing large clear corneas and normal iris structure. Bottom. Case three: Note diffuse corneal edema, aniridia and edge of clear lens (arrow).
TABLE 1. Clinical findings and course of affected children.
Genetic testing revealed a novel mutation in the CYP1B1 gene (g.8291 C > T; p.S485F) in a homozygous status in the affected father and two of his affected daughters available for genotyping, as well as a heterozygous status in the carrier mother. This mutation is predicted to be probably damaging based on PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) in silico analysis, interspecies conservation for Serine at codon 485 was high and the mutation was not detected in 200 glaucoma free controls from matching ethnicity.
CYP1B1 mutations are a common cause of primary congenital glaucoma in Saudi Arabia that demonstrates a severe phenotype. Though the phenotype is severe, the clinical outcomes in patients with CYP1B1 mutations are not necessarily dismal.Citation1 The unusual findings in the affected sisters included glaucoma that was recalcitrant to multiple surgical procedures and the findings of aniridia in two of the three siblings. PAX6 mutation screening was negative in the family members tested.
Aniridia is typically associated with the PAX6 gene mutation and can be sporadic or familial. In Saudi Arabia, partial aniridia was described in eight unrelated probands who harbored CYP1B1 mutations and these patients were negative for PAX6. FOXC1, and PITX2 gene abnormalities.Citation2 In addition, bilateral complete aniridia and glaucoma associated with a FOXC1 gene mutation has been reported from Saudi Arabia.Citation3
The findings of complete aniridia in two siblings associated with a novel mutation in CYP1B1 demonstrate that a spectrum of iris abnormalities can occur in association with primary congenital glaucoma. Some of the associated anterior segment findings and clinical course in the patients in our study are not typical of the anterior segment findings in congenital aniridia with PAX6 gene mutations. As for the PAX6 gene, we could only detect two non-pathologic single nucleotide polymorphisms, rs3026401 and rs1506.The glaucoma seen in classic aniridia more commonly occurs later in life, unlike that seen in the siblings in this study where glaucoma manifested at a very early age. Corneal findings in typical aniridia include peripheral and central vascularization, opacification, and surface keratinization. In this family the corneal findings included diffuse corneal stromal haze and scarring without central opacification and/or diffuse corneal thinning as one might see in Peters anomaly. We suggest that the aniridia seen in the two of the three sisters represents an extreme form of iris hypoplasia associated with corneal and anterior chamber angle dysgenesis.
The novel mutation (g. 8291 C > T; p.S485F) detected in exon 2 of the CYP1B1 gene corresponds to the major cytochrome P450 chain (extending from amino acid 1–490). Most mutations reported to date in the CYP1B1 gene fall within this major chain. It therefore remains unclear from this family whether this mutation is specific for this phenotype or why mutations from a similar region result in wide range of phenotypic abnormalities that include primary congenital glaucoma, Peters anomaly, Rieger’s anomaly and now, aniridia.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
- Abu-Amero KK, Osman EA, Mousa A, et al. Screening of CYP1B1 and LTBP2 genes in Saudi families with primary congenital glaucoma: genotype-phenotype correlation. Mol Vis 2011;17:2911–2919
- Khan AO, Aldahmesh MA, Al-Abdi L, et al. Molecular characterization of newborn glaucoma including a distinct aniridic phenotype. Ophthalmic Genet Sep 2011;32:138–142
- Khan AO, Aldahmesh MA, Al-Amri A. Heterozygous FOXC1 mutation (M161K) associated with congenital glaucoma and aniridia in an infant and a milder phenotype in her mother. Ophthalmic Genet Jun 2008;29:67–71