Non-Syndromic Unilateral Congenital Cataract - Crybb1 Related

Approximately 1/3 of the congenital cataracts are genetically inherited and have been linked to over 100 pathogenic gene mutations. Majority of cases are bilateral with predominantly autosomal dominant inheritance. Mutations in the crystalline genes account for about 50% of non-syndromic cataracts. Particularly CRYBB1 mutations determine dense, bilateral lens changes by a rapid protein aggregation process in the embryonic lens (nuclear or pulverulent phenotypes).   

We report hereby the findings in two female siblings with unilateral non-syndromic congenital, lamellar cataracts, that have been linked to the CRYBB1 mutation.

 M.C, female aged 6 years old, was referred to Moorfields Eye Hospital - Pediatric Cataract Service in 2020 for poor vision in the right eye (RE).

Clinical examination revealed lamellar lens opacities in the RE, while the left eye (LE) was completely normal. Parameters in both eyes, such as white-to-white corneal diameter, pachymetry, intraocular pressure and biometry calculations were within normal limits. Any persistence of fetal vasculature was excluded by clinical examination (fundus visible in both eyes) and ultrasound examination (posterior capsule intact). Refraction showed a small amount of myopia (spherical equivalent -1.25D) in the RE only. The initial vision at presentation (RE=0.5 logMAR, LE=0.00 logMAR) improved in the RE during the follow up interval upon optic correction and patching to 0.3 logMAR. Surgery hans't been  considered, but active monitoring for changes.

The younger sister RC, born at 32 weeks due to an emergency C-section (abruptio placentae), has been consecutively  diagnosed with lamellar cataract in her LE at the age of 5; the RE was completely normal with bilateral healthy fundus. Vision (logMAR) was excellent at presentation (RE=0.18, LE=0.14) with hyperopic astigmatic correction (2D, cyl) and has remained unchanged throughout the follow up interval.

Important environmental factors were excluded (TORCH syndrome, trauma and iatrogenic causes), as well as any mild form of PVF. Genetic testing confirmed identical mutation in the two siblings, CRYBB1, with negative genetic findings in the mother. The father, also diagnosed with unilateral cataract, did not participate in the  analysis.

Massive audit data from the Pediatric Cataract Service in Moorfields Eye Hospital (111 children/ 5 years) demonstrated that CRYBB1- related cataracts are bilateral (nuclear and pulverulent types) and visually significant at early age, mandating prompt surgical intervention. The two presented cases prove that a gene’s expression and function during lens development might be variable, leading to various phenotypes (mild, unilateral, lamellar cataract), despite a well identified mutation. Further genetic tests to investigate potential missense mutations in CRYBB1 should be considered.