Brittle Cornea Syndrome · BCS

Description

Brittle Cornea Syndrome, BCS, is an autosomal recessive connective tissue disorder defined by extreme thinning of the cornea, spontaneous corneal rupture from minor trauma, blue sclerae, progressive keratoconus or keratoglobus, sensorineural hearing loss, and generalized joint hypermobility. The 2017 international classification reclassified BCS as an Ehlers-Danlos syndrome subtype (Malfait and colleagues, American Journal of Medical Genetics Part C, 2017), even though the responsible genes do not encode a structural collagen. Two molecular forms are recognized: BCS1 caused by biallelic variants in ZNF469 and BCS2 caused by biallelic variants in PRDM5. Both genes encode transcriptional regulators that govern extracellular matrix gene expression. ZNF469 was identified by Abu and colleagues in the American Journal of Human Genetics in 2008. PRDM5 was identified by Burkitt Wright and colleagues in the American Journal of Human Genetics in 2011.

Clinical diagnosis under the 2017 criteria rests on thin cornea, typically below 400 micrometers on central pachymetry, plus at least one of early-onset progressive keratoconus, early-onset progressive keratoglobus, or blue sclerae. Minor criteria include corneal rupture after minor trauma, hearing loss with high-frequency emphasis, hypercompliant tympanic membranes, and joint hypermobility with hip dysplasia in childhood. Confirmation requires biallelic pathogenic variants in ZNF469 or PRDM5 on gene sequencing.

BCS is concentrated in populations with high rates of consanguinity. Founder variants have been described across North African, Middle Eastern, and Tunisian Jewish communities, and in South Asian families. Reported cases worldwide remain in the low hundreds, and the disease is almost certainly underdiagnosed where pachymetry and genetic testing are not part of routine ophthalmology workup.

Treatments to date

Care is preventive and surgical. There is no approved disease-modifying therapy, no enzyme replacement, and no gene therapy in clinical use.

Eye protection is the central intervention from the time of diagnosis. Polycarbonate protective eyewear is worn during waking hours throughout childhood and adulthood. Contact sports and activities with projectile or blunt-trauma risk are avoided. Scleral contact lenses provide additional mechanical protection of the corneal surface and improve vision in eyes with progressive corneal ectasia.

Corneal cross-linking with riboflavin and ultraviolet-A light, originally developed for keratoconus, has been used to slow progression of corneal thinning in BCS. Reports remain small and outcomes mixed, reflecting the underlying matrix defect rather than a primarily biomechanical problem. Penetrating keratoplasty and deep anterior lamellar keratoplasty are performed after corneal rupture or when vision-limiting ectasia advances. Graft outcomes in BCS are poorer than in keratoconus because the recipient bed is fragile, dehiscence rates are elevated, and subsequent rupture of the operated globe is reported. High-volume corneal centers experienced with connective tissue disease are preferred.

Audiologic surveillance is lifelong, with hearing aids or cochlear implants used when sensorineural loss progresses. Skeletal and joint findings are managed with the standard EDS toolkit of physical therapy and bracing. No drug is approved by the FDA or EMA for BCS, and no targeted therapeutic candidate is in late-stage development.