Brittle Cornea Syndrome

Brittle cornea syndrome is a rare autosomal recessive connective tissue disorder with extreme corneal thinning, blue sclerae and rupture of the globe after minimal trauma. It is caused by ZNF469 or PRDM5 variants and is also classified within the Ehlers-Danlos group.

Pathophysiology. ZNF469 and PRDM5 regulate expression of fibrillar collagens and extracellular matrix. Loss of function leads to thin, weak cornea and sclera and, outside the eye, joint hypermobility, hearing loss and hip dysplasia.

Corneal rupture can occur spontaneously or after trivial trauma, and visual outcome is often poor if protection is not started early.

Prevention is the central strategy.

• Blue sclerae
• Thin cornea (central thickness often under 400 micrometres), keratoconus or keratoglobus
• Spontaneous or trauma induced corneal or scleral rupture
• High myopia, retinal detachment
• Conductive and sensorineural hearing loss
• Developmental dysplasia of the hip
• Joint hypermobility, soft skin and scoliosis
• Arachnodactyly and hernia

• Genetic testing of ZNF469 and PRDM5 with deletion and duplication analysis.
• Ophthalmic examination: slit lamp, corneal pachymetry (thin cornea), topography, and fundus examination under gentle conditions. Avoid pressure on the globe.
• Audiometry at baseline.
• Hip ultrasound or radiograph in infants.
• Exclusion of osteogenesis imperfecta: normal bone density and no fractures in the blue sclera setting, with COL1A1 and COL1A2 testing when doubt exists.

Differential diagnosis.

• Osteogenesis imperfecta
• Ehlers-Danlos syndromes (kyphoscoliotic type)
• Marfan syndrome with ectopia lentis
• Keratoconus and keratoglobus of other cause
• Ocular trauma and non-accidental injury
• Congenital glaucoma and megalocornea

• Eye protection: polycarbonate spectacles worn at all times from early childhood, with side shields and avoidance of contact and ball sports, rough play and eye rubbing.
• Emergency for ocular rupture: shield the eye without pressure, give nothing by mouth, systemic antibiotic cover (for example, intravenous cefuroxime 1.5 g every 8 hours in adults; children 25 mg/kg every 8 hours), and urgent surgical repair by an ophthalmologist. Give antiemetics to prevent straining.
• Surgery on the eye: avoid elective surgery where possible. Corneal grafting and intraocular surgery have high complication rates and need an expert unit.
• Intraocular pressure measurement: use non-contact tonometry and avoid applanation or indentation.
• Hearing: hearing aids and ENT follow up.
• Hips and joints: early orthopaedic treatment of hip dysplasia (harness), and physiotherapy.
• Anaesthesia: avoid suxamethonium, which causes fasciculation and raises intraocular pressure, and avoid straining or coughing during intubation.
• Genetic counselling: each sibling of an affected child has a 25% chance of being affected.

Special groups.

• Children: educate carers and school staff on protective eyewear and an emergency plan.

Monitoring. Ophthalmology review every 3 to 6 months. Audiometry every 1 to 2 years. Hip review in infancy and during growth.

Referral and escalation. Refer to clinical genetics and a corneal or paediatric ophthalmology service. Emergency for any eye injury, sudden pain or visual loss.