Brittle Cornea Syndrome: Molecular Diagnosis and Management

Abstract

Background and Clinical Significance: Brittle cornea syndrome (BCS) is a rare, autosomal recessive connective tissue disorder characterized by extreme corneal thinning, high myopia, and increased risk of spontaneous or trauma-induced ocular rupture. It is primarily caused by mutations in the ZNF469 or PRDM5 genes, which regulate extracellular matrix integrity. Early recognition and diagnosis of BCS are crucial to prevent severe visual impairment. This report presents two genetically confirmed cases of BCS in Albanian siblings, emphasizing the diagnostic value of whole-exome sequencing and individualized surgical management strategies. Case Presentation: Two siblings-a 28-year-old male and a 25-year-old female-presented with progressive visual deterioration and marked corneal thinning (<200 µm). Both had a history of spontaneous ocular rupture following minor trauma in the contralateral eye. Detailed ophthalmologic evaluation revealed keratoglobus, high myopia, and irregular astigmatism. Genetic testing identified the homozygous pathogenic variant c.974delG (p.Cys325LeufsX2) in the PRDM5 gene in both cases. The male underwent penetrating keratoplasty (PKP), achieving a best-corrected visual acuity (BCVA) of 20/30. The female initially underwent deep anterior lamellar keratoplasty (DALK), which was converted to PKP intraoperatively due to central endothelial perforation, resulting in a BCVA of 20/25. Both patients remained complication-free over a 7-year follow-up period. Conclusions: These cases highlight the importance of early genetic diagnosis and a tailored surgical approach in managing BCS. Long-term monitoring and protective strategies are essential to prevent complications. Incorporating genetic testing into clinical practice can enhance diagnostic accuracy and guide personalized treatment plans in patients with hereditary corneal dystrophies.

Keywords: PRDM5 gene; central corneal thinning; genetic corneal disease; irregular astigmatism; keratoglobus; pachymetry.

Figure 3

Pentacam refractive maps showing diffusely thin cornea on pachymetry map and abnormal keratometry values. (Case 1) (A) K-Max 88.6, AC depth 5.22 mm, thinnest point 151 µm; (Case 2) (B) K-Max 73, AC depth 3.84 mm, thinnest point 157 µm.

Figure 4

Hyperextensible metacarpophalangeal joint.

Figure 1

Ocular findings in a patient with brittle cornea syndrome. (A) Narrow slit-beam view of the right cornea with ectasia (Case 1), (B) (Case 2).

Figure 2

Optical coherence tomography (OCT-Visante) showing thin cornea right eye (Case 1) (A) and (Case 2) (B).