Brittle Cornea Syndrome 2

A number sign (#) is used with this entry because of evidence that brittle cornea syndrome-2 (BCS2) is caused by homozygous mutation in the PRDM5 gene (614161) on chromosome 4q27.

Description

Brittle cornea syndrome (BCS) is characterized by blue sclerae, corneal rupture after minor trauma, keratoconus or keratoglobus, hyperelasticity of the skin, and hypermobility of the joints (Al-Hussain et al., 2004). It is classified as a form of Ehlers-Danlos syndrome (Malfait et al., 2017).

For a discussion of genetic heterogeneity of brittle cornea syndrome, see BCS1 (229200).

Clinical Features

Cameron (1993) described 11 patients with blue sclerae, limbus-to-limbus corneal thinning, hypermobile joints, and consanguineous parents. Corneal rupture occurred in 7 patients (9 eyes) either spontaneously or following minimal trauma. Acute hydrops occurred in 3 patients. Bilateral microcornea was present in 1 patient, and 2 patients had unilateral increased corneal diameter due to secondary glaucoma after trauma. Peripheral sclerocornea was present bilaterally in 5 patients. Curvature abnormalities included cornea plana, keratoconus, and keratoglobus. Systemic abnormalities included increased skin laxity, pectus excavatum, scoliosis, congenital hip dislocation, recurrent shoulder dislocation, high-frequency hearing loss, high-arched palate, and mitral valve prolapse. Cameron (1993) stated that the term 'blue sclera' in this syndrome is a misnomer, as the sclera is more transparent and thinner than normal, revealing underlying uveal tissue; the blue appearance is most apparent in the region of the ciliary body, giving the appearance of a 'halo' at the limbus. In addition, photographic comparisons in patients followed for more than 5 years showed a less prominent blue appearance of the sclera with increasing age.

Burkitt Wright et al. (2011) reported a large consanguineous Pakistani family (BC-001) in which 4 sisters had corneal rupture after minor trauma. The affected sisters had high myopia, blue sclerae, keratoconus, keratoglobus, soft skin with easy bruising, hypermobility of the small joints, femoral epiphyseal changes, abnormal gait, hypercompliance of tympanic membranes, and mixed conductive and sensorineural deafness. Burkitt Wright et al. (2011) identified a second consanguineous Pakistani family (BC-002) in which affected individuals had thin corneas, blue sclerae, mixed sensorineural/conductive deafness with hypercompliant tympanic membranes, and small joint hypermobility. Patients from both families had normal lysylpyridinoline/hydroxylysylpyridinoline urinary excretion ratios, thus excluding Ehlers-Danlos syndrome type VI (225400).

Pathogenesis

Porter et al. (2015) performed immunohistochemistry on the enucleated eyes of 2 Pakistani cousins with BCS2, originally reported by Burkitt Wright et al. (2011) and found to be homozygous for a deletion in the PRDM5 gene (614161.0001). One cousin experienced spontaneous perforation of the eye, whereas the other cousin had perforation after minor trauma. Both eyes had retinal thinning and reduced cell densities in the inner and outer nuclear layers. Extracellular matrix components were diminished around retinal capillaries with decreased capillary staining for collagens I (see 120150), III (120180), and V (see 120215). Other retinal microvascular abnormalities included a paucity of retinal capillaries, with reduced staining for the endothelial marker CD31 (PECAM1; 173445).

Mapping

In affected members of 2 consanguineous Pakistani families with brittle cornea syndrome, known to be negative for mutations in the ZNF469 gene (612078), Burkitt Wright et al. (2011) performed autozygosity mapping and identified a single 18-Mb region of autozygosity on chromosome 4 that was shared by affected individuals across both families. There was no evidence for a shared haplotype between the 2 families.

Molecular Genetics

In affected members of a consanguineous Pakistani family (BC-001) with brittle cornea syndrome mapping to chromosome 4, Burkitt Wright et al. (2011) identified a 52.46-kb homozygous deletion involving exons 9 to 14 of the PRDM5 gene (614161.0001). Heterozygous carriers of the deletion had blue sclerae, small joint hypermobility, and central corneal thickness that was more mildly reduced than that of homozygous mutation carriers. In affected members of another consanguineous Pakistani family with BCS (BC-002), Burkitt Wright et al. (2011) identified homozygosity for a nonsense mutation in PRDM5 (614161.0002). Further screening of patient samples identified homozygous mutations in PRDM5 in 5 additional BCS families, including 2 families previously studied by Cameron (1993) (see, e.g., 614161.0003-614161.0005). Burkitt Wright et al. (2011) noted that the phenotypic spectrum in BCS patients with mutations in either the ZNF469 (612078) or PRDM5 genes is extremely similar if not identical (see BCS1, 229200), suggesting that the 2 genes act within the same developmental pathway; expression microarray analysis confirmed that both genes participate in a pathway regulating expression of extracellular matrix (ECM) components.

In a 2-year-old Saudi girl with BCS2, born of healthy, first-cousin parents, Aldahmesh et al. (2012) identified a homozygous mutation in the PRDM5 gene (614165.0006). The parents were heterozygous for the mutation.

Porter et al. (2015) identified homozygosity for PRDM5 mutations in 2 additional patients with brittle cornea syndrome, and restudied patients from the Pakistani families previously reported by Burkitt Wright et al. (2011). Using patient fibroblasts from eye and skin, Porter et al. (2015) analyzed dysregulated PRDM5 target genes and found enrichment for ECM genes involved in vascular integrity and development, consistent with the retinal microvascular abnormalities and associated cellular loss seen in BCS2 patients.